Risk-assessment algorithm and recommendations for venous thromboembolism prophylaxis in medical patients

Figures & data

Table 1 Classification of levels of evidence for the studies

1A Level of evidence	Studies about risk factors
A	Evidence derived from several RCTs, cohorts using screening methods for VTE and/or case-control studies suggesting that the risk factor is directly associated with the disease.
B	Evidence derives from a limited number of RCTs, cohorts and/or case-control studies, or with conflicting information and/or divergence of opinion that the risk factor is directly associated with the disease.
C	Evidence from RCTs, cohorts and/or case-control studies, that the risk factor is NOT directly associated with the disease.
1B Level of evidence	Studies about treatment, prevention or etiology
A	Evidence derived from RCTs.
B	Evidence derived from RCTs with methodologic flaws, or published only as abstracts, or nonrandomized studies, or observational registries.
C	Primary basis for the recommendations was expert’s consensus.

Abbreviations: RCTs, randomized controlled trials; VTE, venous thromboembolism.

Table 2 Classifi cation of recommendations

Strength of recommendations	Recommendations based on evidence and expert opinion
Class I	Conditions for which there is evidence for and/or agreement of opinion that the procedure (or treatment) is useful/effective.
Class II	Conditions for which there is little evidence for and/or divergence of opinion that the procedure (or treatment) is useful/effective. a The weight of evidence or opinion favors the procedure (or treatment). b Usefulness/efficacy is less established by evidence or opinion.
Class III	Conditions for which there is evidence for and/or agreement of opinion that the procedure (or treatment) is NOT useful/effective and in some cases may be harmful.

Table 3 Risk factors for VTE in medical patients according to the level of evidence

A	B
Age ≥ 55 years	Active rheumatologic diseases
AMI	Inflammatory bowel diseases
Cancer	Infections
Chemotherapy	Obesity
CHF class III or IV	Peripheral arterial insufficiency
CVC and PAC	Reduced mobility
HCVA	Varices/chronic venous insufficiency
Hormonotherapy
HRT and HC
ICU admission
ICVA
Nephrotic syndrome
Paresis/paralysis of legs
Pregnancy and puerperium
Previous VTE
Severe respiratory diseases
Thrombophilias

Abbreviations: AMI, acute myocardial infarction; CHF, congestive heart failure; CVC, central venous catheters for general use and hemodialysis catheters; HC, hormonal contraceptives; HCVA, hemorrhagic cerebral vascular accident; HRT, hormonal replacement therapy; ICU, intensive care unit; ICVA, ischemic cerebral vascular accident; PAC, pulmonary artery catheters; VTE, venous thromboembolism.

Table 4 Frequency of DVT in hospitalized patients according to their medical condition

Condition	DVT (%)
CVA	28–75
CHF class III or IV	15–71
AMI	10–63
Nephrotic syndrome	14–43
ICU admission	25–31
Active rheumatologic diseases	10–30
Severe respiratory diseases	9–29
Infection	7–16

Abbreviations: AMI, acute myocardial infarction; CVA, cerebral vascular accident; CHF, congestive heart failure; DVT, deep venous thrombosis; ICU, intensive care unit.

Note: Frequency based on studies using screening for DVT in patients without prophylaxis.

Table 5 Relative risk for VTE in different neoplasias

Origin	Patients with VTE	Total of patients	RR (95% CI)
Head and neck	35	20,924	0.29 (0.2–0.4)
Bladder	180	74,517	0.42 (0.36–049)
Breast	469	186,273	0.44 (0.4–0.48)
Esophagus	64	147,42	0.76 (058–0.97)
Cervix	53	102,36	0.90 (0.68–1.18)
Liver	121	229,38	0.92 (0.76–1.110)
Prostate	1230	218,743	0.98 (0.93–1.04)
No cancer	46.848	8,177,634	1.0
Rectum	417	65,837	1.11 (1.0–1.22)
Lung	1.504	232,764	1.13 (1.07–119)
Colon	1.320	168,832	1.36 (1.29–1.44)
Renal	278	34,376	1.41 (1.25–1.59)
Stomach	280	32,655	1.49 (1.33–1.68)
Lymphoma	537	52,042	1.80 (1.65–1.96)
Pancreas	488	41,551	2.05 (1.87–2.24)
Ovarium	327	26,406	2.16 (1.93–2.41)
Leukemia	591	47,234	2.18 (2.01–2.37)
Brain	184	13,529	2.37 (2.04–274)
Uterus	226	11,606	3.34 (2.97–3.87)

Table 6 Factors associated with venous thrombosis in patients with catheters

Variables	Relative risk
Catheterization of femoral vein1	4.7–6.0 (OR 7.7–23.5)
Catheterization of axilary, subclavian or internal jugular veins2	3.9–11.6
Catheterization of femoral vein vs. subclavian or internal jugular veins3	4.7–7.4
Catheterization of internal jugular vein vs. subclavian vein4	4.1
Catheterization of left subclavian vein vs. right subclavain vein5	1.2
Infusion of parenteral nutrition vs.	2.6
other solutions6
Catheter material (polyvinyl or polyethylene vs. polyurethane or silicone)7	3.6–6.0
Catheter duration8	1.04
Number of attempts to insertion (one vs. two)9	11.8
Long-term central catheters vs. long-term peripherakl catheters10	2.2
Catheters in patients with anti-thrombin III deficiency11	OR 8.4
Catheters in patients with factor V Leiden12	2.3

1 Notes:(Trottier et al 1995; Durbec et al 1997a; Mian et al 1997; Joynt et al 2000)

2 (Kerr et al 1990; Martin et al 1999)

3 (Trottier et al 1995; Merrer et al 2001)

4 (De et al 1997; Timsit et al 1998)

5 (Gould et al 1993; De et al 1997)

6 (Koksoy et al 1995)

7 (Bozzetti et al 1983; Monreal et al 1994)

8 (Brismar et al 1981; Ibrahim et al 2002)

9 (Koksoy et al 1995)

10 (Kuriakose et al 2002)

11 (Lokich and Becker, 1983; De et al 1995)

12 (Van Rooden et al 2004)

Table 7 Reduced mobility as a risk factor for VTE

Degree of immobility	OR	95% CI	P
Normal	1.0	-	-
Limited	1.73	1.08–2.75	0.02
Wheel-chair ≥ 30 days	2.43	1.37–4.30	0.002
Bedrest ≥ 30 days	2.73	1.20–6.20	0.02
Wheel-chair 15–30 days	3.33	1.26–8.84	0.02
Bedrest 15–30 days	3.37	1.00–11.29	0.05
Wheel-chair <15 days	4.32	1.50–12.45	0.007
Bedrest <15 days	5.64	2.04–15.56	0.0008

Table 8 Annual incidence and VTE risk in hereditary thrombophilias

Author, year	Patients/controls	Design	ATIII	PC	PS	FVL	MPG	Combination
Finazzi and Barbui 1994	28/53†	PC/8 years	12.0%	2.80%	3.30%	-	-	-
Pabinger et al 1994	44/49	PC	-	2.50%	3.50%	-	-	-
Koster et al 1995	474/474	CC	OR 2.2–5.0	OR 3.1–6.5	OR 0.7–1.6§	-	-	-
Poort et al 1996	442/463	CC	-	-	-	-	OR 2.8	-
Kapur et al 1997	50/50	CC	-	-	-	-	OR 11.5	-
Hillarp et al 1997	99/282	CC	-	-	-	-	OR 3.8	-
Cumming et al 1997	219/164	CC	-	-	-	-	OR 5.4	-
Brown et al 1997	504	RC	-	-	-	OR 5.8	OR 2.0	-
Faioni et al 1997	327/317	CC	-	-	OR 2.4	-	-	-
Leroyer et al 1998	366/400	CC	-	-	-	x	OR 3.7	OR 4.8
Souto et al 1998	116/201	CC	-	-	-	-	OR 3.1	-
Middeldorp et al 1998	437	RC	-	-	-	0.45%. RR 4.2	-	-
Martinelli et al 1998	150/723	RC	RR 8.1	RR 7.3	RR 8.5	RR 2.2	-	-
Mateo et al 1998	583	RC	OR 21.2	OR 12.6	OR 19.9	-	-	OR 9.0
Sanson et al 1999	94/208†	PC/3 years	1.60%	1.00%	0.40%	-	-	-
Bucciarelli etal (1999)	233/513	RC	1.07%	0.54%	0.50%	0.30%
Simioni et al 1999	793	RC	x	x	x	0.11%. RR 2.5		0.40%. RR 10.6
Rodeghiero and Tosetto 1999	15109	TC	-	OR 1.7	-	RR 3.3	-	-
van Boven et al 1999	48/44	CC	1.10%	-	-	x	x	4.60%
Aznar et al 2000	229/246	CC	-	-	-	OR 6.9	OR 2.4	-
Lensen et al 2000	233	RC	-	-	-	0.56%	-	-
Middeldorp et al 2001	247/470†	PC/3.3 years	-	-	-	0.58%	-	-
Folsom et al 2002^a	14358	PC/8.1 years		RR 3.36
Folsom et al 2002^b	335/668	CC	-	-	-	OR 3.7	-	-
Simioni et al 2002	131/313-248*	PC/4 years	-	-	-	0.17%. RR 6.6	-	-
Oger et al 2002^b	621/406	CC	-	-	-	OR 3.2¥	-	-
Vossen et al 2004	846/1212	CC	-	x	x	0.15%	-	0.84%

Abbreviations: ATIII, antithrombin III deficiency; CC, case-control; FVL, factor V Leiden; MPG, mutation of the prothrombin gene; OR, odds ratio; PC, prospective cohort; PC, protein C; PS, protein S; RC, retrospective cohort; RR, relative risk; TC, transversal cohort.

† Notes: Patients/asymptomatic holders

* Patients/asymptomatic holders-controls

§ Not a risk factor

¥ Not a risk factor for age >70 years (OR 0.8; 95% CI 0.4–1.7): Thrombophilias evaluated in combination.

Figure 1 Algorithm for VTE prevention in hospitalized medical patients.

Table 9 Evidence-based recommendations for VTE prophylaxis in patients with specific medical conditions Ψ

Condition	Method	Evidence	Recommendation	Dose
Previous VTE +	LDUH	C1	I	5.000 IU 8–8h
risky condition	LMWH	C2	I	Dalteparin (5.000 IU/day) or enoxaparin (40 mg/day)
Chronic venous insufficiency/varices	Enoxaparin	A3	IIa	40 mg/day
	Dalteparin	A4	IIa	5.000 IU/day
Obesity + risky conditions	Enoxaparin	B5	IIa	40 mg/day
	Dalteparin	A6	IIa	5.000 IU/day
Thrombophilias + risky conditions	LDUH, LMWH or Warfarin	B7	I	5.000 IU 8+8h or dalteparin (5.000 IU/day) or enoxaparin (40 mg/day) or warfarin (RNI 2+3)
HRT/HC + risky conditions	LDUH	C8	I	5.000 IU 8–8h
	LMWH	C9	I	Dalteparin (5.000 IU/day) or enoxaparin (40 mg/day)
CHF	LDUH	A10	I	5.000 IU 8–8h
	Enoxaparin	A11	I	40 mg/day
	Dalteparin	A12	I	5.000 IU/day
AMI	LDUH	B13	I	5.000 IU 12–12h or full dose
	Dalteparin	B14	I	120 IU/Kg
	Ambulation	B15	IIa	–
	ES	B16	IIa	–
Ischemic CVA	LDUH*	A17	I or III	5.000 IU 8–8h or 12–12h
	LMWH*	B18	I or III	Dalteparin (2.500 IU 12–12h) or enoxaparin (40 mg/day)
	ES* *	B19	IIb	–
	IPC + LDUH* * *	B20	IIb	IPC + HNF 5.000 IU 12–12h
Hemorrhagic CVA	INITIAL phase:
	LDUH or LMWH	B21	III	CONTRAINDICATED
	ES/IPC* * and * * *	B22	IIb	–
	LATE phase:	C23	IIb	–
	LDUH or LMWH* * * *
Acute rheumatological diseases/IBD	Enoxaparin	B24	I	40 mg/day
	Dalteparin	A25	I	5.000 IU/day
Severe respiratory diseases	LDUH	A26	I	5.000 IU 8–8h
	Enoxaparin	A27	I	40 mg/day
	Dalteparin	A28	I	5.000 IU/day
	ES	B29	IIa	Continuous
Infections	LDUH	B30	I	5.000 IU 8–8h or 12–12h
	Enoxaparin	A31	I	40 mg/day
	Dalteparin	A32	I	5.000 IU/day
Nephrotic syndrome	Enoxaparin	B33	I	40 mg/day
Neoplasias	Enoxaparin	B34	IIa	40 mg/day
Admission to ICU	LDUH	B35	I	5.000 IU 12–12h
	Enoxaparin	B36	I	40 mg/day
	Nadroparin	B37	I	3.800 IU or 5.700 IU/day
	ES/IPC* * and * * *	B38	IIa	–
CVC for PN	LDUH	A39	IIb	5.000 IU 6–6h or 12–12h SC, or 1U/mL – 3 U/mL in PN
CVC in cancer	Dalteparin	A40	I	2.500 IU/day
patients†	Nadroparin	B41	IIa	2.850UI a 7.600 IU/day
	Warfarin* * * * *	B41	IIb	1mg/day

Notes: §Nadroparin and LDUH were equivalent, but more patients in the nadroparin group died (2.8% vs 1.2%; p = 0.02)

† In cancer patients, hospitalized and with reduced mobility, prevail the recommendations related to the clinical situation not to the catheter.

* In patients with a well defined deficit with reduced mobility, and cerebral hemorrhage excluded with CT or NMR – RECOMMENDATION I. RECOMMENDATION III for systematic use in all patients due to the increased risk of bleeding.

* * Lower efficacy in very high-risk patients.

* * * Attention to the IPC contraindications, like arterial peripheral disease.

* * * * Prophylaxis may be considered after 10 days of the onset, provided patient is clinically and radiologically stable.

* * * * * Patients with high risk for bleeding must be excluded (liver metastasis or use of fluoracil and derivates).

Ψ High prophylactic doses: LDUH 5.000 IU every 8 hours, enoxaparin 40 mg daily, dalteparin 5.000 IU daily or nadroparin (3.800 IU for <70 kg and 5.700 IU ≥70 kg) daily are the ones recommended (GRADE I) for most hospitalized edical patients on the algorithm.

Abbreviations: CHF congestive heart failure; AMI, acute myocardial infarction; CVA, cerebral vascular accident; ARD, active rheumatological disease; IBD, inflammatory bowel disease; ICU, intensive care unit; VTE, venous thromboembolism; LMWH, low molecular weigh heparin, LDUH, low dose unfractionated heparin; ES, elastic stockings; IPC, intermittent pneumatic compression; CVC, central venous catheter and PN, parenteral nutrition.

1 Citations: (Harenberg et al 1996)

2 (Samama et al 1999; Leizorovicz et al 2004)

3 (Alikhan et al 2003)

4 (Leizorovicz et al 2004)

5 (Alikhan et al 2003)

6 (Leizorovicz et al 2004)

7 (Sanson et al 1999; Simioni et al 1999)

8 (Harenberg et al 1996)

9 (Leizorovicz et al 1999)

10 (Belch et al 1981; Harenberg et al 1996, 1999; Lechler et al 1996; Kleber et al 2003)

11 (Lechler et al 1996; Harenberg et al 1999; Samama et al 1999; Kleber et al 2003)

12 (Leizorovicz et al 2004)

13 (Emerson and Marks 1977; Pitt et al 1980; Zawilska et al 1989; Scala et al 1990)

14 (Scala et al 1990)

15 (Miller et al 1976)

16 (Kierkegaard and Norgren 1993)

17 (McCarthy et al 1977; McCarthy and Turner 1986; Sandercock et al 1993; IST 1997; Bath et al 2000)

18 (Prins et al 1989; Hillbom et al 1999; Bath et al 2000; Counsell and Sandercock 2001)

19 (Prasad et al 1982; Muir et al 2000; Mazzone et al 2004)

20 (Kamran et al 1998)

21 (Dickmann et al 1988; Boeer et al 1991)

22 (Prasad et al 1982; Kamran et al 1998; Muir et al 2000; Mazzone et al 2004)

23 (Dickmann et al 1988; Boeer et al 1991)

24 (Alikhan et al 2003)

25 (Leizorovicz et al 2004)

26 (Belch et al 1981; Ibarra-Perez et al 1988; Kleber et al 2003)

27 (Harenberg et al 1999; Alikhan et al 2003; Kleber et al 2003)

28 (Leizorovicz et al 2004)

29 (Ibarra-Perez et al 1988)

30 (Gardlund 1996; Harenberg et al 1996)

31 (Samama et al 1999)

32 (Leizorovicz et al 2004)

33 (Sarasin and Schifferli 1994; Rostoker et al 1995)

34 (Alikhan et al 2003; Zangari et al 2004)

35 (Cade 1982; Kapoor et al 1999; Goldhaber et al 2000)

36 (Goldhaber et al 2000)

37 (Fraisse et al 2000)

38 (Ibarra-Perez et al 1988; Cook et al 2000; Jimenez et al 2001; Rocha et al 2003)

39 (Randolph et al 1998; Klerk et al 2003)

40 (Monreal et al 1996; Klerk et al 2003)

41 (Van Rooden et al 2004)

⁴²(Bern et al 1990; Couban et al 2002; Heaton et al 2002; Klerk et al 2003).

Table 10 The most common diseases and risk factors for VTE found in four large RCTs about efficacy of prophylaxis in hospitalized medical patients1–4

Disease/Risk factor	%
Congestive heart failure	30–52
Respiratory disease	24–53
Infection	20–54
Obesity	27–53
Varices	22–27
Cancer	4.6–20
Active rheumatologic disease	7.6–11
Past history of VTE	3.4–8.4
Estrogen therapy	1.4–1.8
Bowel inflammatory disease	0.5–0.8

1 Notes: Harenberg et al 1996

2 Lechler et al 1996

3 Samama et al 1999

4 Leizorovicz et al 2004.

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