113

Thromboprophylaxis with Low-Molecular-Weight Heparins: An Assessment of the Methodological Quality of Studies Giancarlo Agnelli, MD1 Paolo Prandoni, MD2 Giovanni Di Minno, MD3 Claudio Cimminiello, MD4 Francesco Scaglione, MD, PhD5 Patrizia Boracchi, PhD6 Mauro Molteni, MD4 Hernan Polo Friz, MD4 Matteo Nicola Dario Di Minno, MD3 Giuseppe Marano, PhD6

Perugia, Perugia, Italy 2 Department of Cardiothoracic and Vascular Sciences, Clinica Medica 2, University of Padua, Padua, Italy 3 Department of Clinical and Experimental Medicine, Federico II University Hospital, Naples, Italy 4 Department of Medicine, Vimercate Hospital Azienda Ospedaliera di Desio e Vimercate, Vimercate, Italy 5 Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy 6 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

Address for correspondence Claudio Cimminiello, MD, Department of Medicine, Vimercate Hospital, Azienda Ospedaliera di Desio e Vimercate, via Santi Cosma e Damiano 10. ZIP 20871, Vimercate, Italy (e-mail: [email protected]).

Semin Thromb Hemost 2015;41:113–132.

Abstract

Keywords

► low-molecular-weight heparin ► evidence-based practice ► therapeutic equivalency ► venous thromboembolism ► systematic review

Low-molecular-weight heparin (LMWH) represents the standard of care for prophylaxis of venous thromboembolism (VTE). We conducted a review of the evidence supporting the use of the different LMWHs employed in VTE prophylaxis, in different clinical settings, and analyzed its progression over time. To evaluate the standards of methodological quality of studies, we elaborated a quality assessment tool. By electronic databases, PubMed, MEDLINE, and Scopus databases, 249 articles deemed eligible for the analysis were selected. Several LMWHs did not have publications in all clinical settings. Extended duration of prophylaxis was documented only for a few LMWH. The quality score yielded statistically significant differences between the medians of the four settings (p ¼ 0.0021) with a higher score in major orthopedic surgery (median, 16; 95% confidence interval [CI], 15–16) when compared with general surgery (median, 14; 95% CI, 13–14; p < 0.001). Median score for studies published after the year 1990 was higher than for those published earlier (p < 0.001). We conclude that the quality of the studies supporting LMWH for VTE prophylaxis in the different clinical settings is not homogeneous and inferior for studies performed before the year 1990. Clinical interchangeability of LMWHs in clinical practice remains a critical issue, and the selection of a product should be based on evidence available for each agent, and for each clinical indication derived from clinical trials.

Venous thromboembolism (VTE) is one of the most common complications of hospitalization.1 VTE and its sequelae include deep vein thrombosis (DVT), fatal and nonfatal pulmonary embolism (PE), chronic postthrombotic syndrome,

and chronic thromboembolic pulmonary hypertension.2 PE is the third most common fatal vascular disorder and one of the leading causes of preventable hospital death.2,3 Thus, VTE is a major public health concern, with a high clinical impact on

published online February 17, 2015

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

Issue Theme Anticoagulant Therapy: Present and Future; Guest Editor: Job Harenberg, MD.

DOI http://dx.doi.org/ 10.1055/s-0035-1544228. ISSN 0094-6176.

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1 Internal and Cardiovascular Medicine-Stroke Unit, University of

Thromboprophylaxis with Low-Molecular-Weight Heparins morbidity and mortality and a considerable economic burden. The pioneering study by Sevitt and Gallagher in 1959 demonstrated that an oral anticoagulant administered to patients who had surgical repair of hip fractures reduced symptomatic VTE and death without an increase in clinically important bleeding.4 Since then, hundreds of clinical trials have shown that thromboprophylaxis reduces the rates of VTE events in a broad spectrum of hospitalized patients with a low risk of adverse effects.1,5–7 Several evidence-based guidelines recommending routine thromboprophylaxis in different setting of hospitalized patients have been published.8–12 Anticoagulants have become the mainstay of prophylaxis options in most surgical and medical patients, with nonpharmacologic prophylaxis having a more limited role.8 Several meta-analyses demonstrated a significant reduction in DVT, PE, and mortality and acceptable increase of bleeding complications with unfractionated heparin (UFH) as compared with placebo or an active comparator and a higher efficacy and a reduced bleeding with low-molecular-weight heparin (LMWH) as compared with UFH.5–7,13,14 Therefore, LMWHs represent the standard of care for VTE prophylaxis and are used as the reference treatment in trials with new anticoagulants. Several LMWHs are currently available for clinical use. Because of several differences for each product involving biochemical, pharmacokinetic, and production process, both the United States Food and Drug Administration (FDA) and the World Health Organization have classified each LMWH as a distinct drug.15 Nevertheless, LMWHs are often quoted as a single class of drugs. As LMWH preparations vary considerably in their pharmacological properties and costs, their relative efficacy and safety is a relevant issue from a clinical and pharmacoeconomic point of view. The topic of interchangeability between the different molecules of LMWH has hitherto been addressed by comparing safety and efficacy of the various molecules. However, the paucity of data on direct comparison and the poor quality of the existing head-to-head studies do not allow definitive conclusions.16–18 Nevertheless, an aspect so far neglected is the evaluation of the quality of evidence in support of the various LMWH products. This kind of approach may help to better understand potentials and risks of interchangeability between different molecules available for the prophylaxis of VTE. The scope of this study was to review the evidence supporting the use of the different types of LMWH available for the prophylaxis of VTE in different surgical and medical settings, and to analyze the progression over time of the quality of the studies performed in this field.

Methods We conducted a review by performing a database search of literature on the evidence supporting the use of the different types of LMWH used in the prophylaxis of VTE, an analysis of all prospective clinical trials using a prearranged scoring grid to assess their methodological quality, and an analysis of the evolution of these features over time. Seminars in Thrombosis & Hemostasis

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Agnelli et al. Literature Search To systematically retrieve all studies, two investigators (M.M. and C.C.) independently performed a computerized search of the published literature to identify published prospective clinical trials on VTE prophylaxis using LMWH. Studies were eligible if prospective and controlled regardless whether the comparator was placebo, UFH, aspirin, mechanical, or other antithrombotic prophylaxis (e.g., dextran, dihydroergotamine, etc.) or nihil. Head-to-head comparisons between different LMWHs and studies where a LMWH was the reference therapy in comparison to a new antithrombotic drug were also considered. Prospective, even if uncontrolled, studies reporting data of efficacy on VTE events and/or safety of a specific LMWH molecule were also considered eligible. The keywords “low molecular weight heparin prophylaxis” were combined to search MEDLINE/PubMed database. The additional filters—“Clinical Trial,” “Meta-Analysis,” “Review,” “Abstract available,” “Publication date from 1980/01/01 to 2013/06/31,” “Humans,” “English”—were applied to the search, yielding a total of 2,228 results. Excluding meta-analyses and reviews, initially identified studies became 919. EMBASE database was searched by using “low molecular weight heparin prophylaxis” as keywords, with additional filters “title,” “clinical trial,” “controlled clinical trial,” “randomized clinical trial,” “meta-analysis,” “human,” publication date from 1984 through 2013. Keywords “low molecular weight heparin prophylaxis” were used to search SCOPUS database, additional filters: “title,” “article” or “review,” “English,” publication date from 1980 through 2013. EMBASE and SCOPUS database searches retrieved 230 and 215 articles, respectively. Subsequent hand searching of reference list of all eligible trials identified through these electronic databases was completed. Reviews and meta-analyses were not included in the analysis but a hand search of the bibliographies of each retrieved article was conducted to identify prospective clinical trials. The process of study selection is shown in ►Fig. 1.

Study Selection Criteria All retrieved prospective clinical trials evaluating VTE prophylaxis with LMWH as stated earlier were included and the fulltext version analyzed. The MEDLINE/PubMed search was limited to studies published in the English language; however, studies published in French, German, Spanish, and Italian language mentioned in different meta-analyses were included if they fulfilled the inclusion criteria. Studies were excluded if they were not prospective studies, if they were reviews or meta-analyses, if the clinical endpoints were other than VTE events (e.g., catheter patency in patients with cancer indwelling central venous catheters), or if the clinical setting was hemodialysis, pregnancy and its complications, pediatrics, coronary artery disease including by-pass surgery.

Settings Each study was assigned to one of the following clinical settings:

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Fig. 1 Process of study selection.

1. General surgery: including noncancer, general and abdominal-pelvic surgery, such as gastrointestinal surgery, gynecologic surgery, urological surgery, cancer surgery, bariatric surgery, laparoscopic surgery. 2. Nonmajor orthopedic and other surgery: including nonmajor orthopedic surgery such as isolated lower-extremity injuries distal to the knee, arthroscopic procedures, trauma, vascular surgery, neurosurgery, thoracic surgery, elective spinal surgery, and spinal cord injury. 3. Major orthopedic surgery: including elective hip replacement, elective knee replacement, hip fracture surgery. 4. Nonsurgical patients: including hospitalized, acutely ill medical patients, critically ill patients, stroke patients, patients with cancer receiving chemotherapy in the outpatient setting. Moreover, subsettings of prophylaxis of standard or extended duration were also analyzed.

Study Quality Assessment We elaborated a quality assessment tool to evaluate the standards of methodological quality of selected studies. A 20-item score was developed, adapted from the criteria of McMaster to evaluate the validity of studies about prognosis,19 Jadad score,20 GRADE system,21 and other scales22 (►Table 1). The main features assessed were as follows: inclusion and exclusion criteria, experimental design, ethic adequacy of control treatment, endpoints, drug treatment, follow-up, statistical analysis, and study limitations. Each question was to be answered with either a yes or a no. Each yes would score a single point, each no zero points. Thus, this Quality Indicators Score yielded a minimum score of 0 points and a maximum score of 19 points, because question 17 was alternative to question 16.

Statistics The distribution of the quality score for the studies in each clinical setting was described by range (minimum and maximum score), median, and first (25%) and third (75%) quartiles. Ninety-five percent confidence intervals (95% CI) for the population median were calculated by nonparametric methods based on the order statistics using binomial distribution. The analysis of the progression over time of the quality score was assessed subdividing the publications in three periods (before 1990, from 1990 through 2000, and after 2000). First, the medians of the distribution of overall score for each clinical setting and for the three periods were compared by nonparametric Brown Mood test. When the result of the overall test was statistically significant (p < ¼0.05), pairwise comparisons were performed adjusting the significance level by Bonferroni method. For each item, the association between publication period and the quality score was evaluated by odds ratio (OR) with pertinent 95% CI. With this aim, a logistic model was applied on the percentages of studies with yes response, including in the model predictor two dummy variables coded as follows: 0,0 before 1990; 1,0 between 1990 and 2000; 1,1 after 2000.

Results From the studies initially identified (919 from PubMed/ MEDLINE, 230 from EMBASE, and 215 from SCOPUS databases), 1,160 were excluded. Forty-five studies were added by subsequent hand searching of reference list of trials, meta-analyses, and reviews, resulting in a total of 249 studies that met inclusion criteria (Appendix 1; ►Fig. 1). Ten LMWH products had at least one study published, so were considered in the analysis that included a total of 249 studies and 225,923 patients in the aforementioned four

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Thromboprophylaxis with Low-Molecular-Weight Heparins

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Table 1 Quality indicators items 1. Inclusion criteria clearly described 2. Exclusion criteria clearly described 3. Percentage of patients excluded of total eligible patients, by causes of exclusion, clearly described 4. Appropriateness of the experimental design: randomized study 5. Appropriateness of the experimental design: controlled study 6. Appropriateness of the experimental design: double-blind study 7. Ethic adequacy of control treatment (e.g., active or placebo) 8. Primary and secondary endpoints of efficacy clearly defined and objectively documented 9. Safety endpoint clearly defined and objectively documented 10. In the case of surrogate endpoints (e.g., instrumental tests): accuracy of the chosen endpoint 11. Dosage and duration of drug treatment clearly described 12. Duration and modality of follow-up clearly described 13. Appropriateness of the statistical analysis: calculation of the sample size 14. Appropriateness of the statistical analysis: accurate presentation of estimates of the endpoints and results expressed in terms of confidence intervals 15. Appropriateness of the statistical analysis: analysis of efficacy according to the intention to treat 16. Appropriateness of the statistical analysis: multivariate analysis adjusted for the effect of the treatments 17. If multivariate analysis adjusted for the effect of the treatments was not performed, the comparison groups were well balanced on basal characteristic 18. Assessment of primary endpoint in at least 85% of enrolled patients 19. Percentage of patients lost to follow-up (even for safety endpoints) 20. Discussion of possible study limitations

clinical settings. Two studies were considered as “Other LMWHs” because a clear and unambiguous identification of the specific LMWH agent was not possible. Several products did not have published studies in all clinical settings. ►Table 2 shows the number of studies, patients included, and other characteristics of prospective clinical trials on VTE prophylaxis, by clinical setting, and by duration (standard and extended duration prophylaxis). Evaluation of the methodological quality of the studies using the Quality Indicators Score yielded statistically significant differences between the medians of the four settings (p ¼ 0.0021) with a higher score in major orthopedic surgery (median, 16; 95% CI, 15–16) when compared with general surgery (median, 14; 95% CI, 13–14; p < 0.001) (►Table 3). Median (95% CI) of Quality Indicator Score was 14 (13–14), 16 (14–16), and 17 (12–16) for studies published before 1990, since 1990 through 2000, and after 2000, respectively (p < 0.001, ►Table 4). Median score for studies published after 1990 was significantly higher than that of studies published before 1990 (p < 0.001), but no significant difference was found between the score of studies published between 1990 and 2000 and studies published after 2000. A significant association was found between the Quality Indicator Score and period of publication for the items 2, 3, 8, 9, 10, 13, 14, 16, and 20 (95% CI of OR > 1.0). For the abovementioned items, the Quality Indicator Score increased Seminars in Thrombosis & Hemostasis

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significantly over time (►Table 5). ►Appendix 1 shows citations of all analyzed studies by clinical settings.

Discussion Routine thromboprophylaxis is largely recommended for hospitalized patients in different clinical settings. As a huge number of studies showed the benefits of LMWH as a whole, they represent the standard of care for VTE prophylaxis.8–12 However, differences between the several LMWHs currently available for clinical use related to the methods of preparation, pharmacological properties, and costs had raised questions about clinical equivalence and interchangeability of these products in clinical practice. There are few trials of direct comparison of different LMWHs. In almost all such trials, the comparator is UFH.23 Therefore, several systematic reviews and meta-analysis attempted to compare efficacy and safety of the various LMWHs,6,7,13,14,24–26 but a methodological quality assessment of studies was lacking. Therefore, we addressed this issue by performing a systematic review of the evidence supporting the use of the different types of LMWH and analyzing the methodological quality of the studies and its evolution over time. We found large differences in the quality of the evidence supporting each of the LMWH products currently available for VTE prophylaxis, and some points are worthy of mention.

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116

4,584

30,476

27,628

117,056

21,550

2,048

7,256

7,198

4,399

281

225,923

Bemiparin

Certoparin

Dalteparin

Enoxaparin

Nadroparin

Parnaparin

Reviparin

Semuloparin

Tinzaparin

Other LMWHs

Total

249

2

11

3

8

10

29

107

48

20

7

4

Total studies (n)

1,461

915

4,519

72,381

1,390

289

3,323

4,026

1,922

0

93,673

Bemiparin

Certoparin

Dalteparin

Enoxaparin

Nadroparin

Parnaparin

Reviparin

Semuloparin

Tinzaparin

Other LMWHs

Total

111

0

5

2

3

3

7

68

12

3

4

4

23

0

2

1

0

1

0

10

5

2

0

2

55

0

3

2

1

1

5

20

16

3

2

2

LMWH vs. placebo

0

0

707

803

2,333

Ardeparin

Bemiparin

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Certoparin

Dalteparin

Enoxaparin

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11

6

3

0

0

2

2

0

0

0

Setting: nonmajor orthopedic and other surgery

3,447

Ardeparin

Setting: major orthopedic surgery

3,447

Patients (n)

Ardeparin

All settings

Product

0

1

1

0

0

3

0

0

0

0

0

2

1

0

0

0

0

11

0

1

0

1

0

4

2

2

1

0

0

LMWH vs. no treatment

0

1

0

0

0

2

0

0

0

0

0

0

1

0

0

1

0

10

1

1

0

0

2

1

1

2

0

2

0

4

0

0

0

0

9

0

0

0

0

0

2

7

0

0

0

0

18

0

1

0

1

0

4

12

0

0

0

0

LMWH vs. mechanical treatment

0

0

0

0

0

3

0

0

0

0

0

0

2

1

0

0

0

3

0

0

0

0

0

0

2

1

0

0

0

LMWH vs. aspirin

1

0

0

0

0

11

0

1

0

1

0

0

4

3

0

0

2

14

0

1

0

1

0

1

5

4

0

0

2

LMWH vs. VKAs

0

0

0

0

0

11

0

2

0

0

0

3

6

0

0

0

0

15

0

2

0

0

0

4

7

1

1

0

0

LMWH vs. other treatment

5

1

1

0

0

22

0

0

0

1

2

1

12

4

1

1

0

82

1

1

0

3

5

7

29

21

14

1

0

LMWH vs. UFH

0

1

1

0

0

12

0

0

1

1

0

0

8

0

0

2

0

26

0

1

1

1

2

4

11

3

1

2

0

LMWH vs. other LMWH

0

0

0

0

0

23

0

0

0

0

0

0

23

0

0

0

0

25

0

0

0

0

0

0

25

0

0

0

0

LMWH vs. NOA

5

4

0

0

0

22

0

0

1

1

0

1

13

4

1

0

1

50

0

4

1

2

0

5

25

10

1

1

1

Extended duration

(Continued)

6

2

3

0

0

89

0

5

1

2

3

6

55

8

2

4

3

199

2

7

2

6

10

24

82

38

19

6

3

Standard duration

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LMWH (noncontrolled)

Table 2 Main study characteristics of prospective clinical trials on VTE prophylaxis, by type of LMWH and clinical setting

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593

0

989

78

12,055

Parnaparin

Reviparin

Semuloparin

Tinzaparin

Other LMWHs

Total

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0

3,172

0

0

61,879

Parnaparin

Reviparin

Semuloparin

Tinzaparin

Other LMWHs

Total

58,316

Other LMWHs

Total

60

1

3

0

3

4

8

14

18

8

1

0

5

0

1

0

0

0

0

2

1

0

1

0

22

0

0

1

0

0

5

6

8

1

1

0

5

0

0

0

1

0

0

LMWH vs. placebo

2

0

0

0

0

0

1

1

0

0

0

0

1

0

0

0

0

0

0

0

1

0

0

0

5

0

1

0

1

0

1

LMWH vs. no treatment

0

0

0

0

0

0

0

0

0

0

0

0

2

0

0

0

0

0

0

0

1

0

1

0

6

1

1

0

0

2

1

LMWH (noncontrolled)

2

0

1

0

1

0

0

0

0

0

0

0

1

0

0

0

0

0

0

1

0

0

0

0

6

0

0

0

0

0

2

LMWH vs. mechanical treatment

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

LMWH vs. aspirin

0

0

0

0

0

0

0

0

0

0

0

0

2

0

0

0

0

0

1

0

1

0

0

0

1

0

0

0

0

0

0

LMWH vs. VKAs

2

0

0

0

0

0

0

1

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1

0

0

0

0

0

1

LMWH vs. other treatment

39

1

1

0

2

3

4

7

14

7

0

0

14

0

0

0

0

0

2

5

2

5

0

0

7

0

0

0

0

0

0

LMWH vs. UFH

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Abbreviations: LMWH, low-molecular-weight heparin; NOA, new oral anticoagulants; VKAs, vitamin K antagonists; VTE, venous thromboembolism.

1,488

203

Tinzaparin

0

5,724

Nadroparin

Semuloparin

7,521

Enoxaparin

1,118

13,670

Dalteparin

3,340

24,626

Certoparin

Reviparin

626

Bemiparin

Parnaparin

0

Ardeparin

43

0

0

1

0

0

8

14

12

6

2

0

35

1

3

0

2

3

6

Total studies (n)

9

0

0

0

0

1

3

3

2

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

5

0

1

0

0

1

1

LMWH vs. other LMWH

0

0

0

0

0

0

0

0

0

0

0

0

2

0

0

0

0

0

0

2

0

0

0

0

0

0

0

0

0

0

0

LMWH vs. NOA

6

0

1

0

0

0

0

3

1

0

1

0

6

0

0

0

0

0

1

4

1

0

0

0

16

0

3

0

1

0

3

Extended duration

54

1

2

0

3

4

8

11

17

8

0

0

37

0

0

1

0

0

7

10

11

6

2

0

19

1

0

0

1

3

3

Standard duration

Thromboprophylaxis with Low-Molecular-Weight Heparins

Setting: general surgery

8,525

0

Nadroparin

8,636

34,821

4,228

Certoparin

Enoxaparin

2,497

Bemiparin

Dalteparin

0

Ardeparin

Setting: nonsurgical patients

5,911

641

Nadroparin

Patients (n)

Product

Table 2 (Continued)

118 Agnelli et al.

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119

Table 3 Assessment of studies on venous thromboembolism prophylaxis with LMWH. Summary of the quality indicators score by clinical settings Setting

Patients (n)

Total studies (n)

Quality indicators score Minimum

Maximum

Q1: 25%

Q2: 50% Median

Q3: 75%

95% CI

Nonmajor orthopedic and other surgery

12,055

35

4

19

12.75

15a

17.25

14–16

Major orthopedic surgery

93,673

111

10

19

14

16a

17

15–16

a

16

14–19

15.25

13–14

Nonsurgical patients

61,879

43

8

19

13

15

General surgery

58,316

60

6

18

11

14a

Abbreviations: Q1, first quartile (25%); Q2: second quartile (50%) median; Q3: third quartile (75%); 95% CI; 95% Confidence Interval for the median. a Mood test: all median comparisons (two-sided) p ¼ 0.002. Between groups’ median comparison: differences between major orthopedic surgery and nonmajor orthopedic and other surgery, p ¼ 0.0001. Comparisons between other groups: nonstatistically significant.

Year of publication

Patients (n)

Total studies total (n)

Quality indicators score Minimum

Maximum

Q1: 25%

Q2: 50% Median

Q3: 75%

95% CI

Before 1990

9,938

34

6

17

11.5

13a

14

13–14

Since 1990 through 2000

51,183

96

8

19

13

15a

16

14–16

After 2000

164,802

119

4

19

14

16a

17

12–16

Abbreviations: Q1, first quartile (25%); Q2, second quartile (50%) median; Q3, third quartile (75%); 95% CI, 95% confidence interval for the median. a Mood test: all median comparisons (two-sided), p ¼ 0.0005. Between groups’ median comparison: differences between period “Before 1990” and “Since 1990 through 2000,” p ¼ 0.02; period “Before 1990” and “After 2000,” p ¼ 0.0001. Other comparisons between groups: nonstatistically significant.

First, the number of prospective clinical trials and the total number of patients included markedly differ between LMWHs in general and for each clinical setting. All the 10 different LMWH products included in the analysis had at least one study published in the clinical setting of major orthopedic surgery, but several products had no published studies in the other three settings. For instance, in nonsurgical patients, six products had been tested, but most studies assessed only three of these six agents, as shown in ►Table 2. Second, to comprehensively evaluate the standards of methodological quality of prospected studies, we elaborated a 20-item Quality Indicator Score, adapted from the criteria of McMaster,19 Jadad score,20 GRADE system,21 and other scales.22 Different approaches to measure the methodological quality of clinical trials have been proposed, but most of them had not been rigorously validated.22 The Jadad Scale20 presented a large validity and reliability evidence; however, its validity for thromboprophylaxis with heparin trials has not been supported and critics have charged it of being oversimplistic and placing too much emphasis on blinding.27 Another tool to assess the quality of evidence to support a particular recommendation is the GRADE system. It classifies the quality of evidence in one of four levels: high, moderate, low, and very low, but it was mainly designed to define strength of recommendations for developing guidelines.21 By using this Quality Indicator Score, we found that the quality of the studies supporting LMWH in the

differences clinical setting is not homogeneous, with studies performed in some clinical setting showing higher scores than other. This point raised questions about the interchangeability of these products in general, and on the appropriateness of using agents that have not demonstrated efficacy and safety in the specific clinical setting we intend to prescribe them. Third, we performed an analysis of the evolution of the features of the Quality Indicator Score over time. Studies published since the years 1990 through 2000 and after the year 2000 performed better than those published before 1990. No significant difference was found between the score of studies published between years 1990 and 2000 and those published later. Finally, the evolution over time of the single items of the Quality Indicator Score showed an improvement in several items related to exclusion criteria, assessment of efficacy and safety, and statistical analysis and experimental design, and acknowledged limitations. It is interesting to note that we were unable to show any difference in the quality of the studies published before 2000 compared with those published subsequently. In the early 2000s, the application of mandatory CONSORT rules was required by the main scientific journals.28,29 Those rules, which have also inspired the score we propose, improves significantly the description of a randomized clinical trial. Nevertheless, the introduction and the more extensive Seminars in Thrombosis & Hemostasis

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Table 4 Quality indicators score assessment of studies on venous thromboembolism prophylaxis, over time

82.47

94.02

247

231

110

232

233

138

205

234

202

176

248

1. Inclusion criteria clearly described

2. Exclusion criteria clearly described

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5. Appropriateness of the experimental design: controlled study

6. Appropriateness of the experimental design: doubleblind study

7. Ethic adequacy of control treatment (e.g., active or placebo)

8. Primary and secondary endpoints of efficacy clearly defined and objectively documented

9. Safety endpoint clearly defined and objectively documented

10. In the case of surrogate endpoints (e.g., instrumental tests): accuracy of the chosen endpoint

11. Dosage and duration of drug treatment clearly described

99.60

70.92

81.27

34

12

16

29

29

19

33

32

20

28

34

100.00

35.29

47.06

85.29

85.29

55.88

97.06

94.12

58.82

82.35

100.00

“Yes” answer (%)

96

68

80

92

83

53

92

92

47

90

96

Studies (n)

100.00

70.83

83.33

95.83

86.46

55.21

95.83

95.83

48.96

93.75

100.00

“Yes” answer (%)

Since 1990 through 2000

118

96

106

113

93

66

108

108

43

113

117

Studies (n)

After 2000

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Studies (n)

Before 1990

99.17

80.99

89.26

95.04

78.51

56.20

90.91

90.91

36.36

95.04

98.35

“Yes” answer (%)

1.00

1.43

1.44

1.11

1.01

0.99

0.99

1.02

0.91

1.12

1.00

OR

0.98–1.03

1.21–1.69

1.25–1.66

1.01–1.22

0.87–1.17

0.82–1.21

0.90–1.09

0.92–1.12

0.75–1.10

1.01–1.24

0.97–1.04

95% CI

Since 1990 through 2000 vs. before 1990

0.99

1.58

1.52

1.10

0.93

1 00

0.94

0.97

0.80

1.14

0.98

OR

0.97–1.02

1.34–1.86

1.33–1.75

1.01–1.21

0.81–1.08

0.83–1.21

0.86–1.03

0.88–1.07

0.66–0.96

1.03–1.25

0.95–1.02

95% CI

After 2000 vs. before 1990

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55.78

93.63

93.23

44.22

92.83

99.20

Studies (n)

Indicators

“Yes” answer (%)

Table 5 All quality indicators of studies on venous thromboembolism prophylaxis with LMWH, over time

120 Agnelli et al.

180

17. If multivariate analysis adjusted for the effect of the treatments was not performed, the comparison groups were well balanced on basal characteristics

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71.71

60.96

59.76

72.11

56.18

13

18

30

28

0

16

3

5

32

Studies (n)

Before 1990

38.24

52.94

88.24

82.35

0

47.06

8.82

14.71

94.12

“Yes” answer (%)

69

60

63

70

17

48

50

48

94

Studies (n)

71.88

62.50

65.62

72.92

17.71

50.00

52.08

50.00

97.92

“Yes” answer (%)

Since 1990 through 2000

97

73

56

82

30

73

85

86

112

Studies (n)

After 2000

80.99

61.98

47.11

68.60

25.62

60.33

71.90

72.73

94.21

“Yes” answer (%)

1.40

1.10

0.80

0.91

1.19

1.03

1.54

1.42

1.04

OR

1.18–1.66

0.91–1.33

0.66–0.96

0.76–1.08

1.03–1.39

0.85–1.25

1.29–1.84

1.19–1.70

0.96–1.13

95% CI

Since 1990 through 2000 vs. before 1990

1.53

1.09

0.66

0.87

1.29

1.14

1.88

1.79

1.00

OR

1.30–1.81

0.91–1.32

0.55–0.79

0.73–1.03

1.12–1.50

0.94–1.38

1.58–2.23

1.50–2.13

0.93–1.08

95% CI

After 2000 vs. before 1990

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Abbreviations: OR, logistic regression model estimated odds ratio; 95% CI, 95% confidence interval for odds ratio. Note: A statistical significant association (p  0.05) is found when 1.00 is not included in the 95% CI.

20. Discussion of possible study limitations

151

47

16. Appropriateness of the statistical analysis: Multivariate analysis adjusted for the effect of the treatments

19. Percentage of patients lost to follow-up (even for safety endpoints)

19.12

137

15. Appropriateness of the statistical analysis: Analysis of efficacy according to the intention to treat

149

54.58

138

14. Appropriateness of the statistical analysis: Accurate presentation of estimates of the endpoints and results expressed in terms of confidence intervals

18. Assessment of primary endpoint in at least 85% of enrolled patients

55.78

139

13. Appropriateness of the statistical analysis: Calculation of the sample size

95.62

238

12. Duration and modality of follow-up clearly described

“Yes” answer (%)

Studies (n)

Indicators

Table 5 (Continued)

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adoption of the CONSORT do not seem to have had a significant impact on the quality of the studies on LMWHs. A limitation of our study lies in the fact that we did not perform an efficacy and safety comparison between LMWHs. As mentioned, systematic reviews and meta-analysis in different clinical settings on this topic were already published, so we chose an approach based on a methodological quality assessment of studies. In addition, the Quality Indicator Score tool we used has not been yet validated. In conclusion, differences in the number of studies and patients included as well as a large heterogeneity in the methodological quality of the prospective clinical trials supporting each of the different LMWH products currently available for VTE prophylaxis were found. These differences were more evident when considering the various clinical settings where LMWHs are used. Although several aspects of the methodological quality of studies improved over time, the question of the clinical equivalence and interchangeability of each individual LMWH product in clinical practice remains a critical issue. These data support an approach based on an accurate selection of LMWH products considering the safety and efficacy demonstrated for each agent, for each clinical indication, and at dosages derived from clinical trials.

5 Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal

Conflict of Interest Statement This article was developed independently by the authors, following an advisory board meeting sponsored by Sanofi S.p.A.

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Acknowledgments We thank Drs. Pasquale Ambrosino (Department of Clinical and Experimental Medicine, Federico II University Hospital, Naples, Italy), Laura Franco, and Maria Giulia Galli (Internal and Cardiovascular Medicine-Stroke Unit, University of Perugia, Perugia, Italy) for their support in setting up electronic databases and hand searching of eligible studies.

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Appendix 1 List of analyzed studies on venous thromboembolism prophylaxis with LMWH, by clinical settings Nonmajor orthopedic and other surgery patients 1. Agnelli G, Piovella F, Buoncristiani P, et al. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 1998;339(2):80–85 2. Dickinson LD, Miller LD, Patel CP, Gupta SK. Enoxaparin increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery 1998;43(5):1074–1081 3. Macdonald RL, Amidei C, Baron J, et al. Randomized, pilot study of intermittent pneumatic compression devices plus dalteparin versus intermittent pneumatic compression devices plus heparin for prevention of venous thromboembolism in patients undergoing craniotomy. Surg Neurol 2003;59(5):363–372, discussion 372–374 4. Gerlach R, Raabe A, Beck J, Woszczyk A, Seifert V. Postoperative nadroparin administration for prophylaxis of thromboembolic events is not associated with an increased risk of hemorrhage after spinal surgery. Eur Spine J 2004;13(1):9–13 5. Chibbaro S, Tacconi L. Safety of deep venous thrombosis prophylaxis with low-molecular-weight heparin in brain surgery. Prospective study on 746 patients. Surg Neurol 2008;70(2):117–121, discussion 121 6. Goldhaber SZ, Dunn K, Gerhard-Herman M, Park JK, Black PM. Low rate of venous thromboembolism after craniotomy for brain tumor using multimodality prophylaxis. Chest 2002;122(6):1933–1937 7. Kurtoglu M, Yanar H, Bilsel Y, et al. Venous thromboembolism prophylaxis after head and spinal trauma: intermittent pneumatic compression devices versus low molecular weight heparin. World J Surg 2004;28(8):807–811 8. Voth D, Schwarz M, Hahn K, Dei-Anang K, al Butmeh S, Wolf H. Prevention of deep vein thrombosis in neurosurgical patients: a prospective double-blind comparison of two prophylactic regimen. Neurosurg Rev 1992;15(4):289–294 9. Farkas JC, Chapuis C, Combe S, et al. A randomised controlled trial of a low-molecular-weight heparin (Enoxaparin) to prevent deep-vein thrombosis in patients undergoing vascular surgery. Eur J Vasc Surg 1993;7(5):554–560 10. Michot M, Conen D, Holtz D, et al. Prevention of deep-vein thrombosis in ambulatory arthroscopic knee surgery: A randomized trial of prophylaxis with low—molecular weight heparin. Arthroscopy 2002;18(3):257–263 11. Schippinger G, Wirnsberger GH, Obernosterer A, Babinski K. Thromboembolic complications after arthroscopic knee surgery. Incidence and risk factors in 101 patients. Acta Orthop Scand 1998;69(2):144–146 12. Wirth T, Schneider B, Misselwitz F, et al. Prevention of venous thromboembolism after knee arthroscopy with low-molecular weight heparin (reviparin): Results of a randomized controlled trial. Arthroscopy 2001;17(4):393–399 13. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of venous thromboembolism after knee arthroplasty. A randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med 1996;124(7):619–626 14. Montebugnoli M, Bugamelli S, Calò P, Zangheri E, Ferrari P. Prophylaxis of venous thromboembolism in minor orthopedic surgery with parnaparin. Clin Appl Thromb Hemost 2007;13(3):249–258 15. Zhi-jian S, Yu Z, Giu-xing Q, et al. Efficacy and safety of low molecular weight heparin prophylaxis for venous thromboembolism following lumbar decompression surgery. Chin Med Sci J 2011;26(4):221–226 16. Camporese G, Bernardi E, Prandoni P, et al; KANT (Knee Arthroscopy Nadroparin Thromboprophylaxis) Study Group. Low-molecular-weight heparin versus compression stockings for thromboprophylaxis after knee arthroscopy: a randomized trial. Ann Intern Med 2008;149(2):73–82 17. Marlovits S, Striessnig G, Schuster R, et al. Extended-duration thromboprophylaxis with enoxaparin after arthroscopic surgery of the anterior cruciate ligament: a prospective, randomized, placebo-controlled study. Arthroscopy 2007;23(7):696–702 18. Jørgensen PS, Warming T, Hansen K, et al. Low molecular weight heparin (Innohep) as thromboprophylaxis in outpatients with a plaster cast: a venografic controlled study. Thromb Res 2002;105(6):477–480 19. Kock H-J, Schmit-Neuerburg KP, Hanke J, Rudofsky G, Hirche H. Thromboprophylaxis with low-molecular-weight heparin in outpatients with plaster-cast immobilisation of the leg. Lancet 1995;346(8973):459–461 20. Lapidus LJ, Ponzer S, Elvin A, et al. Prolonged thromboprophylaxis with Dalteparin during immobilization after ankle fracture surgery: a randomized placebo-controlled, double-blind study. Acta Orthop 2007;78(4):528–535 21. Lassen MR, Borris LC, Nakov RL. Use of the low-molecular-weight heparin reviparin to prevent deep-vein thrombosis after leg injury requiring immobilization. N Engl J Med 2002;347(10):726–730 22. Spinal Cord Injury Thromboprophylaxis Investigators. Prevention of venous thromboembolism in the acute treatment phase after spinal cord injury: a randomized, multicenter trial comparing low-dose heparin plus intermittent pneumatic compression with enoxaparin. J Trauma 2003;54(6):1116–1124, discussion 1125–1126 23. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996;335(10):701–707 24. Haentjens P. Thromboembolic prophylaxis in orthopaedic trauma patients: a comparison between a fixed dose and an individually adjusted dose of a low molecular weight heparin (nadroparin calcium). Injury 1996;27(6):385–390 25. Lastória S, Rollo HA, Yoshida WB, Giannini M, Moura R, Maffei FHA. Prophylaxis of deep-vein thrombosis after lower extremity amputation: comparison of low molecular weight heparin with unfractionated heparin. Acta Cir Bras 2006;21(3):184–186 26. Perry SL, Bohlin C, Reardon DA, et al. Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients. J Neurooncol 2009;95(1):129–134 27. Samama CM, Lecoules N, Kierzek G, et al; FONDACAST Study Group. Comparison of fondaparinux with low molecular weight heparin for venous thromboembolism prevention in patients requiring rigid or semi-rigid immobilization for isolated non-surgical below-knee injury. J Thromb Haemost 2013;11(10):1833–1843 28. Nurmohamed MT, van Riel AM, Henkens CM, et al. Low molecular weight heparin and compression stockings in the

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Appendix 1 (Continued) prevention of venous thromboembolism in neurosurgery. Thromb Haemost 1996;75(2):233–238 29. Chiou-Tan FY, Garza H, Chan KT, et al. Comparison of dalteparin and enoxaparin for deep venous thrombosis prophylaxis in patients with spinal cord injury. Am J Phys Med Rehabil 2003;82(9):678–685 30. W. Janni, F. Bergauer, D. Rjosk, K. Lohscheidt, F.-W. Hagena. Prospektiv randomisierte Studie zum Vergleich der Wirksamkeit und der Vertraglichkeit verschiedener niedermolekularer Heparine bei Hochriskopatienten. Zentralbl Chir 2001;126(1):32–38. 31. Stannard JP, Lopez-Ben RR, Volgas DA, et al. Prophylaxis against deep-vein thrombosis following trauma: a prospective, randomized comparison of mechanical and pharmacologic prophylaxis. J Bone Joint Surg Am 2006;88(2):261–266 32. Kujath P, Spannagel U, Habscheid W. Incidence and prophylaxis of deep venous thrombosis in outpatients with injury of the lower limb. Haemostasis 1993;23(Suppl 1):20–26 33. Lapidus LJ, Rosfors S, Ponzer S, et al. Prolonged thromboprophylaxis with dalteparin after surgical treatment of Achilles tendon rupture: a randomized, placebo-controlled study. J Orthop Trauma 2007;21(1):52–57 34. Speziale F, Verardi S, Taurino M, et al. Low molecular weight heparin prevention of post-operative deep vein thrombosis in vascular surgery. Pharmatherapeutica 1988;5(4):261–268 35. Gossetti B, Irace L, Gattuso R, et al. Prevention of deep venous thrombosis in vascular surgical procedures by LMW-heparin. Int Angiol 1988;7(3, Suppl):25–27 36. Bergqvist D, Agnelli G, Cohen AT, et al; ENOXACAN II Investigators. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002;346(13):975–980 37. Lausen I, Jensen R, Jorgensen LN, et al. Incidence and prevention of deep venous thrombosis occurring late after general surgery: randomised controlled study of prolonged thromboprophylaxis. Eur J Surg 1998;164(9):657–663 38. 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