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Superficial thrombophlebitis of the legs: still a lot to learn

2005; Elsevier BV; Volume: 3; Issue: 6 Linguagem: Inglês

10.1111/j.1538-7836.2005.01445.x

1538-7933

Hervé Decousus, Alain Leizorovicz,

Central Venous Catheters and Hemodialysis

The controlled clinical trial published in this issue [1The Vesalio Investigators GroupHigh vs. low doses of low‐molecular‐weight heparin for the treatment of superficial vein thrombosis of the legs: a double blind, randomized trial.J Thromb Haemost. 2005; 3: 1152-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] represents a new contribution to the treatment of superficial thrombophlebitis (ST) of the legs, a pathology in which this kind of trial is rare. Also known as superficial vein thrombosis, ST is a frequent pathology, but its exact incidence remains to be determined, and up to now it has been the object of few studies [2Decousus H. Epinat M. Guillot K. Quenet S. Boissier C. Tardy B. Superficial vein thrombosis: risk factors, diagnosis, and treatment.Curr Opin Pulm Med. 2003; 9: 393-7Crossref PubMed Scopus (100) Google Scholar, 3Becker F. Thrombose veineuse superficielle et thrombose veineuse profonde: maladies distinctes ou continuum.STV. 1994; 6: 403-5Google Scholar, 4Leon L. Giannoukas A.D. Dodd D. Chan P. Labropoulos N. Clinical significance of superficial vein thrombosis.Eur J Vasc Endovasc Surg. 2005; 29: 10-7Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar]. Superficial thrombophlebitis of the legs is by far the most common form of ST. In 60%–80% of such cases, ST is localized in the greater saphenous vein, in 10%–20% in the lesser saphenous vein and in 10%–20% in other veins of the legs, occurring bilaterally in 5%–10% [5Lutter K.S. Kerr T.M. Roedersheimer L.R. Lohr J.M. Sampson M.G. Cranley J.J. Superficial thrombophlebitis diagnosed by duplex scanning.Surgery. 1991; 110: 42-6PubMed Google Scholar, 6Barrelier M.T. Thromboses veineuses superficielles des membres inférieurs.Actualités Vasculaires Internationales. 1993; 17: 7-9Google Scholar]. Superficial thrombophlebitis may also develop in the chest wall or the penis (Mondor disease) or in the upper limbs and the neck [7Samlaska C.P. James W.D. Superficial thrombophlebitis. II. Secondary hypercoagulable states.J Am Acad Dermatol. 1990; 23: 1-18Abstract Full Text PDF PubMed Google Scholar]. With regard to etiology, there are evident links between ST and thromboembolism of the deep veins (VTE); the risk factors are common to both these pathologies [2Decousus H. Epinat M. Guillot K. Quenet S. Boissier C. Tardy B. Superficial vein thrombosis: risk factors, diagnosis, and treatment.Curr Opin Pulm Med. 2003; 9: 393-7Crossref PubMed Scopus (100) Google Scholar, 4Leon L. Giannoukas A.D. Dodd D. Chan P. Labropoulos N. Clinical significance of superficial vein thrombosis.Eur J Vasc Endovasc Surg. 2005; 29: 10-7Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar] and ST is itself a risk factor for the development [8Heit J.A. Silverstein M.D. Mohr D.N. Petterson T.M. Lohse C.M. O'Fallon W.M. Melton LJ, I.I.I. The epidemiology of venous thromboembolism in the community.Thromb Haemost. 2001; 86: 452-63Crossref PubMed Google Scholar] and relapse [9Schönauer V. Kyrle P.A. Weltermann A. Minar E. Bialonczyk C. Hirschl M. Quehenberger P. Schneider B. Partsch H. Eichinger S. Superficial thrombophlebitis and risk for recurrent venous thromboembolism.J Vasc Surg. 2003; 37: 834-8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] of VTE. As for VTE, there is a close relationship between ST and thrombophilia [10Martinelli I. Cattaneo M. Taioli E. De Stefano V. Chiusolo P. Mannucci P.M. Genetic risk factors for superficial vein thrombosis.Thromb Haemost. 1999; 82: 1215-7Crossref PubMed Google Scholar, 11De Moerloose P. Wutschert R. Heinzmann M. Perneger T. Reber G. Bounameaux H. Superficial vein thrombosis of lower limbs: influence of factor V Leiden, factor II G20210A and overweight.Thromb Haemost. 1998; 80: 239-41Crossref PubMed Google Scholar, 12De Godoy J.M. Batigalia F. Braile D.M. Superficial thrombophlebitis and anticardiolipin antibodies. Report of association.Angiology. 2001; 52: 127-9Crossref PubMed Google Scholar] or autoimmune diseases [7Samlaska C.P. James W.D. Superficial thrombophlebitis. II. Secondary hypercoagulable states.J Am Acad Dermatol. 1990; 23: 1-18Abstract Full Text PDF PubMed Google Scholar]. The links between cancer and ST seem less clear than for VTE, but there is a dearth of studies focusing on this issue [6Barrelier M.T. Thromboses veineuses superficielles des membres inférieurs.Actualités Vasculaires Internationales. 1993; 17: 7-9Google Scholar, 13Trousseau A. Phlegmasia alba dolens.Clinique Médicale de l'Hôtel‐Dieu de Paris. JB Ballière, 1864: 654-712Google Scholar, 14Bergqvist D. Jaroszewski H. Deep vein thrombosis in patients with superficial thrombophlebitis of the leg.BMJ. 1986; 292: 658-9Crossref PubMed Google Scholar]. There are nevertheless two major differences between ST and VTE. First of all, venous insufficiency with varicose veins is much more common in the context of ST (70% of cases) [5Lutter K.S. Kerr T.M. Roedersheimer L.R. Lohr J.M. Sampson M.G. Cranley J.J. Superficial thrombophlebitis diagnosed by duplex scanning.Surgery. 1991; 110: 42-6PubMed Google Scholar, 6Barrelier M.T. Thromboses veineuses superficielles des membres inférieurs.Actualités Vasculaires Internationales. 1993; 17: 7-9Google Scholar], representing a crucial factor in the etiology of this disease, in contrast to VTE. Secondly, ST is characterized by a much lower comorbidity, as reflected by 3‐month mortality rates, respectively 01%–1% for ST [6Barrelier M.T. Thromboses veineuses superficielles des membres inférieurs.Actualités Vasculaires Internationales. 1993; 17: 7-9Google Scholar, 15Gillet J.L. Perrin M. Cayman R. Thromboses veineuses superficielles des membres inférieurs: etude prospective portant sur 100 patients.J Mal Vasc. 2001; 26: 16-22PubMed Google Scholar, 16The STENOX Study GroupA randomized double‐blind comparison of low‐molecular‐weight heparin, a non‐steroidal anti‐inflammatory agent, and placebo in the treatment of superficial‐vein thrombosis.Arch Intern Med. 2003; 163: 1657-63Crossref PubMed Scopus (0) Google Scholar, 17Marchiori A. Verlato F. Sabbion P. Camporese G. Rosso F. Mosena L. Andreozzi G.M. Prandoni P. High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study.Haematologica. 2002; 87: 523-7PubMed Google Scholar] and 5% for VTE [18Gould M.K. Dembitzer A.D. Doyle R.L. Hastie T.J. Garber A.M. Low‐molecular‐weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta‐analysis of randomized, controlled trials.Ann Intern Med. 1999; 18: 800-9Crossref Scopus (610) Google Scholar]. Superficial thrombophlebitis has long been regarded as a benign condition. However, the practice of systematic ultrasonography has revealed a large number of deep‐vein thromboses (DVT) concomitant with ST, present in between 6% and 36% of patients according to the study [5Lutter K.S. Kerr T.M. Roedersheimer L.R. Lohr J.M. Sampson M.G. Cranley J.J. Superficial thrombophlebitis diagnosed by duplex scanning.Surgery. 1991; 110: 42-6PubMed Google Scholar, 6Barrelier M.T. Thromboses veineuses superficielles des membres inférieurs.Actualités Vasculaires Internationales. 1993; 17: 7-9Google Scholar, 14Bergqvist D. Jaroszewski H. Deep vein thrombosis in patients with superficial thrombophlebitis of the leg.BMJ. 1986; 292: 658-9Crossref PubMed Google Scholar, 15Gillet J.L. Perrin M. Cayman R. Thromboses veineuses superficielles des membres inférieurs: etude prospective portant sur 100 patients.J Mal Vasc. 2001; 26: 16-22PubMed Google Scholar, 19Bounameaux H. Reber‐Wasem M.A. Superficial thrombophlebitis and deep vein thrombosis. A controversial association.Arch Intern Med. 1997; 157: 1822-4Crossref PubMed Google Scholar, 20Blumenberg R.M. Barton E. Gelfand M.L. Skudder P. Brennan J. Occult deep venous thrombosis complicating superficial thrombophlebitis.J Vasc Surg. 1998; 27: 338-43Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar]. The high variability of these results clearly calls for complementary studies. Two mechanisms conceivably underlie this association: (1) migration of the thrombus toward the deep venous system via the saphenous–femoral junction or a perforating vein and (2) a state of hypercoagulability that may explain the non‐contiguous coexistence of the two types of thrombosis [5Lutter K.S. Kerr T.M. Roedersheimer L.R. Lohr J.M. Sampson M.G. Cranley J.J. Superficial thrombophlebitis diagnosed by duplex scanning.Surgery. 1991; 110: 42-6PubMed Google Scholar, 6Barrelier M.T. Thromboses veineuses superficielles des membres inférieurs.Actualités Vasculaires Internationales. 1993; 17: 7-9Google Scholar]. The practice of systematic lung scanning also resulted in positive findings in up to 33% of patients with ST [21Verlato F. Zucchetta P. Prandoni P. Camporese G. Mazzola M.C. Salmistrano G. Bui F. Martín R. Rosso F. Andreozzi G.M. An unexpectedly high rate of pulmonary embolism in patients with superficial thrombophlebitis of the thigh.J Vasc Surg. 1999; 30: 1113-5Abstract Full Text Full Text PDF PubMed Google Scholar]. The time of onset of ST, the severity of the underlying venous insufficiency and a history of VTE appear to be predictive factors for such thromboembolic complications [22Quenet S. Laporte S. Decousus H. Leizorovicz A. Epinat M. Mismetti P. and The STENOX GroupFactors predictive of venous thrombotic complications in patients with isolated superficial‐vein thrombosis.J Vasc Surg. 2003; 38: 944-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], but many issues remain obscure in this area. The existence of these complications, even if their significance remains controversial [19Bounameaux H. Reber‐Wasem M.A. Superficial thrombophlebitis and deep vein thrombosis. A controversial association.Arch Intern Med. 1997; 157: 1822-4Crossref PubMed Google Scholar], has nevertheless led to a renewed interest in ST. For a long time, ST was treated by non‐steroidal anti‐inflammatory drugs (NSAID) [23Hyers T.M. Agnelli G. Hull R.D. Morris T.A. Samama M. Tapson V. Weg J.G. Sixth ACCP Consensus Conference on antithrombotic therapy. Antithrombotic therapy for venous thromboembolic disease.Chest. 2001; 119: 176S-93SAbstract Full Text Full Text PDF Google Scholar], in combination with elastic stockings, thrombectomy in patients suffering intense pain and stripping of associated varicose veins. More recently, randomized clinical trials have attempted to evaluate, in patients with ST not accompanied by VTE, treatments also capable of preventing thromboembolic complications, namely antithrombotic therapy and ligation of the saphenous–femoral junction. Two trials compared this ligation with antithrombotic therapy [24Belcaro G. Nicolaides A.N. Errichi B.M. Cesarone M.R. De Sanctis M.T. Incandela L. Venniker R. Superficial thrombophlebitis of the legs: a randomised, controlled follow‐up study.Angiology. 1999; 50: 523-9Crossref PubMed Google Scholar, 25Lozano F.S. Almazan A. Low‐molecular‐weight heparin versus saphenofemoral disconnection for the treatment of above‐knee greater saphenous thrombophlebitis: a prospective study.Vasc Endovascular Surg. 2003; 37: 415-20Crossref PubMed Scopus (0) Google Scholar] and found no difference in the occurrence of DVT, although the small number of patients included does not allow a definitive conclusion to be drawn. One trial compared different doses of unfractionated heparin (UFH) [17Marchiori A. Verlato F. Sabbion P. Camporese G. Rosso F. Mosena L. Andreozzi G.M. Prandoni P. High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study.Haematologica. 2002; 87: 523-7PubMed Google Scholar] and another trial compared different doses of low‐molecular‐weight heparin (LMWH) [16The STENOX Study GroupA randomized double‐blind comparison of low‐molecular‐weight heparin, a non‐steroidal anti‐inflammatory agent, and placebo in the treatment of superficial‐vein thrombosis.Arch Intern Med. 2003; 163: 1657-63Crossref PubMed Scopus (0) Google Scholar]. The first of these, an open‐label study on 60 patients treated for 1 month, concluded in favor of superiority of therapeutic doses of UFH [17Marchiori A. Verlato F. Sabbion P. Camporese G. Rosso F. Mosena L. Andreozzi G.M. Prandoni P. High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study.Haematologica. 2002; 87: 523-7PubMed Google Scholar]. The second, STENOX, a double‐blind trial including a placebo group conducted on 427 patients treated for 10 days, led to the opposite conclusion, favoring prophylactic doses of LMWH (enoxaparin), the 10‐day treatment period appearing to be too short [16The STENOX Study GroupA randomized double‐blind comparison of low‐molecular‐weight heparin, a non‐steroidal anti‐inflammatory agent, and placebo in the treatment of superficial‐vein thrombosis.Arch Intern Med. 2003; 163: 1657-63Crossref PubMed Scopus (0) Google Scholar]. Two trials compared LMWH to NSAID [16The STENOX Study GroupA randomized double‐blind comparison of low‐molecular‐weight heparin, a non‐steroidal anti‐inflammatory agent, and placebo in the treatment of superficial‐vein thrombosis.Arch Intern Med. 2003; 163: 1657-63Crossref PubMed Scopus (0) Google Scholar, 26Titon J.P. Auger D. Grange P. Hecquet J.P. Remond A. Ulliac P. Vaissie J.J. Traitement curatif des thromboses veineuses superficielles par nadroparine calcique. Recherche posologique et comparaison à un anti‐inflammatoire non stéroïdien.Ann Cardiol Angéiol. 1994; 43: 160-6PubMed Google Scholar]; in both cases, the results were more in favor of LMWH. Finally, the 7th ACCP Conference on antithrombotic therapy suggested intermediate dosages of UFH or LMWH for at least 4 weeks for the treatment of ST, a Grade 2 B recommendation, acknowledging that the risk‐to‐benefit ratio of such a strategy is unclear [27Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease. The Seventh ACCP Conference on antithrombotic and thrombolytic therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. In this context, the importance of the trial performed by the Vesalio Investigators Group is evident. First of all, it is important to highlight the methodological quality of this trial (double‐blind study, blinded central adjudication committee and ultrasound thrombus extension assessed by two independent operators), even if the absence of a placebo group is regrettable. This trial compared two doses of LMWH (nadroparin) prescribed for 1 month in 164 patients presenting ST localized in the greater saphenous vein. Its conclusions suggest that therapeutic doses of LMWH do not improve the overall results at 3 months compared with prophylactic doses. These findings plead, like those of the STENOX trial, for the choice of prophylactic doses of LMWH in ST. However, the limited number of patients studied up to now [1The Vesalio Investigators GroupHigh vs. low doses of low‐molecular‐weight heparin for the treatment of superficial vein thrombosis of the legs: a double blind, randomized trial.J Thromb Haemost. 2005; 3: 1152-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 16The STENOX Study GroupA randomized double‐blind comparison of low‐molecular‐weight heparin, a non‐steroidal anti‐inflammatory agent, and placebo in the treatment of superficial‐vein thrombosis.Arch Intern Med. 2003; 163: 1657-63Crossref PubMed Scopus (0) Google Scholar] does not allow a definite conclusion to be drawn. In addition, as mentioned by the authors of the report on the Vesalio Investigators Group trial, the proportion of patients experiencing complications during the 1‐month treatment period was higher in the prophylactic dosage regimen group: of the seven patients randomized to prophylactic doses of nadroparin who developed complications, five (71.4%) experienced a thromboembolic event during the first month, as compared with two (33.3%) of the six patients randomized to full doses of nadroparin. Thus, the 1‐month LMWH therapeutic dosage regimen may provide a more effective protection than a prophylactic dosage regimen. The occurrence of the majority of thromboembolic events during the second and third months after treatment discontinuation in the therapeutic dosage group once again raises the issue of the optimal duration of antithrombotic treatment. Finally, as pointed out by the authors, this trial shows that a substantial number of patients with ST (3.1%, 5/164) experienced symptomatic venous thromboembolism during the 3‐month follow‐up, irrespective of the study treatment. In the STENOX trial, the corresponding rate was 3.3% (14/427). These rates confirm the need for further trials in order to determine the optimal antithrombotic therapeutic strategy to reduce this risk, in terms of type of drug, dosage regimen and treatment duration. Comparative trials of such treatments vs. ligation of the saphenous–femoral junction could then be envisaged. In any case, prior complementary epidemiological studies appear to be fully warranted, if only to better define, in this still poorly understood condition, the subjects at greatest risk of experiencing a thromboembolic complication.