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Management of VenousThromboembolism

VENOUS thromboembolism is a common disorderbut its management has been little studied. A survey ofconsultants in Scotland1 found that although themajority treated their patients with intravenous

heparin followed by oral warfarin, the usual durationof treatment for both agents varied considerably.These findings reflect the wide variation in publishedrecommendations. The longer the duration, the

greater are the risks of bleeding and other adversereactions, as are the costs in time and money topatients and to the health service. It is thereforeimportant to establish, by randomised studies,whether or not anticoagulants are beneficial; and if so,for how long. Meanwhile, what guidelines can begiven?Does the patient really have venous

thromboembolism? It is pointless to treat a disease if itis not present; because anticoagulants are a leadingcause of drug-induced disease and death, it is alsodangerous. Only 1 in 3 patients presenting withsymptoms and signs suggestive of either deep veinthrombosis of the leg (DVT) or pulmonarythromboembolism (PTE) has the diagnosis confirmedby the "gold standard" investigations (venography orpulmonary angiography).3 Moreover, differentiationof patients with and without DVT or PTE on the basis

1. Prentice AG, Lowe GDO, Forbes CD. Diagnosis and treatment of venousthromboembolism by consultants in Scotland. Br Med J 1982, 285: 630-32.

2 Kelton JG, Hirsh J. Bleeding associated with antithrombotic therapy Sem Hematol1980; 17: 259-91.

3. Gallus AS. Established venous thrombosis and pulmonary embolism. Clin Haematol1981; 10: 583-611.

of clinical features is impossible.3-6 Whilst it may bereasonable to start anticoagulants on clinical

suspicion, it is desirable to carry out objective tests(usually venography and/or isotope lung scanning) assoon as is feasible. In the Scottish survey, manyconsultants did not use reliable objective methods toconfirm or refute the diagnosis.1 This practice resultsin most patients being treated needlessly, 1,4 as well asin greater expense.4,7 If adequate tests do not confirmthe diagnosis, anticoagulants should be stopped.

Are anticoagulants beneficial in established DVTor PTE? After almost 50 years of use, it is unfortunatethat we do not know.8-10 No placebo-controlled trial inthe treatment of DVT has been reported in full.

However, in a preliminary report of a randomisedstudy, Nielsen and colleaguesll found no clinicalor objective benefit (repeat venograms and lungscans) from conventional heparin (6 days) plusphenprocoumon (3 months) compared withmobilisation plus phenylbutazone in 90 patients withvenogram-proven DVT. Two studies of

anticoagulants versus no anticoagulants in patientswith "clinical PTE" have been reported."" Barrittand Jordanl2 stopped their randomised study when 10of 19 control patients had clinical recurrent PTE,compared with none of 16 patients treated with

heparin (36 hours) plus nicoumalone (2-4 weeks).Johnson and Charnley,13 in a non-randomised studyof patients undergoing hip surgery, found that only 10of 380 control patients had clinical recurrent PTE,compared with 39 of 295 patients treated with heparin(2-7 days) and/or warfarin (3-6 weeks). Both studieshave major limitations.8-10 In particular, since thediagnosis of both initial and recurrent PTE was madeon clinical grounds, it is likely that only about a third ofpatients in these two studies had the disorder, and thatperhaps only a third of episodes of "recurrent PTE"were genuinely recurrent PTE. In the absence of fullyreported, placebo-controlled randomised trials withobjective inclusion criteria and endpoints, the case foranticoagulating patients with proven DVT or PTE isbased on circumstantial evidence,"-10 including theincreased risk of objective recurrence when

anticoagulation is below the "therapeutic range" 3 14-164. Ramsay LE. Impact of venography on the diagnosis and management of deep vein

thrombosis. Br Med J 1983; 286: 698-99.5. Goldhaber SZ, ed Pulmonary embolism and deep venous thrombosis. Philadelphia:

W B Saunders, 1985.6. Hirsh J, ed. Venous thrombosis and pulmonary embolism: diagnostic methods.

Edinburgh Churchill Livingstone, 1987.7. Hull R, Hirsh J, Sackett DL, Stoddart G. Cost effectiveness of clinical diagnosis,

venography and non-invasive testing in patients with symptomatic deep veinthrombosis. N Engl J Med 1981; 304: 1561-67.

8. Egermayer P. Value of anticoagulants in the treatment of pulmonary embolism: adiscussion paper. J R Soc Med 1981; 74: 675-81

9. Moms GK. Anticoagulants and venous thromboembolism. In: Meade TW, ed.Anticoagulants and myocardial infarction: a reappraisal. Chichester. Wiley, 1984.243-62

10. Lowe GDO, Prentice CRM. Thrombosis In: Bowie EJW, Sharp AA, eds.

Haemostasis and thrombosis. London. Butterworths, 1985: 284-318.11. Nielsen HK, Husted SE, Krusell L, et al Anticoagulant therapy in deep venous

thrombosis. A randomized controlled study. Thromb Haemostas 1985; 54: 233(abstr)

12. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonaryembolism: a controlled trial. Lancet 1960; i: 1309-12.

13. Johnson R, Charnley J Treatment of pulmonary embolism in total hip replacement.Clin Orthop 1977; 124: 149-54.

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or when low-dose heparin is used instead of warfarinfor maintenance anticoagulation. 17

If heparin is used, for how long should it be given?North American workers have long advocated

prolonged heparin treatment (7-14 days)5,16-20 buthave never provided evidence for the superiority ofthis expensive regimen over short-duration heparin incontrolled trials. British practice advocates givingheparin only until simultaneously started oral

anticoagulants prolong the prothrombin time ratiointo the therapeutic range--eg, for 3 days.21 Tworandomised studies suggest that the latter practice is aseffective as prolonged treatment and reduces hospitaltime and costS.zO,22 Schulman et al randomisedpatients with proven DVT to high-dose or low-dosewarfarin from the first day in two studies .21 Theystopped heparin when a stable warfarin effect hadbeen achieved (international normalised ratio, [INR] .> 2-5—2-6 for 2 consecutive days): this was after amean of 5 days and 6 days, respectively, in the firststudy, and after a mean of 4 days and 5 days,respectively, in the second study. There was only oneproven thromboembolic recurrence in 169 patients .20Gallus and colleagues22 randomised 318 patients withproven DVT and/or PTE to long or short durationheparin. In the group given warfarin from the firstday, heparin was stopped when the prothombin timeratio was over 20 (mean duration 4 days). Bycomparison with the group given warfarin from the7th day (mean duration of heparin 9-5 days),frequencies of clinical and objective recurrences (legand lung scans) were similar. Thus it seems reasonableto start warfarin on the first day and to continueheparin only until warfarin has prolonged the INRinto the therapeutic range.

If oral anticoagulants are used, for how long shouldthey be given? Oral anticoagulants have often beencontinued for 3-6 months, since Coon et al observedthat the incidence of clinical recurrences was highestduring this period.23 Again, the unreliability of clinicaldiagnosis limits the value of such studies. However,several more recent studies have confirmed that

14. Basu D, Gallus A, Hirsh J, Cade J A prospective study of the value of monitoringhepann treatment with the activated partial thromboplastin time. N Engl J Med1972, 287: 324-27.

15. Schulman S, Lockner D. Relationship between thromboembolic complications andintensity of treatment during long-term prophylaxis with oral anticoagulantsfollowing DVT. Thromb Haemostas 1985; 53: 137-40.

16. Hull R, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared withintermittent subcutaneous heparin in the initial treatment of proximal-veinthrombosis. N Engl J Med 1986; 315: 1109-14.

17 Hull R, Delmore T, Genton E, et al Warfarin sodium versus low-dose heparin in thelong-term treatment of venous thrombosis N Engl J Med 1979; 301: 855-58.

18. Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus warfarinsodium in the long-term treatment of venous thrombosis. N Engl J Med 1982, 306:189-94.

19. Hull R, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in thetreatment of proximal-vein thrombosis. N Engl J Med 1982; 307: 1676-81.

20. Schulman S, Lockner D, Bergstrom K, Blomback M. Intensive initial oral

anticoagulation and shorter heparin treatment in deep vein thrombosis. ThrombHaemostas 1984, 52: 276-80.

21 British National Formulary, no 14. London: British Medical Association andPharmaceutical Society of Great Britain, 1987: 102.

22. Gallus AS, Jackaman J, Tillett J, Mills W, Wycherley A. Safety and efficacy ofwarfarin started early after submassive venous thrombosis or pulmonary embolism.Lancet 1986; ii 1293-96.

23. Coon W, Willis PW, III, Symons MJ. Assessment of anticoagulant treatment ofvenous thromboembolism. Ann Surg 1969, 170: 559-68.

recurrent thromboembolism is common when

diagnosed by objective methods. Lagerstedt andcolleagues24 randomised 53 patients with

symptomatic DVT, confined to the calf veins at

venography, to receive 3 months of warfarin or none,after initial treatment with heparin for 5 days. Theirtherapeutic aim was equivalent to an INR of 2-5-4-2.After 90 days there were no recurrences in thewarfarin group, and a 29 % proven recurrence rate inthe control group (p < 0-01). 1 patient in each grouphad a recurrence in the subsequent 9 months. Threerandomised studies have compared warfarin withlow-dose heparin for periods of 6 weeks to 6monthsy,18,25 Warfarin was associated with a

significantly higher risk of bleeding in all studies. Bycomparison with fixed-dose heparin, the frequency ofrecurrent thromboembolism (objective evidence) wassimilar5 or lessp and it was approximately the sameas with adjusted-dose heparin.18 The high risk ofbleeding in the McMaster studies 17,111 was associatedwith the high intensity of anticoagulation (INRequivalent 3-0-4-5). A later McMaster study showedthat less intense anticoagulation (INR 20-25)reduced the risk of bleeding from 22 % to 4 % and wasequally effective in preventing recurrent

thromboembolism. 19,27

Three randomised studies of different durations oforal anticoagulant therapy have been reported,27-29O’SullivanZ’ randomised 186 patients with DVT orPTE (usually diagnosed objectively) to 6 weeks or 6months of warfarin. After 1 year, the clinicalrecurrence rate was 7 % in the 6-week group and 10 %in the 6-month group. Holmgren et al have presenteda preliminary report28 on 135 patients with objectivelydiagnosed DVT randomised to 4 weeks or 6 months oforal anticoagulants. After 1 year, the clinical recurrencerate was 16% in the 4-week group and 17% in the6-month group, but there were seven recurrencesbetween 4 weeks and 6 months in the 4-week groupcompared with only one in the 6-month group.Fennerty et a129 randomised 100 patients with DVTand/or PTE to receive 3 weeks or 6 weeks of warfarin,following 5 days of heparin treatment. After 1 year, therecurrence rates were 10% in the 3-week group and12% in the 6-week group. However, only 54% ofpatients had an objective diagnosis on entry to thestudy, and only 4 of the 11 recurrences were

confirmed by objective methods. It is unfortunate thatmany recurrences in the two fully reported studies21,29

24. Lagerstedt CI, Olsson C-G, Fagher BO, Oqvist BW, Albrechtsson U. Need forlong-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet1985; ii: 515-18.

25. Bynum LJ, Wilson JE, III. Low-dose heparin therapy in the long-term managementof venous thromboembolism. Am J Med 1979; 67: 553-56.

26. Poller L. Oral anticoagulant therapy. In: Bloom AL, Thomas DP, eds. Haemostasisand thrombosis, 2nd ed. Edinburgh: Churchill Livingstone, 1987: 870-85.

27. O’Sullivan EF. Duration of anticoagulant therapy in venous thromboembolism. MedJ Aust 1972; ii: 1104-07.

28. Holmgren K, Andersson G, Fagrell B, et al. One month versus six months therapywith oral anticoagulants after symptomatic deep-vein thrombosis. ThrombHaemostas 1983; 50: 310 (abstr).

29. Fennerty AG, Dolben J, Thomas P, et al. A comparison of 3 and 6 weeks’anticoagulation in the treatment of venous thromboembolism Clin Lab Haematol1987; 9: 17-21.

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were not confirmed objectively. Whilst recurrenceappears most frequent during the first month, it

continues for several months afterwards, especially ifthere are continuing risk factors, such as malignancy,other chronic illnesses, or surgery.s&deg;ls-194’z9Thus, a range of opinion is possible for the duration

of oral anticoagulation. Pragmatic advice is to giveoral anticoagulants for 6 weeks to 3 months for provenDVT, and for 3-6 months for proven PTE, if there areno contraindications. The therapeutic rangerecommended is an INR of 2-0-3;06 this stand issupported by an increased risk of recurrence when theINR is less than 2-0 and by an increased risk ofbleeding when the INR is greater than 3-0.

Geography, patient reliability, and the performance ofthe local anticoagulant clinic will also influencedecisions on duration of therapy. Further randomisedstudies of varying durations of anticoagulant therapyare needed. Patients are already "randomised" to awide variety of anticoagulant regimens according tothe consultant under whose care they fall.’ It is surelymore ethical to conduct randomised trials of treatmentwhich has been proven to cause bleeding, but whoseefficacy is debated, than to perpetuate widelydiverging practices. ,

Splints Don’t Stop Colds&mdash;Surprising!

EVERYONE knows what it is like to catch a cold, yetwe know surprisingly little about how it happens.Years ago we thought we knew. A textbook of medicine

that mentioned colds said they were spread by talking,coughing, and sneezing and a 1939-45 war-timeposter admonished the British population thus:

"Coughs and sneezes spread diseases. Stop the germsby using your handkerchief". But when the war wasover workers at the Common Cold Unit, Salisbury,tried to get some evidence on the subject and the yearsthat followed witnessed several rather bizarre

experiments. They found that colds seemed to spreadparticularly in families, but the second attack rate wasnot high ;’ the same results were obtained in classicstudies in the USA.2 Researchers at the CommonCold Unit rigged up volunteers with a gadget thatmade fluorescein-labelled fluid trickle from their nose,in imitation of the running nose of a cold, and showedwith a fluorescent lamp that the fluid spread to theirhands and everything they touched.3 The questionwas "Would nasal discharge from a real cold get to arecipient nose in this way?" In search of the answerchildren with fresh colds were invited up from a

nearby sclool.4 When they played table games with

1. Lidwell OM, Sommerville T. Observations on the incidence and distribution of thecommon cold in a rural community during 1948 and 1949. J Hyg (Camb) 1951; 49:365-81. 81.

2. Dingle JD, Badger GF, Jordan WS Jr. Illness in the home: a study of 25 000 illnessesin a group of Cleveland families. Cleveland: Western Reserve University, 1964.

3. Andrewes CH. The common cold. Br Med Bull 1953; 9: 206-07.4. Lovelock JE, Porterfield JS, Roden AT, Sommerville T, Andrewes CH. Further

studies on the natural transmission of the common cold. Lancet 1952; ii: 657-60.

volunteers, the volunteers got colds; but if thevolunteers played the same games with cards &cwhich the children had soiled then they did not getcolds. In another experiment, children at one end of ahut played games with each other while volunteerswaited at the other, divided from them by a blanketscreen. The only connection was the air space abovethe blanket and a fan to drive the air across, and yetvolunteers caught colds as they did after breathingvirus dispersed as a mist. These experiments werebased on small numbers, and as there were no

laboratory tests for cold viruses at that time there wasno virological control.

However, when viruses began to be detected theearly results were in some measure confirmed. Forexample, soon after rhinovirus type 2 (RV2) wasgrown it was shown that it affected volunteers if

applied to the nasal epithelium or the conjunctiva, butnot to the external nares or the pharynx.5 An artificial"sneeze" of a related virus (coxsackievirus A21) wassquirted into a modified wardrobe into whichvolunteers poked their heads, and it was found that theinhalation of one tissue culture infectious unit in thisway could infect a volunteer?,7In the USA, infectedvolunteers were kept at the end of a hut, whileuninfected subjects lived at the other, separated fromthem by a wire mesh barrier but with fans to assist airmovement-yet the infection got from one group tothe other. Moreover, it was shown that sneezes andnose blows produced virus-bearing droplets of theright size to be inhaled and trapped on the nasalmucosa, although most virus was in large drops or"blobs" which would not be airborne, and the largestnumber of particles were too small and dry to carrymuch virus.8

Despite these observations it has often proveddifficult to transmit colds in experiments even whenthe subjects are living continuously in the sameaccommodation. Statistical analysis of large numbersof volunteers housed together at Salisbury providesevidence that some such transmission occurs, yetwhen RV2 was taken to the Antarctic and inoculatedinto some of the staff of a base there, it spreadeffectively among the remainder. Nevertheless, thelimited evidence supported the idea that cold virusescould be, and probably were, transmitted as airbornedroplets.

During the 1970s the idea of transmission by fingersand fomites was reinvestigated. It has been assumedthat virus would probably die quickly on skin or othersurfaces, but at the University of Virginia9 it was

5. Bynoe ML, Hobson D, Homer J, Kipps A, Schild GC, Tyrrell DAJ. Inoculation ofhuman volunteers with a strain of virus isolated from a common cold Lancet 1961;i: 1194-96.

6. Buckland FE, Bynoe ML, Tyrrell DAJ. Experiments on the spread of colds. II.Studies in volunteers with coxsackievirus A21. J Hyg ( Camb) 1965; 63: 327-43.

7. Buckland FE, Tyrrell DAJ. Experiments with spread of colds. I. Laboratory studieson the dispersal of nasal secretion. J Hyg (Camb ) 1964; 62: 365-77.

8. Couch RB, Douglas RG, Lindgren KM, Gerone PJ, Knight V. Airborne transmissionof respiratory infection with coxsackie virus type 21. Am J Epidemiol 1970; 9: 78-86.

9. Hendley JO, Wenzel RP, Gwaltney JM Jr. Transmission of rhinovirus colds byself-inoculation. N Engl J Med 1973; 288: 1361-64