- Email: [email protected]
Pulmonary embolism: Epidemiology and registries
Presse Med. 2015; 44: e377–e383
REVIEW
on line on www.em-consulte.com/revue/lpm www.sciencedirect.com
Quarterly Medical Review
Pulmonary embolism: Epidemiology and registries Manuel Monreal 1, Isabelle Mahé 2, Alessandra Bura-Riviere 3, Paolo Prandoni 4, Peter Verhamme 5, Benjamin Brenner 6, Phil S. Wells 7, Pierpaolo Di Micco 8, Laurent Bertoletti 9
Available online: 4 November 2015
1. Universidad Católica de Murcia, Hospital Universitario Germans Trias i Pujol de Badalona, department of internal medicine, Spain 2. AP–HP, university Paris 7, hôpital Louis-Mourier, department of internal medicine, 92700 Colombes, France 3. Hôpital de Rangueil, department of vascular medicine, 33000 Toulouse, France 4. University of Padua, department of clinical medicine, Padua, Italy 5. University of Leuven, vascular medicine and haemostasis, Leuven, Belgium 6. Rambam health care campus, department of haematology and bone marrow transplantation, Haifa, Israel 7. University of Ottawa, Ottawa hospital research institute, department of medicine, Ottawa, Ontario, Canada 8. Ospedale Buonconsiglio Fatebenefratelli, department of internal medicine and emergency room, Naples, Italy 9. CHU de Saint-Étienne, hôpital Nord, Department of medicine and therapeutics, 63000 Saint-Étienne, France
Correspondence: Manuel Monreal, Hospital Universitario Germans Trias i Pujol, Servicio de Medicina Interna, 08916 Badalona (Barcelona), Spain. [email protected]
Pulmonary embolism: An update L. Bertoletti et al., SaintÉtienne, France Pulmonary embolism: Epidemiology and registries M. Monreal et al., Murcia, Spain Diagnosis of pulmonary embolism M. Righini et al., Geneva, Switzerland Treatment of pulmonary embolism H. Decousus et al., SaintÉtienne, France Risk assessment and management of high and intermediate risk pulmonary embolism G. Meyer et al., Paris, France Chronic thromboembolic pulmonary hypertension C. O'Connell, Le KremlinBicêtre, France
tome 44 > n812 > December 2015 http://dx.doi.org/10.1016/j.lpm.2015.10.006 © 2015 Elsevier Masson SAS. All rights reserved.
Summary Real-life data is important in understanding the needs of patients in routine clinical practice, particularly owing to the fact that almost a quarter of patients with venous thromoboembolism (VTE) have at least one exclusion criterion preventing their recruitment into randomized clinical trials. The Registro Informatizado de Enfermedad Trombo Embólica (RIETE) registry is an ongoing, international, multicentre, prospective registry of consecutive patients presenting with acute VTE. In this chapter, we summarized some of the most relevant data concerning the epidemiology of VTE in the RIETE registry.
Venous thromboembolism in real-life Acute venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disorder with an annual incidence of approximately 1 or 2 cases per 1000 persons in the general population [1–3]. Until recently, most of the published information on the prevention, current therapy and natural history of patients with VTE came from randomized clinical trials, with strict inclusion and exclusion criteria, fixed doses of anticoagulant drugs, and limited follow-up, mostly focused to obtain data on efficacy and safety. Thus, although randomized clinical trials provide high-level evidence on the efficacy and safety of therapeutic interventions,
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they generally involve well-defined study populations that exclude complex patients and have standardized protocols for management with closer monitoring and stricter followup than is typical of routine clinical practice. Also there is scarce information on the current therapy in real-life (drugs, doses, duration and approach to patients with VTE recurrences and/or bleeding complications). Thus, their results are not always directly applicable to the general population or routine practice. Real-life data are of utmost importance to collect information on the safety, efficacy and drug utilization of any drug. This information may be very useful for patients, clinicians and to healthcare providers, who will all benefit from the data about many aspects of VTE not previously considered in detail in a broad unselected population. Traditional observational studies, often limited to small patient populations and performed at a single institution, are giving way to multicenter registries, supported by the transfer of information to larger databases. Structured data collection can provide complementary data to that from the trials, better understand the treatment pathway of patients, inform the generation of new hypotheses and help to test established ones.
Real-life registries on VTE
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Real-life data is important in understanding the needs of patients in routine clinical practice, particularly owing to the fact that almost a quarter of patients with VTE have at least one exclusion criterion preventing their recruitment into randomized clinical trials [4]. So far, a number of registries have been developed, such as RIETE, IPER, Dresden NOAC, PREFER and Garfield, among others. The Italian Pulmonary Embolism Registry (IPER) enrolls patients with confirmed acute PE in Cardiology, Emergency or Internal Medicine Departments in 47 hospitals in Italy. Its aim is to report on demographics, clinical features, management, and outcomes of patients diagnosed with PE in everyday clinical practice, and in 2012 had recruited 1716 patients [5]. The Dresden NOAC registry is another prospective, observational database of patients with VTE or non-valvular atrial fibrillation enrolled through a network of private practices and community hospitals in Saxony, Germany. A total of 2667 patients have been enrolled as of June, 2014 [6]. Prevention of Thromboembolic EventsEuropean Registry in Venous Thromboembolism (PREFER in VTE) is a prospective, observational, multicentre study that has enrolled 3546 patients with VTE up to July 2014 across sites in Austria, France, Germany, Italy, Spain, Switzerland and the UK. This registry gathered data on important risk factors, diagnosis pathways and treatment modalities; healthcare resource use; patient quality of life and treatment satisfaction [7]. Another ongoing real-life study is GARFIELD-VTE-Global Anticoagulant Registry in the FIELD (ClinicalTrials.gov Identifier: NCT02155491) – that will evaluate treatment patterns in the field of VTE.
The RIETE registry The observational Registro Informatizado de Enfermedad Trombo Embólica (RIETE) registry is an ongoing, international, multicentre, prospective registry of consecutive patients presenting with acute VTE. RIETE was initiated in Spain in 2001, and six years later the database was translated into English, with the aim to expand the Registry to other countries. The goal was to allow physicians worldwide to use the database to select the most appropriate therapy for their patients. Currently, participating countries include Spain, Italy, France, Israel, Portugal, Germany, Belgium, Switzerland, Czech Republic, Macedonia, Greece, Argentina, United States, Canada, Brazil, and Ecuador. In May 2015, over 57,500 patients with acute VTE have been recruited. Data from this registry have been used to evaluate outcomes after acute VTE, such as the frequency of recurrent VTE, major bleeding and mortality, and risk factors for such outcomes [8–12]. In this chapter, we will summarize some of the most relevant data concerning the epidemiology of VTE in the RIETE registry.
Influence of gender on VTE The influence of gender on the natural history of patients with acute VTE has not been thoroughly studied. In a manuscript published in 2014, 47,499 patients were enrolled in RIETE, of whom 24,280 (51%) were women [13]. Compared with men, women were older, more likely presented with PE (53% vs. 47%), more likely had recent immobilization and less likely had cancer, unprovoked VTE or prior VTE. Most (78%) women aged < 40 years and one in every three (39%) women aged > 80 years had transient risk factors for VTE, including hormonal therapy (n = 1491) or pregnancy (n = 566) in women under the age of 40, and immobility (n = 2382) in those aged > 80 years (figure 1). On the contrary, one in every two men (50%) had unprovoked VTE, irrespective of age. We found no gender differences in the proportion of patients initially treated with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH), but women received slightly higher LMWH doses per body weight than men (for initialand for long-term therapy). During the course of anticoagulation (mean duration: 253 days), women had a lower rate of DVT recurrences (hazard ratio [HR]: 0.78; 95% CI: 0.67–0.91), a similar rate of PE recurrences (HR: 0.98; 95% CI: 0.83–1.15) and a higher rate of major bleeding (HR: 1.21; 95% CI: 1.09– 1.35) than men but with multivariate analysis, these genderndifferences for recurrent DVT (HR: 0.88; 95% CI: 0.75–1.03), major bleeding (HR: 1.10; 95% CI: 0.98–1.24) and fatal PE (HR: 1.01; 95% CI: 0.84–1.22) were not significant. A number of studies previously reported a lower rate of VTE recurrences in women, but most were focused on the recurrence rate after discontinuing anticoagulant therapy [14–16]. However, our registry suggests there is no difference in the rates of
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900 Women at risk
800
Men at risk
700
Count
600 500 400 300 200 100 0 10
20
30
40
50
60
70
80
90
100
Age
Women, N Men, N Surgery, women Surgery, men Immobility, women Immobility, men Cancer, women Cancer, men Estrogen use, women Estrogen use, men Pregnancy/ puerperium Unprovoked, women Unprovoked, men
<40 y 3,013 2,552 421 (14%) 322 (13%) 453 (15%) 565 (22%) 170 (5.6%) 161 (6.3%) 1,491 (50%) 9 (0.3%) 566 (19%) 644 (21%) 1,532 (60%)
41-50 y 1,748 2,401 280 (16%) 311 (13%) 299 (17%) 480 (20%) 383 (21%) 343 (14%) 347 (20%) 3 (0.1%) 36 (2.1%) 726 (42%) 1,370 (57%)
51-60 y 2,028 3,490 325 (16%) 444 (13%) 415 (20%) 599 (17%) 656 (32%) 880 (25%) 117 (5.9%) 4 (0.1%) 12 (0.6%) 906 (45%) 1,949 (56%)
61-70 y 3,939 5,196 569 (14%) 621 (12%) 759 (19%) 911 (18%) 1,143 (29%) 1,568 (30%) 80 (2.1%) 14 (0.3%) 1,997 (51%) 2,845 (55%)
71-80 y 7,126 6,327 826 (12%) 653 (10%) 1,906 (27%) 1,241 (20%) 1,472 (21%) 1,853 (29%) 61 (0.9%) 47 (0.8%) 3,838 (54%) 3,466 (55%)
>80 y 6,426 3,253 435 (6.8%) 229 (7.0%) 2,382 (37%) 857 (26%) 1,020 (16%) 877 (27%) 69 (1.1%) 38 (1.2%) 3,332 (52%) 1,783 (55%)
Figure 1 Prevalence of VTE in different age groups according to gender
VTE and patient age The treatment of VTE in the elderly presents certain unique problems related to aging, such as lower body weight, renal insufficiency and a tendency to more comorbidities, which complicate therapy. Current guidelines from the ACCP, based on evidence from clinical trials, recommend that all patients with VTE be treated initially with either LMWH, fondaparinux, or UFH for at least 5 days overlapped and followed by long-term treatment with a VKA [21]. However, elderly patients are often excluded from clinical trials of anticoagulant treatment because of short life expectancy, higher risk of drug interactions,
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malnutrition, dehydration, or difficulties with periodic monitoring of the prothrombin time, which means that treatment regimens based on the results from randomized trials might not be suitable for all elderly patients with VTE. In one of our first studies, of 13,011 patients with VTE, 2890 (22%) were aged 80 years [22]. During the first 3 months of therapy, 99 patients aged 80 years (3.4%) and 212 aged < 80 years (2.1%) had major bleeding (odds ratio [OR]: 1.7; 95% CI: 1.3–2.1). The rate of recurrent VTE was 2.1% and 2.8%, respectively. Fatal bleeding occurred in 0.8% and 0.4% (OR: 2.0; 95% CI: 1.2–3.4), but 3.7% of patients 80 years and 1.1% < 80 years (1.1%) died of PE (OR: 3.6; 95% CI: 2.7–4.7). Thus, in patients aged 80 years the 3.4% rate of major bleeding slightly exceeded the 2.1% of VTE recurrences, but the 3.7% rate of fatal PE far outweighed the 0.8% of fatal bleeding. Hence, there seems to be more reason to be concerned about fatal PE than about bleeding in elderly patients with VTE. In another study, we compared the outcome in 16,199 presenting with lower-limb DVT according to age [11]. Most patients (96%) received initial therapy with LMWH followed by VKA therapy, but 38% of patients aged 80 years received long-term LMWH
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recurrence while on anticoagulant therapy. Our study did confirm an increased rate of major bleeding events in women as has previously been reported in patients receiving anticoagulation for atrial fibrillation [17–19], but we did not demonstrate this in women with VTE [20]. We did demonstrate a higher rate of haematomas in women but no difference in the rate of gastrointestinal, intracranial or retroperitoneal bleeding. Since the mortality associated with these haematomas was rather low, the rate of fatal bleeding was similar in both genders.
M. Monreal, I. Mahé, A. Bura-Riviere, P. Prandoni, P. Verhamme, B. Brenner, et al.
therapy only. During the first 3 months of anticoagulant therapy, 111 patients (0.7%) were diagnosed with symptomatic PE (31 died; case fatality rate = 28%), and 284 (1.7%) had major bleeding (83 died; case fatality rate = 29%). Thus, although the case fatality rate is the same the risk of fatal bleeding was more than twice as high as the risk of fatal PE during three months of treatment for acute DVT. The relative frequency of fatal PE and fatal bleeding differed according to the period of follow-up: during the first week of treatment, the risk of both fatal bleeding and fatal PE were similar (12 vs. 14 deaths). After the first week, the risk of fatal PE decreased markedly, whereas the risk of fatal bleeding remained high. Interestingly however, the relative frequency of fatal PE and fatal bleeding from Day 8 to Day 90 differed according to patient's age: from Day 8 to Day 90, there were 5 fatal bleeds and 6 fatal PE in patients aged 60 years, but 64 fatal bleeds and 13 fatal PE in patients who were 60 years or older. Differences in intensity of anticoagulation are unlikely to account for the difference in outcomes, since INR control and LMWH doses did not differ according to age. Given the risk of older patients dying from bleeding exceeds the risk of death from recurrent VTE, these patients may benefit from less aggressive anticoagulation. However, randomized trials are needed to test this.
TABLE I Clinical characteristics in 8389 VTE patients with recent immobilization, according to place of immobilization
Patients, n
At home
In hospital
5960
2429
OR (95% CI)
Clinical characteristics Gender (male)
2467 (41%) 1167 (48%) 0.76 (0.69–0.84)
Mean age (years SD)
68 18
69 16
P < 0.05
Body weight (kg SD)
74 17
72 15
P < 0.001
Initial VTE presentation Pulmonary embolism
2957 (50%) 1290 (53%) 0.87 (0.79–0.95)
Underlying conditions Chronic lung disease
816 (14%)
472 (19%) 0.66 (0.58–0.75)
Chronic heart failure
573 (9.6%)
331 (14%) 0.68 (0.58–0.78)
Anemia
1985 (33%) 1331 (55%) 0.41 (0.37–0.45)
Recent major bleeding
93 (1.6%)
268 (11%) 0.13 (0.10–0.16)
Prior VTE
650 (11%)
253 (10%) 1.05 (0.90–1.23)
Cancer
980 (16%)
582 (24%) 0.62 (0.56–0.70)
Concomitant therapies
Influence of risk factors on VTE
Antiplatelets
1022 (18%) 562 (24%) 0.68 (0.61–0.77)
Recent immobilization
NSAIDs
552 (9.8%) 147 (6.4%) 1.59 (1.32–1.92)
Corticosteroids
569 (10%)
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In a study including 18,028 patients with acute symptomatic PE, we used the RIETE data to compare the 3-month mortality rate in patients with PE, according to the presence of recent immobilization or surgery [23]. The rate of fatal PE was higher in the 4169 (23%) of patients with recent immobilization (4.9%; 95% CI: 4.3–5.6) than in the 2212 (12%) patients with recent surgery (1.4%; 95% CI: 1.0–2.0) or in the 11,647 (65%) with neither (2.1%; 95% CI: 1.8–2.3). These results may have been influenced by the use of VTE prophylaxis in 65% of the surgical patients compared to only 25% of those with recent immobilization. Furthermore, patients with recent immobilization were older, more likely had comorbid diseases, and more frequently presented with clinical signs of severity (i.e., hypotension, hypoxemia. . .) than other patients with PE. However, this worse outcome persisted after multivariate adjustment. In another study, we used the RIETE database to compare the use of VTE prophylaxis and the mortality due to PE in a large sample of nonsurgical patients after being immobilized at home or in hospital [24]. Among 5960 patients immobilized at home, 38% had an acute medical illness, 28% trauma, 25% chronic immobility, and 9.5% other reasons (table I). Among 2429 patients immobilized in hospital, 70% were acutely ill, 7.7% had trauma, 6.5% chronic immobility, and 9.5% other. The duration of immobility was longer than 4 weeks in 38% of patients at home and in 7.4% in hospital (OR: 7.64; 95% CI: 6.50–8.98).
389 (17%) 0.56 (0.48–0.64)
Reason for immobilization Acute medical illness
2241 (38%) 1690 (70%) 0.26 (0.24–0.29)
Trauma
1677 (28%) 187 (7.7%) 4.69 (4.00–5.51)
Chronic immobilization
1477 (25%) 159 (6.5%) 4.70 (3.96–5.58)
Other
565 (9.5%)
393 (16%) 0.54 (0.47–0.62)
Duration of immobilization < 7 days
1226 (21%) 944 (39%) 0.41 (0.37–0.45)
1–4 weeks
2398 (41%) 1272 (53%) 0.61 (0.56–0.67)
5–8 weeks
567 (9.7%) 112 (4.7%) 2.18 (1.77–2.69)
> 8 weeks
1670 (28%)
67 (2.8%)
13.9 (10.8–17.7)
VTE prophylaxis Yes Duration (mean days SD) Duration (median days, IQR)
717 (12%) 1351 (56%) 0.11 (0.10–0.12) 30 70
14 15
P < 0.001
17 (10–30)
10 (6–15)
P < 0.001
VTE: venous thromboembolism; SD: standard deviation; CrCl: creatinine clearance; NSAIDs: nonsteroidal anti-inflammatory drugs; IQR: interquartile range; OR: odds ratio; CI: confidence intervals.
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TABLE II Ninety-day outcome in VTE patients with recent immobility, according to site of immobilization At home Patients, n
In hospital
OR (95% CI)
5960
2429
Recurrent DVT
39 (0.7%)
27 (1.1%)
0.58 (0.36–0.96)
Recurrent PE
59 (1.0%)
33 (1.4%)
0.72 (0.47–1.11)
Recurrent VTE
98 (1.6%)
60 (2.5%)
0.66 (0.48–0.92)
Major bleeding
159 (2.7%)
93 (3.8%)
0.69 (0.53–0.89)
Overall death
713 (12%)
396 (16%)
0.70 (0.61–0.80)
Pulmonary embolism
111 (1.9%)
43 (1.8%)
1.05 (0.74–1.49)
Fatal initial PE
91 (1.5%)
35 (1.4%)
1.06 (0.71–1.56)
Fatal recurrent PE
20 (0.3%)
8 (0.3%)
1.02 (0.45–2.33)
Sudden, unexpected
26 (0.4%)
14 (0.6%)
0.75 (0.39–1.45)
Respiratory insufficiency
78 (1.3%)
42 (1.7%)
0.75 (0.52–1.10)
Bleeding
35 (0.6%)
27 (1.1%)
0.53 (0.32–0.87)
Disseminated cancer
173 (2.9%)
97 (4.0%)
0.72 (0.56–0.93)
Infection
69 (1.2%)
50 (2.0%)
0.56 (0.39–0.81)
Ischemic stroke
9 (0.2%)
4 (0.2%)
0.92 (0.28–2.94)
Myocardial infarction
3 (0.1%)
2 (0.1%)
0.61 (0.10–3.70)
Other
110 (1.8%)
75 (3.1%)
0.59 (0.44–0.79)
Unknown
99 (1.7%)
42 (1.7%)
0.96 (0.67–1.39)
Causes of death
DVT: deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; OR: odds ratio; CI: confidence intervals.
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of randomized clinical trials evaluating home VTE prophylaxis in acutely ill medical patients. Given such trials are unlikely to be done we cannot reasonably expect any evidence addressing reduction in the burden of VTE in this population.
Recent surgery In 2006, we retrospectively assessed the clinical characteristics and 3-month outcome of 1602 patients that developed acute VTE after undergoing surgery [25]. The most common types of surgery were: hip fracture repair (7.6%), elective hip arthroplasty (9.1%), knee arthroplasty (7.9%), other orthopaedic surgery (12%), oncologic surgery (13%), abdominopelvic surgery for conditions other than cancer (25%), neurosurgery (7.7%), vascular (6.2%) and other (12%). Patients with VTE after major orthopaedic surgery were more likely female and significantly older than those undergoing either cancer surgery or other surgical procedures. There were no differences between subgroups in the mean time elapsed from surgery to VTE (22 16, 24 16, and 21 15 days, respectively) or in the proportion of patients who developed VTE during the first 15 days after surgery (47%, 41% and 45%, respectively). As for the clinical presentation of VTE, there were no differences in the proportion of patients with clinically overt PE (48%, 48%, and 50% respectively) or in the severity of the PE event. Interestingly, clinically overt PE appeared significantly earlier (20 15 vs. 24 16 days; P < 0.001) than DVT. VTE prophylaxis was used in 1058 (66%) patients, with a higher use in patients undergoing major orthopaedic surgery (96%) than in those with cancer surgery (76%) or other procedures (52%). The vast majority (97%) of patients received prophylactic LMWH. Overall, 478 (47%) patients had their VTE event diagnosed while on prophylaxis, the rest occurred during follow-up.
Cancer Cancer patients with VTE are at increased risk of both recurrent VTE and anticoagulation-related bleeding compared to non-cancer patients. In 2006, a total of 14,391 patients with VTE had been enrolled in RIETE, of whom 2945 (20%) had active cancer [26]. During the first 3 months of therapy, the rate of fatal PE in cancer patients was 2.6%, and that of fatal bleeding 1.0%. These rates were much higher than in VTE patients without cancer (1.4% and 0.3%, respectively). In patients with cancer, abnormal renal function, metastatic disease, recent major bleeding and recent immobility (42% of patients dying from PE had recent immobility) were independent predictors of the risk for fatal PE or fatal bleeding. In addition, PE diagnosis at baseline independently predicted the risk for fatal PE, while body weight < 60 kg predicted fatal bleeding. The data in this analysis indicate that cancer patients with VTE who have recently been immobilized (due to their cancer per se, side-effects of cancer therapy, or for an acute medical illness) have a significantly worse clinical outcome. Of the patients with
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During the first 3 months of anticoagulation, the rate of VTE recurrences (OR: 0.66; 95% CI: 0.48–0.92), major bleeding (OR: 0.69; 95% CI: 0.53–0.89), all-cause death (OR: 0.70; 95% CI: 0.61–0.80) and fatal bleeding (OR: 0.53; 95% CI: 0.32–0.87) were lower in patients immobilized at home than in those in hospital (table II), but the mortality due to PE was similar (OR: 1.05; 95% CI: 0.74–1.49). Since the risk of patients developing VTE after being immobilized at home was over 2-fold higher than those patients developing VTE while staying in hospital, the amount of patients dying of PE after being immobilized at home was also over two-fold higher than in those immobilized in hospital (figure 2). Interestingly however, the use of VTE prophylaxis in patients at home was much lower than in hospital (12% vs. 56%, respectively) perhaps on part due to an absence
M. Monreal, I. Mahé, A. Bura-Riviere, P. Prandoni, P. Verhamme, B. Brenner, et al.
At home. Fatal PE In hospital. Fatal PE At home. Fatal bleeding In hospital. Fatal bleeding
120 110 100 90
Cumulative Incidence
80 70 60 50 40 30 20 10 0 0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
Days
Days At home, Fatal PE Fatal bleeding In hospital, Fatal PE Fatal bleeding
1 5,951 26 (0.44%) 2 (0.03%) 2,423 10 (0.41%) 0
7 5,799 87 (1.46%) 9 (0.15%) 2,366 32 (1.32%) 6
15 5,701 97 (1.63%) 20 (0.34%) 2,281 37 (1.52%) 14
30 5,538 104 (1.74%) 26 (0.44%) 2,187 38 (1.56%) 20
60 5,358 108 (1.81%) 31 (0.52%) 2,094 42 (1.73%) 25
90 5,248 111 (1.86%) 35 (0.59%) 2,034 43 (1.77%) 27
Figure 2 Cumulative mortality for pulmonary embolism or bleeding according to the site of immobilization
recent immobilization who died from a PE or bleeding complication, 41% had non-metastatic cancer and would have had a favorable prognosis for survival from their cancer in the absence of these VTE complications.
Limitations RIETE provides data on the treatment of VTE in a real-world situation with an unselected patient population, in contrast to the rigorously controlled conditions of randomized clinical studies. It can, therefore, provide insights into the natural history of VTE in patients that are not often included in randomized clinical
trials. It can also help to identify practices for providing treatment to patients, and factors associated with better or worse patient outcomes. However, as an observational study, RIETE is not designed to answer questions regarding the relative efficacy and safety of different modalities of therapy. Data from the registry are hypothesis-generating and provides feedback from real-world clinical situations which is invaluable when designing new randomized clinical studies. Disclosure of interest: the authors declare that they have no competing interest.
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[20] Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999;159:457–60. [21] Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy and prevention of thrombosis (9th Edition): American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e419S–94S. [22] López-Jiménez L, Montero M, GonzálezFajardo JA, Arcelus JI, Suárez C, Lobo JL, et al. Venous thromboembolism in very elderly patients: findings from a prospective Registry (RIETE). Haematologica 2006;96:1046–51. [23] Nauffal D, Ballester M, Lopez-Reyes R, Jiménez D, Otero R, Quintavalla S, et al. Influence of recent immobilization and recent surgery on mortality in patients with pulmonary embolism. J Thromb Haemost 2012;10: 1752–60. [24] Lopez-Reyes R, Nauffal D, Ballester M, Martin-Antoran JM, De Sousa MS, RieraMestre A, et al. Venous thromboembolism in patients immobilized at home. Eur Respir J 2015;45:1728–31. [25] Arcelus JI, Monreal M, Caprini JA, GutiérrezGuisado J, Soto MJ, Núñez MJ, et al. Clinical presentation and time-course of postoperative venous thromboembolism: results from the RIETE registry. Thromb Haemost 2008;99: 546–51. [26] Monreal M, Falgá C, Vilaseca B, Suárez C, Gabriel F, Tolosa C, et al. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE Registry. J Thromb Haemost 2006;4:1950–6.
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with acute pulmonary embolism. The Italian Pulmonary Embolism Registry (IPER). Thromb Res 2012;130:847–52. [6] Michalski F, Werth S, Kohler C, Tittl L, Daschkow K, Beyer-Westendorf J. Centrally adjudicated cause of death during NOAC treatment – results of the prospective Dresden NOAC Registry (NCT01588119). Blood 2014;124:2876. [7] Agnelli G, Bauersachs R, Gitt A, Laeis P, Mismetti P, Monreal M, et al. The current use of non-VKA oral anticoagulants (NOACs) for the treatment of VTE in Europe-PREFER in VTE. Eur Heart J 2014;35:1002. [8] Trujillo-Santos J, Herrera S, Page MA, Soto MJ, Raventós A, Sánchez R, et al. Predicting adverse outcome in outpatients with acute deep vein thrombosis. Findings from the RIETE Registry. J Vasc Surg 2006;44:789–93. [9] Ruíz-Giménez N, Suárez C, González R, Nieto JA, Todolí JA, Samperiz AL, et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008;100:26–31. [10] Nieto JA, Solano R, Ruiz-Ribó MD, RuizGiménez N, Prandoni P, Kearon C, et al. Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE Registry. J Thromb Haemost 2010;8:1216–22. [11] Sánchez Muñoz-Torrero JF, Bounameaux H, Pedrajas JM, Lorenzo A, Rubio S, Kearon C, et al. Effects of age on the risk of dying from pulmonary embolism or bleeding during treatment of deep vein thrombosis. J Vasc Surg 2011;54:26S–32S. [12] Muriel A, Jiménez D, Aujesky D, Bertoletti L, Decousus H, Laporte S, et al. Survival effects
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on line on www.em-consulte.com/revue/lpm www.sciencedirect.com
Quarterly Medical Review
Pulmonary embolism: Epidemiology and registries Manuel Monreal 1, Isabelle Mahé 2, Alessandra Bura-Riviere 3, Paolo Prandoni 4, Peter Verhamme 5, Benjamin Brenner 6, Phil S. Wells 7, Pierpaolo Di Micco 8, Laurent Bertoletti 9
Available online: 4 November 2015
1. Universidad Católica de Murcia, Hospital Universitario Germans Trias i Pujol de Badalona, department of internal medicine, Spain 2. AP–HP, university Paris 7, hôpital Louis-Mourier, department of internal medicine, 92700 Colombes, France 3. Hôpital de Rangueil, department of vascular medicine, 33000 Toulouse, France 4. University of Padua, department of clinical medicine, Padua, Italy 5. University of Leuven, vascular medicine and haemostasis, Leuven, Belgium 6. Rambam health care campus, department of haematology and bone marrow transplantation, Haifa, Israel 7. University of Ottawa, Ottawa hospital research institute, department of medicine, Ottawa, Ontario, Canada 8. Ospedale Buonconsiglio Fatebenefratelli, department of internal medicine and emergency room, Naples, Italy 9. CHU de Saint-Étienne, hôpital Nord, Department of medicine and therapeutics, 63000 Saint-Étienne, France
Correspondence: Manuel Monreal, Hospital Universitario Germans Trias i Pujol, Servicio de Medicina Interna, 08916 Badalona (Barcelona), Spain. [email protected]
Pulmonary embolism: An update L. Bertoletti et al., SaintÉtienne, France Pulmonary embolism: Epidemiology and registries M. Monreal et al., Murcia, Spain Diagnosis of pulmonary embolism M. Righini et al., Geneva, Switzerland Treatment of pulmonary embolism H. Decousus et al., SaintÉtienne, France Risk assessment and management of high and intermediate risk pulmonary embolism G. Meyer et al., Paris, France Chronic thromboembolic pulmonary hypertension C. O'Connell, Le KremlinBicêtre, France
tome 44 > n812 > December 2015 http://dx.doi.org/10.1016/j.lpm.2015.10.006 © 2015 Elsevier Masson SAS. All rights reserved.
Summary Real-life data is important in understanding the needs of patients in routine clinical practice, particularly owing to the fact that almost a quarter of patients with venous thromoboembolism (VTE) have at least one exclusion criterion preventing their recruitment into randomized clinical trials. The Registro Informatizado de Enfermedad Trombo Embólica (RIETE) registry is an ongoing, international, multicentre, prospective registry of consecutive patients presenting with acute VTE. In this chapter, we summarized some of the most relevant data concerning the epidemiology of VTE in the RIETE registry.
Venous thromboembolism in real-life Acute venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disorder with an annual incidence of approximately 1 or 2 cases per 1000 persons in the general population [1–3]. Until recently, most of the published information on the prevention, current therapy and natural history of patients with VTE came from randomized clinical trials, with strict inclusion and exclusion criteria, fixed doses of anticoagulant drugs, and limited follow-up, mostly focused to obtain data on efficacy and safety. Thus, although randomized clinical trials provide high-level evidence on the efficacy and safety of therapeutic interventions,
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M. Monreal, I. Mahé, A. Bura-Riviere, P. Prandoni, P. Verhamme, B. Brenner, et al.
they generally involve well-defined study populations that exclude complex patients and have standardized protocols for management with closer monitoring and stricter followup than is typical of routine clinical practice. Also there is scarce information on the current therapy in real-life (drugs, doses, duration and approach to patients with VTE recurrences and/or bleeding complications). Thus, their results are not always directly applicable to the general population or routine practice. Real-life data are of utmost importance to collect information on the safety, efficacy and drug utilization of any drug. This information may be very useful for patients, clinicians and to healthcare providers, who will all benefit from the data about many aspects of VTE not previously considered in detail in a broad unselected population. Traditional observational studies, often limited to small patient populations and performed at a single institution, are giving way to multicenter registries, supported by the transfer of information to larger databases. Structured data collection can provide complementary data to that from the trials, better understand the treatment pathway of patients, inform the generation of new hypotheses and help to test established ones.
Real-life registries on VTE
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Real-life data is important in understanding the needs of patients in routine clinical practice, particularly owing to the fact that almost a quarter of patients with VTE have at least one exclusion criterion preventing their recruitment into randomized clinical trials [4]. So far, a number of registries have been developed, such as RIETE, IPER, Dresden NOAC, PREFER and Garfield, among others. The Italian Pulmonary Embolism Registry (IPER) enrolls patients with confirmed acute PE in Cardiology, Emergency or Internal Medicine Departments in 47 hospitals in Italy. Its aim is to report on demographics, clinical features, management, and outcomes of patients diagnosed with PE in everyday clinical practice, and in 2012 had recruited 1716 patients [5]. The Dresden NOAC registry is another prospective, observational database of patients with VTE or non-valvular atrial fibrillation enrolled through a network of private practices and community hospitals in Saxony, Germany. A total of 2667 patients have been enrolled as of June, 2014 [6]. Prevention of Thromboembolic EventsEuropean Registry in Venous Thromboembolism (PREFER in VTE) is a prospective, observational, multicentre study that has enrolled 3546 patients with VTE up to July 2014 across sites in Austria, France, Germany, Italy, Spain, Switzerland and the UK. This registry gathered data on important risk factors, diagnosis pathways and treatment modalities; healthcare resource use; patient quality of life and treatment satisfaction [7]. Another ongoing real-life study is GARFIELD-VTE-Global Anticoagulant Registry in the FIELD (ClinicalTrials.gov Identifier: NCT02155491) – that will evaluate treatment patterns in the field of VTE.
The RIETE registry The observational Registro Informatizado de Enfermedad Trombo Embólica (RIETE) registry is an ongoing, international, multicentre, prospective registry of consecutive patients presenting with acute VTE. RIETE was initiated in Spain in 2001, and six years later the database was translated into English, with the aim to expand the Registry to other countries. The goal was to allow physicians worldwide to use the database to select the most appropriate therapy for their patients. Currently, participating countries include Spain, Italy, France, Israel, Portugal, Germany, Belgium, Switzerland, Czech Republic, Macedonia, Greece, Argentina, United States, Canada, Brazil, and Ecuador. In May 2015, over 57,500 patients with acute VTE have been recruited. Data from this registry have been used to evaluate outcomes after acute VTE, such as the frequency of recurrent VTE, major bleeding and mortality, and risk factors for such outcomes [8–12]. In this chapter, we will summarize some of the most relevant data concerning the epidemiology of VTE in the RIETE registry.
Influence of gender on VTE The influence of gender on the natural history of patients with acute VTE has not been thoroughly studied. In a manuscript published in 2014, 47,499 patients were enrolled in RIETE, of whom 24,280 (51%) were women [13]. Compared with men, women were older, more likely presented with PE (53% vs. 47%), more likely had recent immobilization and less likely had cancer, unprovoked VTE or prior VTE. Most (78%) women aged < 40 years and one in every three (39%) women aged > 80 years had transient risk factors for VTE, including hormonal therapy (n = 1491) or pregnancy (n = 566) in women under the age of 40, and immobility (n = 2382) in those aged > 80 years (figure 1). On the contrary, one in every two men (50%) had unprovoked VTE, irrespective of age. We found no gender differences in the proportion of patients initially treated with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH), but women received slightly higher LMWH doses per body weight than men (for initialand for long-term therapy). During the course of anticoagulation (mean duration: 253 days), women had a lower rate of DVT recurrences (hazard ratio [HR]: 0.78; 95% CI: 0.67–0.91), a similar rate of PE recurrences (HR: 0.98; 95% CI: 0.83–1.15) and a higher rate of major bleeding (HR: 1.21; 95% CI: 1.09– 1.35) than men but with multivariate analysis, these genderndifferences for recurrent DVT (HR: 0.88; 95% CI: 0.75–1.03), major bleeding (HR: 1.10; 95% CI: 0.98–1.24) and fatal PE (HR: 1.01; 95% CI: 0.84–1.22) were not significant. A number of studies previously reported a lower rate of VTE recurrences in women, but most were focused on the recurrence rate after discontinuing anticoagulant therapy [14–16]. However, our registry suggests there is no difference in the rates of
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900 Women at risk
800
Men at risk
700
Count
600 500 400 300 200 100 0 10
20
30
40
50
60
70
80
90
100
Age
Women, N Men, N Surgery, women Surgery, men Immobility, women Immobility, men Cancer, women Cancer, men Estrogen use, women Estrogen use, men Pregnancy/ puerperium Unprovoked, women Unprovoked, men
<40 y 3,013 2,552 421 (14%) 322 (13%) 453 (15%) 565 (22%) 170 (5.6%) 161 (6.3%) 1,491 (50%) 9 (0.3%) 566 (19%) 644 (21%) 1,532 (60%)
41-50 y 1,748 2,401 280 (16%) 311 (13%) 299 (17%) 480 (20%) 383 (21%) 343 (14%) 347 (20%) 3 (0.1%) 36 (2.1%) 726 (42%) 1,370 (57%)
51-60 y 2,028 3,490 325 (16%) 444 (13%) 415 (20%) 599 (17%) 656 (32%) 880 (25%) 117 (5.9%) 4 (0.1%) 12 (0.6%) 906 (45%) 1,949 (56%)
61-70 y 3,939 5,196 569 (14%) 621 (12%) 759 (19%) 911 (18%) 1,143 (29%) 1,568 (30%) 80 (2.1%) 14 (0.3%) 1,997 (51%) 2,845 (55%)
71-80 y 7,126 6,327 826 (12%) 653 (10%) 1,906 (27%) 1,241 (20%) 1,472 (21%) 1,853 (29%) 61 (0.9%) 47 (0.8%) 3,838 (54%) 3,466 (55%)
>80 y 6,426 3,253 435 (6.8%) 229 (7.0%) 2,382 (37%) 857 (26%) 1,020 (16%) 877 (27%) 69 (1.1%) 38 (1.2%) 3,332 (52%) 1,783 (55%)
Figure 1 Prevalence of VTE in different age groups according to gender
VTE and patient age The treatment of VTE in the elderly presents certain unique problems related to aging, such as lower body weight, renal insufficiency and a tendency to more comorbidities, which complicate therapy. Current guidelines from the ACCP, based on evidence from clinical trials, recommend that all patients with VTE be treated initially with either LMWH, fondaparinux, or UFH for at least 5 days overlapped and followed by long-term treatment with a VKA [21]. However, elderly patients are often excluded from clinical trials of anticoagulant treatment because of short life expectancy, higher risk of drug interactions,
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malnutrition, dehydration, or difficulties with periodic monitoring of the prothrombin time, which means that treatment regimens based on the results from randomized trials might not be suitable for all elderly patients with VTE. In one of our first studies, of 13,011 patients with VTE, 2890 (22%) were aged 80 years [22]. During the first 3 months of therapy, 99 patients aged 80 years (3.4%) and 212 aged < 80 years (2.1%) had major bleeding (odds ratio [OR]: 1.7; 95% CI: 1.3–2.1). The rate of recurrent VTE was 2.1% and 2.8%, respectively. Fatal bleeding occurred in 0.8% and 0.4% (OR: 2.0; 95% CI: 1.2–3.4), but 3.7% of patients 80 years and 1.1% < 80 years (1.1%) died of PE (OR: 3.6; 95% CI: 2.7–4.7). Thus, in patients aged 80 years the 3.4% rate of major bleeding slightly exceeded the 2.1% of VTE recurrences, but the 3.7% rate of fatal PE far outweighed the 0.8% of fatal bleeding. Hence, there seems to be more reason to be concerned about fatal PE than about bleeding in elderly patients with VTE. In another study, we compared the outcome in 16,199 presenting with lower-limb DVT according to age [11]. Most patients (96%) received initial therapy with LMWH followed by VKA therapy, but 38% of patients aged 80 years received long-term LMWH
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recurrence while on anticoagulant therapy. Our study did confirm an increased rate of major bleeding events in women as has previously been reported in patients receiving anticoagulation for atrial fibrillation [17–19], but we did not demonstrate this in women with VTE [20]. We did demonstrate a higher rate of haematomas in women but no difference in the rate of gastrointestinal, intracranial or retroperitoneal bleeding. Since the mortality associated with these haematomas was rather low, the rate of fatal bleeding was similar in both genders.
M. Monreal, I. Mahé, A. Bura-Riviere, P. Prandoni, P. Verhamme, B. Brenner, et al.
therapy only. During the first 3 months of anticoagulant therapy, 111 patients (0.7%) were diagnosed with symptomatic PE (31 died; case fatality rate = 28%), and 284 (1.7%) had major bleeding (83 died; case fatality rate = 29%). Thus, although the case fatality rate is the same the risk of fatal bleeding was more than twice as high as the risk of fatal PE during three months of treatment for acute DVT. The relative frequency of fatal PE and fatal bleeding differed according to the period of follow-up: during the first week of treatment, the risk of both fatal bleeding and fatal PE were similar (12 vs. 14 deaths). After the first week, the risk of fatal PE decreased markedly, whereas the risk of fatal bleeding remained high. Interestingly however, the relative frequency of fatal PE and fatal bleeding from Day 8 to Day 90 differed according to patient's age: from Day 8 to Day 90, there were 5 fatal bleeds and 6 fatal PE in patients aged 60 years, but 64 fatal bleeds and 13 fatal PE in patients who were 60 years or older. Differences in intensity of anticoagulation are unlikely to account for the difference in outcomes, since INR control and LMWH doses did not differ according to age. Given the risk of older patients dying from bleeding exceeds the risk of death from recurrent VTE, these patients may benefit from less aggressive anticoagulation. However, randomized trials are needed to test this.
TABLE I Clinical characteristics in 8389 VTE patients with recent immobilization, according to place of immobilization
Patients, n
At home
In hospital
5960
2429
OR (95% CI)
Clinical characteristics Gender (male)
2467 (41%) 1167 (48%) 0.76 (0.69–0.84)
Mean age (years SD)
68 18
69 16
P < 0.05
Body weight (kg SD)
74 17
72 15
P < 0.001
Initial VTE presentation Pulmonary embolism
2957 (50%) 1290 (53%) 0.87 (0.79–0.95)
Underlying conditions Chronic lung disease
816 (14%)
472 (19%) 0.66 (0.58–0.75)
Chronic heart failure
573 (9.6%)
331 (14%) 0.68 (0.58–0.78)
Anemia
1985 (33%) 1331 (55%) 0.41 (0.37–0.45)
Recent major bleeding
93 (1.6%)
268 (11%) 0.13 (0.10–0.16)
Prior VTE
650 (11%)
253 (10%) 1.05 (0.90–1.23)
Cancer
980 (16%)
582 (24%) 0.62 (0.56–0.70)
Concomitant therapies
Influence of risk factors on VTE
Antiplatelets
1022 (18%) 562 (24%) 0.68 (0.61–0.77)
Recent immobilization
NSAIDs
552 (9.8%) 147 (6.4%) 1.59 (1.32–1.92)
Corticosteroids
569 (10%)
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In a study including 18,028 patients with acute symptomatic PE, we used the RIETE data to compare the 3-month mortality rate in patients with PE, according to the presence of recent immobilization or surgery [23]. The rate of fatal PE was higher in the 4169 (23%) of patients with recent immobilization (4.9%; 95% CI: 4.3–5.6) than in the 2212 (12%) patients with recent surgery (1.4%; 95% CI: 1.0–2.0) or in the 11,647 (65%) with neither (2.1%; 95% CI: 1.8–2.3). These results may have been influenced by the use of VTE prophylaxis in 65% of the surgical patients compared to only 25% of those with recent immobilization. Furthermore, patients with recent immobilization were older, more likely had comorbid diseases, and more frequently presented with clinical signs of severity (i.e., hypotension, hypoxemia. . .) than other patients with PE. However, this worse outcome persisted after multivariate adjustment. In another study, we used the RIETE database to compare the use of VTE prophylaxis and the mortality due to PE in a large sample of nonsurgical patients after being immobilized at home or in hospital [24]. Among 5960 patients immobilized at home, 38% had an acute medical illness, 28% trauma, 25% chronic immobility, and 9.5% other reasons (table I). Among 2429 patients immobilized in hospital, 70% were acutely ill, 7.7% had trauma, 6.5% chronic immobility, and 9.5% other. The duration of immobility was longer than 4 weeks in 38% of patients at home and in 7.4% in hospital (OR: 7.64; 95% CI: 6.50–8.98).
389 (17%) 0.56 (0.48–0.64)
Reason for immobilization Acute medical illness
2241 (38%) 1690 (70%) 0.26 (0.24–0.29)
Trauma
1677 (28%) 187 (7.7%) 4.69 (4.00–5.51)
Chronic immobilization
1477 (25%) 159 (6.5%) 4.70 (3.96–5.58)
Other
565 (9.5%)
393 (16%) 0.54 (0.47–0.62)
Duration of immobilization < 7 days
1226 (21%) 944 (39%) 0.41 (0.37–0.45)
1–4 weeks
2398 (41%) 1272 (53%) 0.61 (0.56–0.67)
5–8 weeks
567 (9.7%) 112 (4.7%) 2.18 (1.77–2.69)
> 8 weeks
1670 (28%)
67 (2.8%)
13.9 (10.8–17.7)
VTE prophylaxis Yes Duration (mean days SD) Duration (median days, IQR)
717 (12%) 1351 (56%) 0.11 (0.10–0.12) 30 70
14 15
P < 0.001
17 (10–30)
10 (6–15)
P < 0.001
VTE: venous thromboembolism; SD: standard deviation; CrCl: creatinine clearance; NSAIDs: nonsteroidal anti-inflammatory drugs; IQR: interquartile range; OR: odds ratio; CI: confidence intervals.
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TABLE II Ninety-day outcome in VTE patients with recent immobility, according to site of immobilization At home Patients, n
In hospital
OR (95% CI)
5960
2429
Recurrent DVT
39 (0.7%)
27 (1.1%)
0.58 (0.36–0.96)
Recurrent PE
59 (1.0%)
33 (1.4%)
0.72 (0.47–1.11)
Recurrent VTE
98 (1.6%)
60 (2.5%)
0.66 (0.48–0.92)
Major bleeding
159 (2.7%)
93 (3.8%)
0.69 (0.53–0.89)
Overall death
713 (12%)
396 (16%)
0.70 (0.61–0.80)
Pulmonary embolism
111 (1.9%)
43 (1.8%)
1.05 (0.74–1.49)
Fatal initial PE
91 (1.5%)
35 (1.4%)
1.06 (0.71–1.56)
Fatal recurrent PE
20 (0.3%)
8 (0.3%)
1.02 (0.45–2.33)
Sudden, unexpected
26 (0.4%)
14 (0.6%)
0.75 (0.39–1.45)
Respiratory insufficiency
78 (1.3%)
42 (1.7%)
0.75 (0.52–1.10)
Bleeding
35 (0.6%)
27 (1.1%)
0.53 (0.32–0.87)
Disseminated cancer
173 (2.9%)
97 (4.0%)
0.72 (0.56–0.93)
Infection
69 (1.2%)
50 (2.0%)
0.56 (0.39–0.81)
Ischemic stroke
9 (0.2%)
4 (0.2%)
0.92 (0.28–2.94)
Myocardial infarction
3 (0.1%)
2 (0.1%)
0.61 (0.10–3.70)
Other
110 (1.8%)
75 (3.1%)
0.59 (0.44–0.79)
Unknown
99 (1.7%)
42 (1.7%)
0.96 (0.67–1.39)
Causes of death
DVT: deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; OR: odds ratio; CI: confidence intervals.
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of randomized clinical trials evaluating home VTE prophylaxis in acutely ill medical patients. Given such trials are unlikely to be done we cannot reasonably expect any evidence addressing reduction in the burden of VTE in this population.
Recent surgery In 2006, we retrospectively assessed the clinical characteristics and 3-month outcome of 1602 patients that developed acute VTE after undergoing surgery [25]. The most common types of surgery were: hip fracture repair (7.6%), elective hip arthroplasty (9.1%), knee arthroplasty (7.9%), other orthopaedic surgery (12%), oncologic surgery (13%), abdominopelvic surgery for conditions other than cancer (25%), neurosurgery (7.7%), vascular (6.2%) and other (12%). Patients with VTE after major orthopaedic surgery were more likely female and significantly older than those undergoing either cancer surgery or other surgical procedures. There were no differences between subgroups in the mean time elapsed from surgery to VTE (22 16, 24 16, and 21 15 days, respectively) or in the proportion of patients who developed VTE during the first 15 days after surgery (47%, 41% and 45%, respectively). As for the clinical presentation of VTE, there were no differences in the proportion of patients with clinically overt PE (48%, 48%, and 50% respectively) or in the severity of the PE event. Interestingly, clinically overt PE appeared significantly earlier (20 15 vs. 24 16 days; P < 0.001) than DVT. VTE prophylaxis was used in 1058 (66%) patients, with a higher use in patients undergoing major orthopaedic surgery (96%) than in those with cancer surgery (76%) or other procedures (52%). The vast majority (97%) of patients received prophylactic LMWH. Overall, 478 (47%) patients had their VTE event diagnosed while on prophylaxis, the rest occurred during follow-up.
Cancer Cancer patients with VTE are at increased risk of both recurrent VTE and anticoagulation-related bleeding compared to non-cancer patients. In 2006, a total of 14,391 patients with VTE had been enrolled in RIETE, of whom 2945 (20%) had active cancer [26]. During the first 3 months of therapy, the rate of fatal PE in cancer patients was 2.6%, and that of fatal bleeding 1.0%. These rates were much higher than in VTE patients without cancer (1.4% and 0.3%, respectively). In patients with cancer, abnormal renal function, metastatic disease, recent major bleeding and recent immobility (42% of patients dying from PE had recent immobility) were independent predictors of the risk for fatal PE or fatal bleeding. In addition, PE diagnosis at baseline independently predicted the risk for fatal PE, while body weight < 60 kg predicted fatal bleeding. The data in this analysis indicate that cancer patients with VTE who have recently been immobilized (due to their cancer per se, side-effects of cancer therapy, or for an acute medical illness) have a significantly worse clinical outcome. Of the patients with
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During the first 3 months of anticoagulation, the rate of VTE recurrences (OR: 0.66; 95% CI: 0.48–0.92), major bleeding (OR: 0.69; 95% CI: 0.53–0.89), all-cause death (OR: 0.70; 95% CI: 0.61–0.80) and fatal bleeding (OR: 0.53; 95% CI: 0.32–0.87) were lower in patients immobilized at home than in those in hospital (table II), but the mortality due to PE was similar (OR: 1.05; 95% CI: 0.74–1.49). Since the risk of patients developing VTE after being immobilized at home was over 2-fold higher than those patients developing VTE while staying in hospital, the amount of patients dying of PE after being immobilized at home was also over two-fold higher than in those immobilized in hospital (figure 2). Interestingly however, the use of VTE prophylaxis in patients at home was much lower than in hospital (12% vs. 56%, respectively) perhaps on part due to an absence
M. Monreal, I. Mahé, A. Bura-Riviere, P. Prandoni, P. Verhamme, B. Brenner, et al.
At home. Fatal PE In hospital. Fatal PE At home. Fatal bleeding In hospital. Fatal bleeding
120 110 100 90
Cumulative Incidence
80 70 60 50 40 30 20 10 0 0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
Days
Days At home, Fatal PE Fatal bleeding In hospital, Fatal PE Fatal bleeding
1 5,951 26 (0.44%) 2 (0.03%) 2,423 10 (0.41%) 0
7 5,799 87 (1.46%) 9 (0.15%) 2,366 32 (1.32%) 6
15 5,701 97 (1.63%) 20 (0.34%) 2,281 37 (1.52%) 14
30 5,538 104 (1.74%) 26 (0.44%) 2,187 38 (1.56%) 20
60 5,358 108 (1.81%) 31 (0.52%) 2,094 42 (1.73%) 25
90 5,248 111 (1.86%) 35 (0.59%) 2,034 43 (1.77%) 27
Figure 2 Cumulative mortality for pulmonary embolism or bleeding according to the site of immobilization
recent immobilization who died from a PE or bleeding complication, 41% had non-metastatic cancer and would have had a favorable prognosis for survival from their cancer in the absence of these VTE complications.
Limitations RIETE provides data on the treatment of VTE in a real-world situation with an unselected patient population, in contrast to the rigorously controlled conditions of randomized clinical studies. It can, therefore, provide insights into the natural history of VTE in patients that are not often included in randomized clinical
trials. It can also help to identify practices for providing treatment to patients, and factors associated with better or worse patient outcomes. However, as an observational study, RIETE is not designed to answer questions regarding the relative efficacy and safety of different modalities of therapy. Data from the registry are hypothesis-generating and provides feedback from real-world clinical situations which is invaluable when designing new randomized clinical studies. Disclosure of interest: the authors declare that they have no competing interest.
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