Effects of interventions
None of the studies evaluated similar treatments on the same study outcomes. Treatment ranged from fondaparinux, LMWH, unfractionated heparin (UFH), NSAIDs, topical treatment, oral treatment, intramuscular treatment, and intravenous treatment to surgery.
The CALISTO study, a large double-blinded, placebo-controlled RCT, evaluated a prophylactic dose (2.5 mg sc once daily) of fondaparinux given for 45 days (Decousus 2010a). The primary efficacy outcome of this RCT (that is, the composite of death from any cause, symptomatic PE, symptomatic DVT, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of ST up to day 47) was reduced by 85% by fondaparinux (RR 0.15; 95% CI 0.08 to 0.26) with a number needed to treat (NNT) of 20. The incidence of each component of the primary efficacy outcome was significantly reduced in the fondaparinux group as compared with the placebo group except for the incidence of death, which did not differ significantly between the two groups (see Analysis 1.6). The risk of the composite of symptomatic DVT or PE was reduced by 85% with fondaparinux as compared with placebo (RR 0.15; 95% CI 0.04 to 0.50) with a NNT of 88. Fondaparinux was associated with lower rates of extension (RR 0.08; 95% CI 0.03 to 0.22) and recurrence of ST (RR 0.21; 95% CI 0.08 to 0.54). By day 47, major bleeding had occurred in one patient (0.1%) in each group (RR 0.99; 95% CI 0.06 to 15.86; P = 1.00). The rate of clinically relevant non-major, minor, and total bleeding and arterial thromboembolic complications did not differ significantly between the two groups.
Low molecular weight heparin (LMWH) and unfractionated heparin (UFH)
Thirteen studies included a LMWH group (Belcaro 1989; Belcaro 1990; Belcaro 1999; Cosmi 2012; Gorski 2005; Katzenschlager 2003; Lozano 2003; Marchiori 2002; Rathbun 2012; Stenox Group 2003; Titon 1994; Uncu 2009; Vesalio Group 2005).
Although not statistically significant, the incidence of VTE tended to be lower with both prophylactic and therapeutic LMWH compared with placebo shortly after treatment (RR 0.25; 95% CI 0.03 to 2.24 and RR 0.26; 95% CI 0.03 to 2.33, respectively) but not at the end of the three-month follow-up (RR 1.22; 95% CI 0.38 to 3.89 and RR 0.85; 95% CI 0.23 to 3.06, respectively), suggesting a catch-up phenomenon (Stenox Group 2003). Prophylactic and therapeutic LMWH given for eight to 12 days significantly reduced ST extension or recurrence, or both, compared with placebo (RR 0.44; 95% CI 0.26 to 0.74 and RR 0.46; 95% CI 0.27 to 0.77, respectively). No episodes of major bleeding or heparin-induced thrombocytopenia (HIT) were observed in any treatment group (Stenox Group 2003).
Combined therapy with LMWH plus elastic compression stockings seemed to reduce the incidence of VTE and ST extension or recurrence, or both, compared with elastic stockings alone (RR 0.08; 95% CI 0.00 to 1.38 and RR 0.08; 95% CI 0.01 to 0.59, respectively), although the former difference was not statistically significant (Belcaro 1999). In this study no data were provided on safety outcomes.
Two studies (Gorski 2005; Katzenschlager 2003) randomised patients to topical treatment with heparin spray gel or LMWH. A non-significant decrease in DVT was found with LMWH (RR 0.30; 95% CI 0.03 to 2.70) while local symptoms were similarly relieved by both treatments at 21 days (Gorski 2005).
LMWH versus surgical treatment (saphenofemoral disconnection) was evaluated in one study (Lozano 2003). A comparable reduction of VTE events and a similar safety profile were observed in the two study groups. Surgery seemed to be associated with a lower risk of ST extension or recurrence, or both, although the differences were not statistically significant (RR 0.33; 95% CI 0.04 to 3.03).
LMWH was evaluated against NSAIDs in three studies (Rathbun 2012; Stenox Group 2003; Titon 1994). Fixed-dose LMWH and weight-adjusted LMWH seemed to produce a similar reduction in VTE (RR 0.93; 95% CI 0.24 to 3.63) and ST recurrence relative to NSAIDs (RR 1.01; 95% CI 0.58 to 1.78). In the study by Rathbun 2012 there was one case of ST progression into the posterior tibial veins and one symptomatic PE, both in the LMWH group. Rathbun 2012 was not pooled with the other two studies for the outcome VTE since the administration of therapeutic LMWH in any patient with thrombus progression during follow-up could have introduced significant confounding. In Stenox Group 2003, which used placebo as a control group, an indirect comparison between prophylactic LMWH and NSAIDs suggested a non-statistically significant reduction in VTE at the end of treatment (RR 0.45; 95% CI 0.04 to 4.89). No major bleeding events nor HIT occurred within the LMWH or NSAIDs groups. Rathbun 2012 reported two episodes of cutaneous rash with LMWH. In addition, a significant reduction in pain was reported in both the LMWH and NSAIDs groups without differences between the two groups.
One study compared LMWH alone versus LMWH combined with the anti-inflammatory agent acemetacin (Uncu 2009). There were no cases of VTE, extension of ST, nor major bleeding in either study group. Combined LMWH plus acemetacin was associated with a significant 10% reduction in pain (mean difference 0.90; 95% CI 0.18 to 1.62).
Two studies compared different regimens of LMWH head-to-head but without using a placebo or inactive control group (Cosmi 2012; Vesalio Group 2005). In Cosmi 2012 (the STEFLUX study), the incidence of symptomatic VTE at the end of treatment and at the three-month follow-up was not different in the 30-day intermediate dose LMWH and 30-day prophylactic dose LMWH groups (see Analysis 4.1; Analysis 4.2), and it was lower in the 30-day intermediate dose LMWH compared with the 10-day intermediate dose LMWH (0.46% versus 4.72%, RR 0.10; 95% CI 0.01 to 0.75; and 1.82% versus 5.19%, RR 0.35; 95% CI 0.11 to 1.09, respectively). At the three-month follow-up, symptomatic PE had occurred in none of the patients of the 30-day intermediate dose group and in one patient of both the 10-day intermediate and 30-day prophylactic dose LMWH groups. The incidence of symptomatic DVT did not differ between the three groups (see Analysis 4.4; Analysis 5.4; Analysis 6.4). ST extension at three months was significantly reduced by the 30-day intermediate dose LMWH in comparison to both the 30-day prophylactic (2.28% versus 8.29%, RR 0.28; 95% CI 0.10 to 0.73) and 10-day intermediate dose LMWH (10.38%, RR 0.22; 95% CI 0.08 to 0.57) while recurrence of ST was similar in the 30-day intermediate dose LMWH and the other two groups (see Analysis 4.6; Analysis 6.6). There were no cases of major bleeding nor HIT. The intensity of local symptoms evaluated by visual analogue scales was comparable in the 30-day intermediate, 10-day intermediate, and the 30-day prophylactic dose LMWH at the start of treatment (5.0, 5.1, 5.1; P = 0.97) as well as at the end of treatment (0.7, 0.6, 0.8; P = 0.10) and at three months (0.2, 0.3, 0.4; P = 0.47). Allergic reactions occurred in 0.4%, 1.4%, and 0%, respectively.
In the Vesalio Group 2005, one-month of weight-adjusted full therapeutic dose of LMWH or fixed prophylactic dose LMWH led to a similar reduction in ST extension or recurrence, or VTE (RR 1.20; 95% CI 0.42 to 3.40) over a three-month follow-up. In the prophylactic dose LMWH group most of the VTE events (77%) occurred while patients were still on treatment, whereas only 33% of patients on therapeutic dose LMWH developed VTE during LMWH administration. This advantage was lost after drug discontinuation with no difference at the end of the study period. No major bleeding nor HIT were observed during the study. Local symptoms and signs regressed faster with therapeutic dose LMWH although the difference was not statistically significant.
Subcutaneous (sc) UFH at prophylactic doses was used as the comparator treatment in two studies (Belcaro 1999; Marchiori 2002). Relative to elastic stockings alone, prophylactic sc UFH plus elastic stockings was associated with a non-statistically significant lower VTE rate (RR 0.08; 95% CI 0.00 to 1.47) and a 83% reduction in ST extension or recurrence (RR 0.17; 95% CI 0.04 to 0.72) (Belcaro 1999). One study compared high- versus low-dose sc UFH. A non-significant 83% reduction in VTE (RR 0.17; 95% CI 0.02 to 1.30) and a 27% (RR 0.73; 95% CI 0.34 to 1.55) reduced rate of ST extension or recurrence were observed among patients treated with high-dose UFH (Marchiori 2002). There were no episodes of major bleeding or HIT in either study group.
Subcutaneous calcium heparin was evaluated in two studies (Belcaro 1989; Belcaro 1990). The combination of elastic stockings plus calcium heparin did not significantly improve local symptoms and signs compared with elastic stockings alone. Treatment with calcium heparin was correlated with a faster reduction of the analogue score and the area at maximum temperature than with defibrotide, although the difference was not significant. There were no side effects.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Six studies included a NSAID group (Anonymous 1970; Ferrari 1992; Nusser 1991; Rathbun 2012; Stenox Group 2003; Titon 1994). Of these, two compared NSAIDs with placebo (Anonymous 1970; Stenox Group 2003), three with LMWH (Rathbun 2012; Stenox Group 2003; Titon 1994), and two randomised patients to two different NSAIDs (Ferrari 1992; Nusser 1991). The trials comparing NSAIDs versus LMWH have been discussed previously (Rathbun 2012; Stenox Group 2003; Titon 1994).
NSAIDs significantly reduced the risk of ST extension or recurrence, or both, by 54% (RR 0.46; 95% CI 0.27 to 0.78) compared with placebo (Stenox Group 2003). However, there were no differences in the incidence of VTE or in the resolution of local symptoms and signs. While no major bleeding episodes were recorded in any of the NSAID or placebo groups, indomethacin carried a significantly higher rate of side effects compared with placebo (RR 2.60; 95% CI 0.95 to 7.08) (Anonymous 1970).
In one study, oral acemetacin led to a better resolution of the local clinical picture than diclofenac (Nusser 1991). Another trial compared nimesulide with diclofenac sodium (Ferrari 1992). Local symptoms were similarly improved by both treatments. In the group of patients randomised to nimesulide, a lower incidence of gastric pain episodes was evident (RR 0.25; 95% CI 0.03 to 2.08) although this difference was not statistically significant (Ferrari 1992).
Nine studies included a topical treatment group (Belcaro 2011; De Sanctis 2001; Gorski 2005; Holzgreve 1989; Incandela 2001; Katzenschlager 2003; Nocker 1991; Pinto 1992; Winter 1986). The comparison of heparin spray gel versus LMWH has been discussed earlier (Gorski 2005; Katzenschlager 2003).
Belcaro 2011 randomised patients to three doses of an heparin spray gel versus placebo for seven to 14 days. After one week, heparin spray gel was associated with a significant reduction in pain assessed by the visual analogue scale (VAS) (-93.13 versus -61.35; P < 0.0001), a lower erythema extension (-92% versus -26%; P < 0.012), and thrombus length (-40.81 versus -4.22; P < 0.0001). No adverse events or drug related reactions were reported by the authors.
One study randomised patients to receive topical methylthioadenosine or placebo (Pinto 1992). Methylthioadenosine was associated with a non-significant reduction in local signs and symptoms relative to placebo.
In a similar way, a significant improvement in the local symptomatology was observed with diclofenac gel (Nocker 1991) and essaven gel (De Sanctis 2001; Incandela 2001) compared with placebo.
Holzgreve 1989 and Winter 1986 compared two different types of gel. Holzgreve 1989 evaluated diclofenac gel versus etofenak gel and showed a comparable efficacy profile of the two topical medications. Winter 1986 compared diclofenac gel and heparin gel and found a better efficacy with the former.
None of the studies evaluating a topical treatment reported data on VTE or ST recurrence.
Three studies included a surgical treatment (Belcaro 1989; Belcaro 1999; Lozano 2003). As described above, one study compared surgery (saphenofemoral disconnection) with LMWH (Lozano 2003). In the remaining two studies surgery combined with elastic stockings was compared with elastic stockings alone (Belcaro 1989; Belcaro 1999).
In the first trial, thrombectomy plus elastic stockings with or without venoruton led to an improvement of the local clinical signs and a greater reduction in the number of veins with ST compared with elastic compression bandages alone (Belcaro 1989). There were no cases of DVT in either study group. In the second trial, ligation of the vein plus elastic stockings was associated with a non-significant reduction in VTE events (RR 0.33; 95% CI 0.07 to 1.60) and ST recurrence and extension (RR 0.46; 95% CI 0.18 to 1.15) relative to the control treatment (Belcaro 1999).
Compared with elastic stockings alone, venous stripping plus elastic stockings decreased the risk of ST extension and recurrence (RR 0.09; 95% CI 0.01 to 0.64) and seemed to be associated with a lower, while non-significant incidence of VTE (RR 0.37; 95% CI 0.08 to 1.78) (Belcaro 1999).
Eight studies evaluated an oral (Archer 1977; Belcaro 1989; Belcaro 1999; Koshkin 2001; Kuhlwein 1985; Messa 1997), intramuscular (Andreozzi 1996), or intravenous (Marshall 2001) treatment.
Compared with placebo, oral vasotonin was associated with a higher proportion of patients who were cured or improved (Kuhlwein 1985). The criteria to determine the response to study treatment were not described. Vasotonin seemed to be well tolerated, with one case of poor tolerability among patients treated with vasotonin (3%) versus five cases (13%) in the placebo arm (RR 0.20; 95% CI 0.02 to 1.63).
The combination of venoruton, thrombectomy, and elastic stockings versus elastic stockings alone has been discussed above (Belcaro 1989). In the same trial, venoruton combined with elastic stockings led to an improvement of local symptoms compared with elastic stockings alone.
One study evaluating oral heparansulphate versus oral sulodexide suggested a greater decrease in local pain, itching, and redness in patients receiving oral heparansulphate than in the group receiving sulodexide (Messa 1997).
Compared with placebo, oxyphenbutazone reduced local tenderness four-fold and halved the intensity of pain and erythema (Archer 1977).
Oral vitamin K antagonists in combination with elastic stockings were evaluated in one study, which suggested a non-significant reduction in VTE events (RR 0.08; 95% CI 0.00 to 1.47) and ST extension or recurrence (RR 0.42; 95% CI 0.16 to 1.13) with the use of vitamin K antagonists and elastic stockings relative to elastic stockings alone (Belcaro 1999).
Two studies addressed the use of enzyme therapy versus placebo (Koshkin 2001; Marshall 2001). Enzyme treatment seemed to improve local symptoms although the criteria to evaluate the response to study treatment were not reported.
The efficacy of three doses of desmin was assessed in one trial (Andreozzi 1996). A better control of local symptoms was obtained with higher doses of desmin without any increase in the risk of adverse events.