9 Anticoagulants in the prevention of venous thromboembolism

9 Anticoagulants in the prevention of venous thromboembolism A. S. G A L L U S

Anticoagulant regimens for preventing venous thromboembolism (VTE) in high-risk patients have been with us for 50 years and the use of small doses of subcutaneous heparin for this purpose has become standard practice, sanctioned by a Consensus Development Conference of the US National Institutes of Health (Conference, 1986) and supported by recently published meta-analyses of data from numerous clinical trials (Colditz et al, 1986; Clagett and Reisch, 1988; Collins et al, 1988). Nevertheless, some important practical questions remain: is there a 'best' all-purpose regimen? or should prophylaxis be tailored to individual circumstance? what are the risks and benefits of prophylaxis? how do anticoagulants compare with other preventive measures? are there groups of patients where anticoagulants fail or the hazard exceeds the benefit? indeed, should all patients broadly thought to be 'at risk' receive anticoagulation? and has there been recent progress?

BACKGROUND

The threat from pulmonary embolism (PE) in hospitalized patients has long been recognized. Not only does routine autopsy find embolism in 10-25% of hospital deaths (Morrell and Dunnill, 1968; Coon, 1976; Goldhaber et al, 1982; Bergqvist and Lindblad, 1985), but 5-20% of post-mortem examinations reveal major PE which is either the only obvious cause of death or is extensive enough to have probably contributed to death (Morrell and Dunnill, 1968; Coon, 1976; Havig, 1977). The prevalence of PE at postmortem examination rose until about 1970 but appears to have stabilized since then (Morrell and Dunnill, 1968; Goldman et al, 1983; Bergqvist and Lindblad, 1985; Dismuke and Wagner, 1986), with the more recent studies confirming its continued importance by reporting major PE in 6-13% of autopsies (corresponding to 0.15--0.3 % of all adult admissions or 0.06-0.6% of all surgical admissions to hospital (Bergqvist and Lindblad, 1985; Dismuke and Wagner, 1986). More importantly, between one-third and three-quarters of patients with fatal embolism after surgery had been ~xpected to recover from their underlying disease (Morrell and Dunnill, t~ailliOre"s Clinical Haematology--

Vol. 3, No. 3, July 1990 [SBN 0-7020-1474-5

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1968; Coon, 1976; Bergqvist and Lindblad, 1985) and, since major PE can be prevented, many of these deaths were potentially avoidable and therefore unnecessary. Anticoagulant therapy for non-fatal VTE is very effective, but there are cogent reasons why further reductions in mortality from PE must come through systematic prophylaxis in high-risk patients rather than a policy of 'wait and treat'. 1.

Review of case notes from patients with major PE at autopsy finds that two-thirds of those dying suddenly (the minority), and 90% of those deteriorating gradually before death (the majority), had a record of symptoms that were consistent with non-fatal embolism but which had been misinterpreted as indicating heart failure or pneumonia (Havig, 1977). As a result, warning episodes of VTE often remain untreated (Havig, 1977) and embolism at autopsy is usually a surprise finding (Coon, 1976; Havig, 1977; Cameron and McGoogan, 1981; Goldhaber et al, 1982; Goldman et al, 1983). 2. Since most patients with acutely fatal embolism die within 1-2 h of its onset (Donaldson et al, 1963; Havig, 1977), there is little time for diagnosis or effective intervention after massive PE. 3. Systematic screening for subclinical venous thrombosis (VT) in highrisk patients, using leg scanning and/or plethysmography followed by Table 1. Hospitalized patients screened for venous thrombosis (VT) with routine leg scanning or venography (abstracted from the original reports). Diagnostic category

Screening test(s)

VT (%)

Medical Myocardial infarction Transvenous pacing Hemiplegia (stroke) Paraplegia Intensive care

Leg scan Leg scan/plethysmography Leg scan/venogram Leg scan/venogram Leg scan

10-38 25 33-53 59-89 13-29

Trauma Hip fracture Tibial fracture Multiple injuries

Venogram Venogram Venogram

40-49 45 35

Elective surgery General abdominal Splenectomy Thoracic Gynaecological Prostatectomy (open) Prostatectomy (closed) Aorto/femoral Neurosurgery Meniscectomy Knee surgery Knee replacement Hip replacement

Leg scan/venogram Leg scan Leg scan Leg scan Leg scan Leg scan Leg scan/venogram Leg scan Venogram Venogram Venogram Venogram

3-51 6 20-45 7-45 29-51 7-10 4-43 29-43 8 17-57 84 30--65

Pregnancy Postpartum

Leg scan

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early treatment to prevent embolism, may well be effective but is far more expensive than routine prophylaxis (Hull et al, 1982; Paiement et al, 1987a) and is not feasible outside specialized centres. Fortunately, there are clinically apparent risk factors for VTE which can be used to select patients for prophylaxis: autopsy studies have long shown strong associations between VTE and increasing age over 40 years, bed rest for longer than 4 days, certain kinds of surgery or recent trauma (especially hip fracture), disseminated malignancy, recent myocardial infarction, and recent stroke (Morrell et al, 1963; Havig, 1977; Bergqvist and Lindblad, 1985); observations confirmed and extended by the use of routine [1251]fibrinogen leg scanning or venography to detect VT among hospital patients in prospective surveys (see below, and Table 1). These newer diagnostic methods have also made possible most of the many recent evaluations of preventive regimens.

DIAGNOSTIC END-POINTS USED IN STUDIES OF VT PREVENTION The credibility of VT prevention trials rests heavily on their choice of diagnostic end-point, so it is unfortunate that those end-points which are clinically the most important and relevant (symptomatic VT and PE, fatal PE, and total mortality) also present the greatest difficulties for would be investigators. Thus clinical diagnosis is sufficiently unreliable to be almost useless for clinical trial purposes (Gallus et al, 1976a), measuring the incidence of VTE post mortem requires a much higher autopsy rate than is now easily attainable, whilst a reduction in either total or cause-specific mortality by prophylaxis could be measured only through forbiddingly large studies. Because of this, most prevention studies since 1970 have used [1251]fibrinogen leg scanning or routine venography to screen for VT. Both methods have their problems but both detect VT in 10--60% of 'high-risk' patients (Table 1), providing convenient high-frequency 'substitute' endpoints for clinical trials in surgical and other settings. Leg scanning exposes patients to small amounts of radioiodine but is otherwise non-invasive and is exquisitely sensitive to calf VT. Its major limitations are a relative insensitivity to femoral VT and complete inability to detect pelvic vein thrombosis (Gallus, 1976), These flaws are probably not critical in general surgical and medical patients where thrombosis usually arises in the calf and extends proximally, so that abnormal leg scans carry a 20% chance of asymptomatic progression to above-knee VT (in turn complicated by symptomatic embolism in perhaps 40% of patients if left untreated; Kakkar et al, 1969), while a negative scan indicates a low risk of either complication. The situation differs radically after hip surgery, where 10-25% of patients develop femoral VT in the operated leg without any more distal involvement (isolated ipsilateral femoral VT: Stamatakis et al, 1977; Nillius and Nylander, 1979), and surgical trauma causes enough leakage of [lesI]fibrinogen into the

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operated thigh for scanning to lose all specificity for proximal VT. As a result, negative calf scans no longer indicate a low risk of femoral VT and embolism. In addition, given the unusual distribution of VT after hip surgery, it is at least possible that some prophylactic methods will prevent calf but not more proximal VT (a finding in two intermittent leg compression trials; Gallus et al, 1983; Paiement et al, 1987a), or even proximal but not more distal VT (Powers et al, 1989). As a result, leg scanning alone becomes unacceptable and the favoured diagnostic method is now routine venography (Paiement et al, 1987a). The point is well illustrated by results from a study using both leg scanning and venography to measure the effects of intermittent calf compression on VT rates after elective hip replacement: leg scanning alone would have been misleading, since this found a reduction in calf VT from 40 to 12% ( P < 0.001), whereas routine venography also showed proximal VT in 23% of treated and 26% of control patients (Gallus et al, 1983). Another possible option is the use of leg scanning (sensitive to calf VT) together with impedance plethysmography (IPG; sensitive to more proximal VT) to screen for VT after hip surgery in prophylactic studies. Unfortunately, this combination also lacks enough sensitivity to be useful, as shown by a recent comparison of these two screening tests with routine bilateral venography done either when the leg scan or IPG became positive or at 10-14 days after hip surgery (Cruikshank et al, 1989). In 685 patients entering a succession of clinical trials at McMaster University, Hamilton, Ontario a positive result of either screening test or of both had a sensitivity of 49.6% and specificity of 93.9% for venographically demonstrable VT, while the sensitivity of IPG alone for proximal VT was a disappointing 28.6% in this setting, presumably because most proximal VT were small and non-occlusive at the time of venography (Cruikshank et al, 1989). This review will be restricted to prospective randomized comparisons of anticoagulants and other preventive measures with each other or with no treatment, provided they have used either leg scanning or venography to detect VT, or lung scanning or autopsy to detect PE. Although comprehensive, it cannot claim to be exhaustive: sources were obtained from the author's reprint collection and through 'Medline' search. Papers tabulated but not listed in the references are available from the author. In general, the results of individual trials were simply pooled before tabulation, but a form of meta-analysis was used when preparing Figure 1, where weighted means and 95% confidence limits were derived from the odds ratios observed in separate clinical trials (Armitage and Berry, 1988). The concluding discussion on the clinical significance of trial results draws on concepts reviewed by Laupacis et al (1988). Some terms used to discuss treatment effects in this review are commonplace in epidemiology but bear definition for the more general reader (Armitage and Berry, 1988; Laupacis et al, 1988). Relative risk reduction: the decrease in adverse outcomes achieved by therapy, expressed as a proportion of the control rate, i.e. if PT = the proportion of adverse outcomes in the treatment group, and Pc = the

655

ANTICOAGULANTS IN PREVENTION OF VENOUS THROMBOEMBOLISM

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Figure 1. The relative influence of various preventive methods on venous thrombosis rates after elective general surgery, as shown by the odds ratios calculated for randomized comparisons with untreated controls in trials which used leg scanning to screen for postoperative venous thrombosis, plus their weighted means and 95% confidence limits. 1, Physiotherapy; 2, calf stimulation; 3, elastic stockings; 4, calf compression; 5, dextran 40 or 70; 6, low-dose heparin; 7, ultra-low-dose heparin; 8, dihydroergotamine/heparin (5000 units); 9, dihydroergotamine/ heparin (2500 units); 10, full-dose warfarin; 11, minidose warfarin.

proportion in the control group, then ( P x - P c ) / P c -- the relative risk reduction.

Relative risk (or risk ratio): the ratio of the probabilities of adverse outcomes in the treatment and control groups (Px/Pc). Odds ratio: the ratio of the 'odds' of an adverse outcome in the treatment group [PT/(1- Px)] and control group [Pc/(1 - P c ) ] , so the 'odds ratio' = [PT/(1 -- PT) ]~[Pc/(1 - Pc) ]. This expression yields a close approximation to 'relative risk' that is favoured by epidemiologists because of its mathematical properties. An odds ratio of 1.0 indicates no treatment effect. ANTICOAGULANT REGIMENS AND OTHER PREVENTIVE METHODS

A number of prophylactic regimens are listed and briefly described in Table 2. These methods prevent thrombotic nidus formation during and soon after surgery (e.g. low-dose heparin prophylaxis), prevent the extension of small thrombi to clinical significance (e.g. the postoperative use of warfarin or of low molecular weight heparin), or aim to achieve both tasks (e.g. two,step warfarin or adjusted dose heparin therapy). They succeed by interfering with either blood coagulation (heparin, warfarin) or fibrin stability (dextrans), or by accelerating venous return (electrical calf muscle stimulation, graded pressure stockings, intermittent leg compression).

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Table 2, Venous thrombosis prevention regimens. Description

Regimen

'Low-dose heparin'

5000 units sodium or calcium heparin, given s.c. 8- or 12hourly, starting 1-2 h before elective surgery 3500 units heparin, given s.c. 8-hourly, then adjust dose from 48 h after surgery to maintain APTT between 31.5 and 36 s (normal = 31.5 + 4.9 s) 1 unit kg -1 h i heparin given by i.v. infusion during and for 3--5 days after surgery 2500-5000 units heparin + 0.5 mg DHE s.c. t2-hourly Various doses of various low molecular weight heparin fragments and fractions, given s.c. once or twice a day Various doses of heparin-like materials (e.g. heparan and/or dermatan sulphate), given s.c. once or twice a day Warfarin to prolong the INR to 2.0-3.5 at or after the time of surgery 10 mg immediately after surgery; adjust for INR = 2.0 by day 5, 2.0-2.7 thereafter Start warfarin 10-14 days preoperatively, aim for 1.5-3 s increase of PT at surgery, PT ratio = 1.5 after surgery ('Simplastin') Start 1 mg/day warfarin 10-14 days preoperatively, then aim for INR = 1.5 after surgery 500-1000 ml dextran 40 or 70 i.v. per- and postoperatively, then daily or 2nd daily for 3+ doses Peroperative electrical calf stimulator, graded pressure stockings, external intermittent calf _+ thigh compression

Adjusted dose s.c. heparin 'Ultra-low-dose' heparin Heparin/DHE Low molecular weight heparin Heparinoids Full-dose warfarin Moderate-dose postoperative warfarin 'Two-step' warfarin 'Minidose" warfarin Dextran 40/70 Venous flow acceleration

DHE, dihydroergotamine; APTr, activated partial thromboplastin time; INR, international normalized ratio; PT, prothrombin time. G i v e n this v a r i e t y , it w o u l d b e s u r p r i s i n g if all r e g i m e n s w e r e e q u a l l y effective in all clinical c i r c u m s t a n c e s . A s a result, t h e e v i d e n c e s u p p o r t i n g t h e i r use will b e r e v i e w e d s e p a r a t e l y for elective a n d e m e r g e n c y g e n e r a l s u r g e r y , in o r t h o p a e d i c s u r g e r y , a n d in m e d i c a l p a t i e n t s .

INDICATIONS FOR PROPHYLAXIS 1. E L E C T I V E

GENERAL SURGERY

A t least in t h e o r y , it s h o u l d n o t b e v e r y difficult to d e v e l o p r e g i m e n s w h i c h p r e v e n t V T a n d P E a f t e r e l e c t i v e a b d o m i n a l o r t h o r a c i c o p e r a t i o n s . M u c h is k n o w n a b o u t t h e risk factors f o r V T E so that h i g h - r i s k p a t i e n t s can be r e a d i l y r e c o g n i z e d ; p r o p h y l a x i s n e e d s to b e a p p l i e d o n l y d u r i n g a n d for s o m e d a y s o r w e e k s b e y o n d t h e t i m e of s u r g e r y since this is w h e n m o s t t h r o m b i f o r m ; a n d leg s c a n n i n g p r o v i d e s a s i m p l e a n d a p p r o p r i a t e s u b s t i t u t e d i a g n o s t i c e n d - p o i n t for clinical trials. A s a result, t h e r e has b e e n a f l o o d o f information about a wide selection of prophylactic methods.

Heparin prophylaxis L o w - d o s e h e p a r i n p r o p h y l a x i s is r o u t i n e l y u s e d in m a n y surgical units a n d is

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Table 3. Elective general surgery. Venous thrombosis (VT) rates measured with leg scanning in randomized comparisons with placebo treatment or no prophylaxis. VT rate Preventive method Low-dose heparin Ultra-low-dose heparin DHE/heparin 5000 units DHE/heparin 2500 units Full-dose warfarin Minidose warfarin Dextran 40/70 Elastic stockings Leg compressors Calf stimulators Physiotherapy LMW heparins Heparinoids

Trials*

Patients C/T

C

T

17/23 2748/2668 0.266 0.099 1/1 24/17 0.333 0.059 1/1 108/214 0.204 0.084 1/2 236/355 0.250 0.138 2/2 85/83 0.256 0.048 1/1 37/32 0.297 0.094 3/5 387/379 0.344 0.243 5/7 571/5555 0.260 0.095 7/10 575/571 0.278 0.112 4/6 398/360 0.302 0.136 0/4 296/297 0.216 0.185 No comparisons with untreated controls No comparisons with untreated controls

Relative risk reductiont 0.63 0.82 0.59 0.45 0.81 0,68 0.29 0.63 0.60 0.55

0.14

* Proportion of available trials favouring prophylaxis (P < 0.05). t See text. $ Several studies compared VT rates in stockinged as opposed to unstockinged legs of the same patients. C, control group; T, treatment group; DHE, dihydroergotamine; LMW, low molecular weight. now the standard of comparison for other preventive methods in clinical trials (Conference, 1986). Figure 1 and Table 3 summarize its influence and that of other preventive regimens on V T rates measured with leg scanning after elective general abdominal, thoracic, or pelvic surgery during randomized comparisons with no treatment or placebo therapy. As admission criteria for most of these trials were very similar (age > 4 0 or > 5 0 years; general anaesthesia lasting > 30 or > 45 min), their results were pooled to calculate average V T rates and their 95% confidence limits in Table 3, and also combined for meta-analysis in Figure 1 (see above). Several conclusions can be drawn. 1.

2.

3.

The extent of the published experience varies greatly for different preventive methods (as measured by the n u m b e r of clinical trials and the n u m b e r of patients studied): that with low-dose heparin is by far the most extensive, while that with ultra-low-dose heparin infusion or minidose warfarin hardly exceeds the stage of pilot studies. T h e r e must have been a broadly similar distribution of risk factors a m o n g patients entering trials of different preventive methods, since the control group V T rates are reasonably uniform. Therefore, it should be valid to c o m p a r e the effectiveness of preventive methods by comparing the relative risk reductions observed after simple pooling of the results from individual trials (Table 3), although it must be r e m e m b e r e d that leg scan studies record mainly calf VT. W h e n judged by this criterion, anticoagulant regimens are the most effective (relative risk reduction for different regimens = 0.45-0.82),

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followed by venous flow acceleration (0.55-0.63), and dextrans (0.29), with physiotherapy alone being the least effective (a relative risk reduction of merely 0.14) (Table 3). More formal 'meta-analysis' yields similar results: the weighted average odds ratios derived from randomized trials of the various anticoagulant regimens reviewed are 0.16-0.50, compared with odds ratios of 0.290.42 for various venous flow acceleration methods, 0.48 for dextran prophylaxis, and 0.82 for physiotherapy (Figure 1). However, the smaller the reported experience the wider the 95% confidence limits (Table 3; Figure 1) and the lower the assurance that a given prophylactic method really works and the reported findings represent 'truth'.

Because proximal VT (popliteat, femoral, and/or iliac VT) is much less frequent than calf VT and is less easily screened for in prospective studies, there are few trials other than some larger low-dose heparin studies which have used this diagnostic end-point (Table 4). Table 4. Low-dose heparin prophylaxis and proximal venous thrombosis (VT) after elective general surgery: randomized comparisons with placebo treatment or no prophylaxis in studies using fibrinogen leg scanning and/or venography to detect VT. VTrates Investigators Nicolaides et al (1972) Rem et al (1975) Rosenberg et al (1975) Gallus et al (1976b) Immelmann et al (1979)

Control

Heparin

9/122 (0.07) 5/ 95 (0.05) 18/ 89 (0.20) 12/412 (0.03) 4/ 83 (0.05)

0/122 (0.00) 1/ 83 (0.01) t3/ 55 (0.00) 4/408 (0,01) 5/ 85 (0.06)

Relative risk reduction 1.00 0,77 1.00 0.66 - 0.22

P value 0.002 n.s, <0.001 <0.04 n.s.

n.s., not significant.

Four of five low-dose heparin trials Showed trends in favour of heparin, three of them statistically significant, but the results were uneven (Table 4). Rosenberg et al (1975) found an atypically high proximal VT rate of 20% in the control group while Immelmann et al (1979; the Groote Schuur Hospital Study) revealed no benefit. Although its small size limited its power to exclude a heparin effect, the Groote Schuur Study is almost unique in its use of both routine venography and leg scanning to screen for proximal VT. It confirmed that leg scanning has low sensitivity for proximal VT (scanning detected 5/9 proximal VT) and found that low-dose heparin prevented calf, but not more proximal, VT. Attempts to measure the influence of prophylaxis on PE have been of two kinds: mutticentre trials designed around this end-point, and retrospective meta-analyses of both small and large studies. Routine lung scanning was used to screen for subclinical PE following surgery in several trials but, while most investigators have found trends (some statistically significant) in favour of low-dose heparin and other preventive methods, the incidence of PE reported among the control and therapy groups is extremely variable, which makes one question the usefulness of this approach. There are two concerns: all studies except one (the

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Table 5. Major pulmonary embolism (PE) at autopsy in large randomized comparisons of low-dose heparin prophylaxis with either no treatment or placebo (proportions are based on the number of autopsies in each study group), Investigators Kakkar et al (1975)

Sagar et al (1975)

Control

Low-dose heparin

Patients Deaths Autopsy All PE Major PE

2076 100 (0.048) 72 (0.72) 22 (0,31) 16 (0,22)

2045 80 (0.039) 53 (0.66) 5 (0,09) 2 (0.04)

Patients Deaths Autopsy All PE Major PE

236 28 (0.119) 28 (1.00) 12 (0.43) 8 (0.29)

264 38 (0.144) 38 (1.00) 2 (0,05) 0 (0.00)

P value n.s. <0,005 < 0.005 n.s. <0,001 0.0005

n.s., not significant,

trial by Browse et al, 1976) used only perfusion scanning (a highly nonspecific method) for diagnosis, and all studies were open (although several relied on 'blind' lung scan interpretation). Large multicentre trials designed to measure the impact of prophylaxis on the incidence of PE at autopsy among patients who die in hospital after elective general surgery have much greater importance and credibility (Table 5). The biggest was a low-dose heparin study in over 4000 patients which found that prophylaxis had impressive and statistically significant effects on two findings at post-rnortem examination: pulmonary embolism of any size, and 'fatal' embolism (major PE thought to have been the cause of death) (Kakkar et al, 1975; the International Multicentre Trial). Similar results were obtained by Sagar et al (1975) in 500 patients (Table 5), while trends reported by Kill et al (1978) were consistent with benefit from heparin. Results of the International Multicentre Trial became controversial after one contributing centre revealed local irregularities in trial execution (Gruber et al, 1977) but were sustained by reanalysis (Kakkar et al, 1977). A further large multicentre trial compared low-dose heparin with dextran 70 in elective orthopaedic and general surgical patients, and found a low incidence of major embolism at autopsy in both treatment groups: there was fatal PE in 6 of 1991 patients given tow-dose heparin and 6 of 1993 who received dextran (Gruber et al, 1980). Meta-analysis confirms that low-dose heparin prevents major PE, since two independent reviews of all trials, large and small, where the number of deaths from PE was reported by investigators, have both reached this conclusion (Clagett and Reisch, 1988; Collins et al, 1988). Clagett and Reisch (1988) examined 24 trials of low-dose heparin in elective abdominal, urological or gynaecological surgery (totalling nearly 9500 patients) and found that prophylaxis reduced the incidence of fatal PE from 0.7% in controls to 0.2% ( P < 0.001). The larger analysis of 74 trials (and 14 000 patients) by Collins et al (1988) included studies of orthopaedic surgery: they found fatal PE in 0.8% of controls and 0.26% of patients given

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heparin, yielding a reduction in odds ratio of 64 + 15% ( P < 0.001), plus a small but statistically significant decrease in total mortality (from 4.2 to 3.3%; P < 0.02).

Variations to the low-dose heparin regimen Most studies have evaluated the use of 5000 units s.c. heparin given 1-2 h before and then 8- or 12-hourly after surgery for 5-7 days (see Table 2), but some investigators have varied the dose (2500 or 5000 units, depending on body weight), the dose interval (8-hourly or 12-hourly), the heparin salt (sodium or calcium), or the timing of preoperative heparin injection (10 h or 2 h before surgery). No study of sufficient size and power has attempted to define which, if any, regimen is best, but the meta-analysis of 49 leg scan based general surgical trials reported by Clagett and Reisch (1988) revealed an average VT rate of 11.8% (95% confidence interval = 10.6-13.1%) in 34 studies where heparin was given 12-hourly, compared with a VT rate of 7.5% in 15 studies of 8-hourly heparin prophylaxis (95% confidence interval =6.4-8.6%). Their survey found no evidence that dosing interval had any influence on the risk of either postoperative wound haematoma or major bleeding (Clagett and Reisch, 1988), suggesting that 8-hourly heparin is preferable. Reducing the heparin dose to 2500 units s.c. 8-hourly may be unwise, since this was followed by a strong trend towards more VT after general surgery (30/125 = 24%) than when 5000 units was given 8-hourly (20/130 = 15%; 0.1 > P>0.05) in the only double-blind comparison (Breddin et al, 1983). There is, however, a more promising approach to dose-reduction: ultra-low-dose' heparin, consisting of 1 units k g - ' h - 1 given i.v. for 3-5 days during and after operation (Negus et al, 1980; see Table 3). This appeared to be effective in a medium-sized leg scan study but the original report has not been followed by others. Careful reading suggests that low-dose heparin should be given until individuals are substantially back on their feet after surgery rather than for any predetermined time. Gallus et al (1976b), who routinely gave 5000 units heparin 8-hourly s.c. for 7 days after elective surgery but continued leg scanning beyond this time, noted that 8 of the 13 VT detected in heparin treated patients developed after the drug was discontinued and that all 8 patients were still partly bedridden at the time. Kiil et al (1978) made similar observations: having also given heparin for 7 days after surgery, they found that 4/5 major PE in their heparin-treated patients developed after the 7th day, when equal numbers of previously heparin-treated and control patients developed major PE. Analogous observations in neurosurgical patients find a critical relationship between the duration of intermittent leg compression and its effectiveness (Turpie et al, 1977, 1979).

Low dose heparin in patients having surgery for malignancy Of seven randomized heparin studies where investigators reported outcomes in patients with malignant disease at operation, six showed trends in favour

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of prophylaxis, and these were statistically significant in three. Heparin achieved a 66% average reduction in VT risk, compared with a 73% reduction in patients without malignancy entering the same clinical trials. The sole exception was a study of patients with gynaecological malignancy where low-dose heparin had no demonstrable benefit (VT rate---13/88, compared with 12/85 in controls; Clarke-Pearson et al, 1983) but intermittent calf compression was effective (Clarke-Pearson et al, 1984).

Selective prophylaxis To a greater or lesser extent, all clinicians practise selective prophylaxis by limiting its use to patients who they believe have a sufficiently high risk of VT to justify the hazards, costs, and inconvenience of preventive measures. Most often, a decision to use prophylaxis depends on the presence of one or more risk factors: age over 40 years, surgery under general anaesthesia lasting beyond 45 min, etc. The more risk factors, the higher the risk. There have been attempts to refine this empirical process by adding laboratory tests to the clinical risk factors and deriving formulas which weight individual risk factors to yield an index which predicts the likelihood of postoperative VT, and therefore a need for prophylaxis, but these indices have proved less than universally helpful because separate investigators have derived different equations which tend to work best in their home laboratory, although most have included age and a measure of fibrinolytic activity (see review by Gallus, 1989). Nevertheless, these indices can be put to use: Crandon et al (1980) restricted low-dose heparin prophylaxis to the 30% of their 104 gynaecological patients whose predictive index was high and achieved a VT rate in all patients after surgery of 4%, compared with leg scan evidence of VT in 16% of similar patients they had previously studied with prophylaxis.

Possible synergisms with other preventive methods Heparin plus dihydroergotamine (DHE). The most extensively evaluated synergism is that between heparin and DHE, a venoconstrictor which encourages venous return and may be weakly thromboprophylactic in its own right (Hor et al, 1976; Breddin et al, 1983; Multicentre Trial Committee, 1984). The drug is given subcutaneously with heparin in a dose of 0.5rag, either using separate injection sites or a specially designed twochambered syringe. Direct comparisons with untreated controls confirm that heparin plus D H E markedly reduces the VT rate after elective general surgery (see Table 3), but the question of much greater interest is whether adding D H E improves the effectiveness of heparin alone. This was tested in eight randomized leg scan trials (Table 6), where combined therapy roughly halved the VT rate obtained with heparin given 8- or 12-hourly in seven studies and the difference reached statistical significance in four. Of two randomized studies which used routine pre- and postoperative perfusion lung scanning to screen for subclinical embolism, the larger found

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Table 6. Randomized comparisons of low-dose heparin alone with combined dihydroergotamine (DttE)/heparin prophylaxis in elective general surgery. VT rate (leg scan) Investigators

Heparin

DHE/heparin

Relative risk P value

Comparisons of" DHE/heparin with 5000 units b.i.d, heparin

Hor et al (1976) Koppenhagen et al (1977) Kunz et al (1977) Witle-Jorgensen et al (1983) Multicentre Trial Committee (1984)

19/117 (0.162) 32/162 (0.197) 13/ 88 (0.148) 25/ 81 (0.309) 32/190(0.168)

10/114(0.088)* 13/150(0.087)* 6/ 90 (0.067)* 10/100(0.100)* 17/181(0.094)* 32/190 (0.168)~

0.54 n.s. 0.44 <0.010 0.45 n.s. 0.32 <0.001 0.56 <0.050 1.00 n.s.

Comparisons of DHE/heparin with 5000 units t. i.d. heparin

Moser et al (1981a) Brucke et al (1983) Pedersen and Christiansen (1983) Breddin et al (1983)

7/ 75 (0.093) 7/ 76 (0.092)* 26/ 88 (0.296) 13/ 91 (0.143)* 9/ 50 (0.180) 6/ 50 (0.120)* 20/130 (0.154) 17/129(0.132):~

0.99 0.48

0.67 0.88

n.s. <0.025 n.s. n.s.

* 0.5 mg DHE/5000 units heparin s.c. 12-hourlypostoperatively. t 0.5 mg DHE/2500 units heparin s.c. 12-hourlypostoperatively. 0.5 mg DHE/2500 units heparin s.c. 8-hourly postoperatively. VT, venous thrombosis; n.s., not significant. fewer new defects after prophylaxis with twice-daily DHE/heparin (2.7%; P < 0 . 0 0 5 ) or b . i . d . s . c . 5000 units heparin alone (5.5%; P < 0 . 0 5 ) than among placebo treated patients (14%) (Koppenhagen et al, 1977), but the smaller showed similar results with both DHE/heparin and placebo (WilleJorgensen et al, 1983). Two double-blind trials have gone further and tested the combination of 0.5 mg D H E with 2500 units heparin, supposing that heparin dose reduction would make prophylaxis safer while the addition of D H E would maintain effectiveness. In the first, Breddin et al (1983) studied 638 patients having elective abdominal, thoracic, or pelvic surgery, divided into five groups given 8hourly s.c. treatment with 5000 units heparin, 2500 units heparin, 0.5 mg D H E , 0.5 mg D H E plus 2500 units heparin, or placebo. They found postoperative V T in 20/130 (0.154), 30/125 (0.240), 31/126 (0.246), 17/129 (0.132), and 37/128 patients (0.289) respectively. Both 8-hourly 5000 units heparin and 8-hourly DHE/2500 units heparin had a similar and statistically significant benefit (Table 6), while neither 8-hourly 2500 units heparin alone nor 8-hourly D H E alone was effective. The second trial examined 12-hourly s.c. prophylaxis (Multicentre Trial Committee, 1984) and compared placebo with 5000 units heparin, 0.5 mg D H E , 0.5 mg D H E plus 2500 units heparin, and 0.5 mg D H E plus 5000 units heparin in 744 compliant patients (efficacy analysis). H e r e , the V T rates in the four active treatment groups were 32/190 (0.168), 18/93 (0.194), 32/190 (0.168), and 17/181 (0.094) respectively, as opposed to 22/90 (0.244) after placebo, with only D H E plus 5000 units heparin having a statistically significant benefit. There was also a trend towards less above-knee V T in the group given DHE/5000 units heparin (5.5%, compared with 10% in placebo

ANTICOAGULANTS IN PREVENTION OF VENOUS THROMBOEMBOL1SM

663

patients). The relationships persisted after 'intention to treat analysis' of all randomized patients, regardless of their compliance. These very detailed studies showed two combined drug regimens, 8hourly DHE/2500 units heparin and 12-hourly DHE/5000 units heparin, to be effective, the first being no less active than 5000 units heparin given 8-hourly (Breddin et al, 1983) while the second was more effective than either 12-hourly heparin alone or 12-hourly DHE combined with 2500 units heparin (P<0.05; Multicentre Trial Committee, 1984), but neither trial found any treatment or treatment combination to be less prone to cause surgical bleeding than another. Given good evidence for efficacy, there are two concerns about DHE/ heparin: safety and cost. There have been case reports where arteriospasm (labelled as ergotism) has followed DHE/heparin prophylaxis; the complication caused limb amputation and death in some patients, develops most often after traumatic fractures, but seems to be very rare after general surgery. Its frequency is uncertain, ranging from 0.23% in a retrospective, questionnaire based, survey of 61000 patients (Gatterer, 1986) to 0/3700--1/5000 in large prospective studies (Gruber, 1982; Schlag et al, 1986). Cost needs also to be considered, since DHE/heparin is somewhat more expensive than heparin alone.

Heparin plus prophylactic methods other than DHE. Surprisingly little is known about heparin synergisms other than that with DHE, although small studies have found little or no additive effect when combining low-dose heparin with graded pressure elastic stockings (Torngren, 1980; WilleJorgensen et al, 1985) or intermittent calf compression (Roberts and Cotton, 1975). Other possible benefits Anticoagulants inhibit tumour spread in experimental animals but no such benefit could be demonstrated in a retrospective study of long-term outcomes after low-dose heparin prophylaxis in patients having surgery for colonic cancer (Kohanna et al, 1983).

Potential hazards Heparin slightly but definitely increases transfusion requirement and the risk of wound bleeding after operations. Meta-analysis of 46 general surgery trials found 'excessive bleeding' in 3.8% of controls and 5.9% of heparin treated patients, with similar results after 8-hourly or 12-hourly prophylaxis and in both 'blind' and open comparisons (Collins et al, 1988). The bleeding risk should not, however, be exaggerated: there was a significant reduction of total mortality of 20% when all available studies (including those of orthopaedic surgery) were pooled (Collins et al, 1988). It seems that the heparin injection site may influence the extent of bleeding after some surgical interventions. De Lange (1982) found that use of the arm

664

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rather than the abdomen for subcutaneous heparin injection significantly reduced the risk of wound haematoma after inguinal herniorrhaphy. Fear of bleeding causes many anaesthetists to avoid spinal or epidural anaesthesia after preoperative low-dose heparin. Yet there were no complications of spinal or epidural anaesthesia in 187 heparin/DHE treated patients followed for 6 weeks after surgery by Allemann et al (1983), or in 58 patients reported by Fredin et al (1984). There is also a small but real hazard from heparin-induced thrombocytopenia (HIT), which tends to cause thrombosis rather than bleeding. Reviews suggest that HIT develops in up to 5 % of patients given therapeutic heparin (Kelton, 1986) but is very rare during subcutaneous heparin prophylaxis (no case was reported in any prospective low dose heparin trial; Kelton, 1986). Nevertheless, since HIT can lead to major venous or arterial occlusion, stroke, amputation, and death (Kelton, 1986), every effort should be made to minimize its likelihood. This can be done by avoiding inappropriate heparin prophylaxis in low-risk patients, by turning to effective alternatives where these are available, by minimizing the length of heparin treatment (most episodes of HIT follow at least 7 days of a first heparin exposure; Kelton, 1986), and by monitoring platelet counts when heparin is given for longer than 7 days (since thrombocytopenia usually resolves uneventfully after stopping heparin in patients with HIT who are free of thrombosis).

Oral anticoagulants Oral anticoagulants were the first mainstay of VT prevention, although their use was largely abandoned when equally effective but fundamentally safer, simpler, and cheaper alternatives which did not require laboratory control became available. There have been a few comparisons with low-dose heparin. For instance, leg scanning showed VT after gynaecological operations in 6% of patients given either nicoumalone or heparin, compared with 23% in randomized controls (Taberner et al, 1978), but the nicoumalone regimen was complex: the drug was given for 5 days to achieve a prothrombin time (PT) ratio of 2.0-2.5 at the time of surgery (INR=2.0-2.5) and then continued for 14 days aiming for a PT ratio of 2.0-4.0 (the PT ratio was measured using British Comparative Thromboplastin and was therefore equivalent to the International Normalized Ratio, or INR). Nevertheless, oral anticoagulants retain a place where simpler and less hazardous methods are relatively ineffective (as in orthopaedics, see below) and in the occasional general surgical patient with a very high thrombosis risk (e.g. recent or frequently recurrent VTE, or known antithrombin deficiency). The risk of bleeding is minimized by realizing that VT can be prevented with the target range of INR set at 2.0-2.5 (which corresponds to a 'Simplastin' Ratio of 1.3-1.4; Hirsh, 1987). A number of early studies using clinical end-points also suggest that warfarin started 2-3 days after surgery is at least partly effective, presumably by preventing extension and embolism of small VT formed during and soon after operation.

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An intriguing recent development is the concept of ~minidose' warfarin. Encouraged by the success of a fixed 2 mg/day warfarin dose in preventing subclavian VT after central venous catheter placement (Bern et al, 1986), Poller et al (1987) gave a fixed dose of i mg/day warfarin for a minimum of 6 days and a mean of 20 days before gynaecological surgery, and then throughout the hospital stay, and found leg scan evidence of postoperative VT in 3/32 patients compared with 1/35 given full-dose nicoumalone and 11/37 untreated controls (both reductions are statistically significant). Minidose warfarin hardly prolonged the prothrombin time and tended to cause less bleeding than standard dose nicoumalone. Further evaluations are eagerly anticipated.

Low molecular weight heparins and heparinoids Low molecular weight (LMW) heparin fractions and fragments differ from their parent drug in both pharmacodynamics and pharmacokinetics. Not only do they have marked anti-factor Xa activity and little effect on the activated partial thromboplastin time (APTT) or thrombin clotting time (TCT) in vitro, but circulating anti-factor Xa activity persists for longer after subcutaneous injection, encouraging the evaluation of once-a-day regimens. In addition, they have minimal antiplatelet activity. However, despite their similarities, the different LMW heparins are sufficiently unlike in their composition to need separate consideration. There has also been great interest in heparinoids like ORG 10172 (a mixture of heparan sulphate, dermatan sulphate, chondroitin sulphate, and a glycosaminoglycan with high affinity for antithrombin III), and in semisynthetic heparin analogues (SSHA and SP54) (Thomas, 1984; Hirsh, 1986; Holmer et al, 1986; Salzman, 1986; Hobbelen et al, 1987). Extensive animal studies have found that several heparinoids and LMW heparins cause less bleeding than unfractionated heparin for an equivalent antithrombotic effect. As a result, many of them have undergone clinical trial in surgical patients, and several are licensed in some countries for use in routine VT prevention. These new materials can be thought of as second generation preventive agents. As a result, there have been no comparisons with placebo treatment in patients having general surgery. Instead, their safety and efficacy after onceor twice-daily injection have been tested mainly against low-dose heparin prophylaxis (Table 7). What emerges is that some LMW heparins may be more effective (two large trials have shown statistically significant reductions in VT rates beyond those seen with standard low-dose heparin regimens while a third showed a strong trend in the same direction) and that LMW heparins can achieve their effect with once-daily subcutaneous injection (Table 7). LMW heparins are not, however, intrinsically safe: once-daily s.c. Kabi 2165 (Fragmin, Kabi; prepared after partial degradation of heparin with nitrous acid) is effective in doses of 2500-7500 anti-factor Xa units/day but 5000-7500 anti-factor Xa units/day has caused excessive wound bleeding, even when the preoperative dose was given on the evening before surgery rather than 2 h before (Table 7). On the other hand, there was apparently no increase in the

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A.S. GALLUS

Table 7. Randomized comparisons between standard heparin and low molecular weight heparins or heparin analogues in general surgery. VTrate Investigators

Dose

Dose interval

Fraxiparine (CY216; Choay-Sanofi) Kakkar and Murray 7500units Daily (1985) European Fraxiparin 7500units Daily Study Group (1988) Fragmin (Kabi 2165; Kabi) Koller et al (1986) 7500 units Daily 2500 units Daily Bergqvist et al (1986) 5000units Daily Caen et al (1988) 2500 units Daily Bergqvist et al (1988) 5000 unitst Daily Fricker et al (1988) 5000 units:~ Daily Enoxaparin (PK 10169; Pharmuka) Samama et al (1988) 60rag Daily 40 mg Daily 20 mg Daily Semisynthetic heparin analogue (SSHA ) Kakkar et al (1978) 7500 units b.i.d. Torngren et al (1984) 37,5mg b.i.d. 50rag b.i.d.

Analogue

Heparin

P value

5/196 (0.026) 14/199(0.070) <0.05 27/960 (0.028) 42/936(0.045)

0.03

1/ 23* (0.043) 1/ 74 (0.014) 13/217' (0.060) 6/195 (0.031) 28/505* (0.055) 2/ 40 (0.050)

n.s. n.s. n.s. n.s. 0.08 n.s.

0/ 20 (0.000) 2/ 72 (0.028) 9/215(0.042) 7/190(0.037) 41/497 (0.083) 0/ 40 (0.000)

4/137 (0.029) 5/133(0.038) 3/106 (0.028) 3/110(0.027) 6/159 (0.038) 12/158(0.076)

n.s. n.s. n.s.

6/ 94 (0,064) 12/ 95 (0,126) 21/154 (0.136) 21/164(0.128) 16/155 (0.103)

n.s. n.s. n.s.

* Excessive surgical bleeding. t Preoperative dose given evening before surgery. .~2500 units 2 h pre- and 12 h postoperatively, then 5000 units daily, VT, venous thrombosis; n.s., not significant. surgical bleeding rate across a three-fold dose range (from 20 to 60 mg/day) with a heparin fraction from P h a r m u k a (enoxaparin, p r e p a r e d by partial depolymerization of a benzyl ester of unfractionated heparin) and, since all doses a p p e a r e d to be equally effective, this material may well have a wider safety margin (Table 7). It is, however, p r e m a t u r e to assume that one L M W heparin is intrinsically safer than another: the excessive surgical bleeding observed with 5000-7500 anti-factor Xa units Fragmin/day may simply reflect excessive dosage, since these amounts yield high circulating anti-factor Xa levels (see Chapter 4). It is likely that the added convenience of once daily injection will be the main advantage of L M W heparins over standard heparin in general surgery, although there m a y also be some gain in efficacy from some of these materials. Speculations that L M W heparins may be less prone than unfractionated heparin to cause thrombocytopenia remain to be tested. O t h e r heparin-like materials have also been evaluated: two trials found prophylaxis with low-dose heparin and twice-daily s.c. S S H A ('semisynthetic heparin analogue', an artificially sulphated m e m b e r of the chondroitin family) to be equally effective after general surgery (Table 7), while another leg scan study found twice-daily s.c. SP54 (an artificially sulphated wood pulp derivative) to be more effective than dextran 70 (Bergqvist and Ljungner, 1981).

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667

2. UROLOGY Urologists are wary of using anticoagulants after transurethral resection of the prostate (TURP) because they fear excessive bleeding from the cauterized prostatic bed, encouraged by infection and exposure to the dilute solution of urokinase in urine. Fortunately, the risk of VT is so low that prophylaxis is rarely needed (see Table 1). One pilot study of the heparinoid ORG 10172 given intravenously after TURP found a dose-dependent increase in urinary blood loss, which became excessive only at the highest dose level given (ten Cate et al, 1987). Another found a moderate but statistically significant increase of urinary bleeding after subcutaneous ORG 10172 (Gallus et al, 1989). 3. EMERGENCY GENERAL ABDOMINAL OR THORACIC SURGERY This important group of patients has received little attention. I11patients can develop thrombosis before surgery if they are bed-ridden for some days while a decision to operate is made, and this happened in 11/50 patients studied with fibrinogen leg scanning by Heatley et al (1976), most often in people with cancer. Logically, then, preventive measures in sick patients should begin at the time of hospital admission but, in practice, low-dose heparin prophylaxis is often delayed until after emergency surgery even though no trials have tested the effects of omitting preoperative heparin. First principles suggest that this would reduce its effectiveness, since many thrombi form during or soon after surgery (Browse and Negus, 1970; Williams, 1971) and it is likely that low-dose heparin can prevent the formation of small venous thrombi but not their extension. 4. NEUROSURGERY, HEAD INJURY, AND SPINAL TRAUMA

Here, there is a very high risk of VTE but even small amounts of excessive bleeding are unacceptable so that, given the consistent success and complete safety of venous flow accelerating devices and graded pressure compression stockings in this setting (Turpie et al, 1977, 1979, 1989a), it is unlikely that a controlled study of low-dose heparin in 100 patients after neurosurgery will encourage its use, although the drug was effective and caused no problems (Cerrato et al, 1978). Low-dose heparin was less effective than full-dose heparin in a small trial of patients with spinal cord injury (Green et al, 1988). 5. ELECTIVE HIP REPLACEMENT AND HIP FRACTURE Without prophylaxis, some 5% of patients having elective hip replacement develop symptomatic PE and up to 0.5% die of this complication, which remains the major cause of postoperative death (Sheppeard et al, 1981). The

668

A . S . GALLUS

problem is even more acute after hip fracture where PE kills about 4% of patients and accounts for almost 20% of deaths in hospital (Sheppeard et al, 1981). Despite these statistics, which are well known, few orthopaedic surgeons routinely use effective prophylaxis (Paiement et al, 1987b), presumably because no simple, safe, widely available and sufficientlypowerful preventive method has yet emerged, largely because orthopaedic surgery poses special problems for both clinical trial methodology and the available prophylactic methods. 1.

The anatomical distribution of VT differs after hip surgery from that seen after abdominal surgery, since routine postoperative venography shows femoral VT in almost 30% of patients (Stamatakis et al, 1977; Nillius and Nylander, 1979), usually originating in valve pockets about level with the lesser trochanter and often without associated calf VT (Stamatakis et al, 1977). Calf VT (with or without proximal extension) is also very frequent (see Table 1). 2. Thus, one can postulate two pathogenetic mechanisms: stasis plus 'hypercoagulability' (largely responsible for calf VT), and a separate component of femoral vein damage (caused by surgical manipulation and largely responsible for isolated femoral VT) (Stamatakis et al, 1977). 3. As a result, methods which prevent calf VT after hip operation may fail to prevent femoral VT (Gallus et al, 1983; Paiement et al, 1987a), whereas others may prevent femoral but not calf VT (Powers et at, 1989). 4. It follows that leg scanning cannot yield an acceptable 'substitute' diagnostic end-point for VT prevention trials after hip surgery since it cannot detect isolated femoral VT, which also eludes the policies of venography done only when the leg scan becomes abnormal (Paiement et al, 1987a), or of screening with a combination of leg scanning and impedance plethysmography (Cruikshank et al, 1989). Most recent trials have therefore relied on routine postoperative venography. 5. The onset of VT may be delayed for some days to weeks after hip surgery (Johnson et al, 1978; Sikorski et al, 1981), so that prophylaxis limited to the immediate perioperative period is likely to be suboptimal. 6. Any preventive method which increases the incidence of wound bleeding is unacceptable, since bleeding predisposes to wound infection: potentially a major catastrophe. This review is limited to studies based on routine postoperative venography, and, since most trials have compared preventive methods with each other rather than with no therapy, the published results for each method have been pooled to calculate average VT rates and their 95% confidence limits, with data concerning elective hip replacement (Table 8) and hip fracture (Table 9) considered separately. A few randomized studies of prophylaxis after hip surgery presented only in abstract are also discussed as a guide to recent progress.

ANTICOAGULANTS tN PREVENTION OF VENOUS THROMBOEMBOLISM

669

Elective hip replacement T h e l i m i t e d s u c c e s s o f m o s t p r e v e n t i v e m e t h o d s is r e a d i l y s e e n : r e g a r d l e s s o f w h e t h e r i n d i v i d u a l trials h a v e r e a c h e d statistical s i g n i f i c a n c e , t h e o v e r a l l r e s u l t f o r m o s t p r e v e n t i v e m e t h o d s is a m o d e s t r e d u c t i o n in V T r a t e f r o m Table 8, Venous thrombosis (VT) prevention and elective hip replacement: simple pooling of data from randomized comparisons using routine venography to screen for VT (16 published and four presented at Tokyo meeting of International Meeting on Thrombosis and Haemostasis in August 1989).

Preventive method

Trials*

Total no. of patients

8 6 3 3 7 3 5 2 2 2

394 257 118 223 621 162 229 141 109 137

Untreated controls Low-dose heparin Adjusted dose heparin Low-dose heparin/DHE LMW heparins Oral anticoagulants Dextran 70 Aspirin Leg compression Elastic stockings

VT (rate)

95% confidence limits

Risk reduction

204 (0.52) 88 (0.34) 13 (0.11) 83 (0.37) 100 (0.16) 30 (0.19) 68 (0.30) 73 (0.52) 26 (0.24) 52 (0.38)

[0.47-0.57] [0.28-0.40] [0.06-0.18] [0.31-0.44] [0.13-0.19] [0.13-0.26] [0.24-0.36] [0.44-4).60] [0.16-0.33] ]0.30-0.47]

0.34 0.79 0.28 0.69 0.64 0.43 0.00 0.54 0.27

* Number of evaluations for each preventive method. Risk reduction: apparent relative risk reduction. DHE, dihydroergotamine; LMW, low molecular weight, Only 8 of 21 trials had untreated controls, the rest were comparisons of prophylactic methods with each other.

Table9, Venous thrombosis (VT) prevention after hip fracture: simple pooling of data from randomized comparisons using routine venography to screen for VT (14 published and two presented at the International Meeting on Thrombosis and Haemostasis held in Tokyo, August 1989).

Preventive method Untreated controls Low-dose heparin Low-dose heparin plus oral anticoagulants Low-dose heparin/DHE LMW heparins Oral anticoagulants Dextran 70 Dextran/DHE Dextran/oral anticoagulants Dextran/aspirin Aspirin

VT (rate)

95% confidence limits

Risk reduction

128 43 75

279 (0.46) 17 (0,40) 46 (0.61)

[0.47-0.57] [0.28-0.40] [0.49-0.72]

- 0.14 -0.34

116 290 301 481 28 39 42 66

42 (0.36) 33 (0.11 ) 74 (0.25) 141 (0,30) 10 (0.36) 4 (0.10) 14 (0.33) 27 (0.41)

[0.27-0.45] [(I,08-0.15] [0.20-0.30] [0.26-0.34] [0. t9-0.55] [0.03-0.24] [0.20-0.47] [0.29-0.54]

0.21 0.75 0.46 0.35 0.22 0.78 0.27 0.11

Trials*

Total no. of patients

8 2 1 2 2 6 8 1 1 1 1

* Number of evaluations for each preventive method. Risk reduction: apparent relative risk reduction. DHE, dihydroergotamine; LMW, low molecular weight. Only 8 of 16 trials had untreated controls, the rest were comparisons of prophylactic methods with each other, or were dose ranging studies.

670

A.S. GALLUS

50% in controls to about 25-45% (seen with low-dose heparin with or without DHE, dextran 70, and intermittent leg compression and elastic stockings, while aspirin is ineffective). The best results are those obtained with oral anticoagulants, adjusted dose heparin and LMW heparins (see Table 8). Adjusted dose heparin (Leyvraz et al, 1983) is a modern and somewhat complex reincarnation of a proposal first made by Bergquist (1940). Eighthourly s.c. heparin was begun 2 days before surgery: the starting amount was 3500 units with subsequent doses adjusted in steps of 500-1000 units to achieve an APTT of 31.5-36s, 6h after injection (normal range = 31.5 + 4.9 s; mean + 2 SD), such that the dose increased gradually to an average of 18 900 units/day by the 7th day after surgery (range 13 500-30 000 units/24 h). Compared with fixed low-dose heparin prophylaxis using 3500 units s.c. 8-hourly, this regimen reduced the overall VT rate (measured by venography of the operated leg on day 7-9 after surgery) from 16/41 (0.39) to 5/38 (0.13) (P < 0.01) without causing increased blood loss, and diminished the incidence of proximal VT from 13/41 (0.32) to 2/38 (0.05) (P<0.003) (Leyvraz et al, 1983). A similar protocol tested in a randomized comparison with a LMW heparin (Kabi 2165; reported in abstract by Potron et al, 1987), yielded a total VT rate of 10% and proximal VTin 5% of 40 patients having hip replacement followed by routine bilateral venography on day 9-10. A double-blind placebo controlled trial of the LMW heparin enoxaparin (PK10169; Pharmuka) reported by Turpie et al (1986) is even more encouraging because it is considerably simpler. Here, the start of prophylaxis was delayed until 12-24 h after hip replacement but the total VT rate was still greatly reduced, from 20/39 (0.51) to 4/37 (0.11) (P<0.0005), while the proximal VT rate was diminished from 9/39 (0.23) to 2/37 (0.05) (P < 0.03), again without excessive bleeding. The importance of this regimen where prophylaxis begins after the operation is twofold: it will appeal to orthopaedic surgeons, who generally dislike the use of anticoagulants during operation, and it bypasses the concerns of anaesthetists about the use of spinal or epidural anaesthesia during anticoagulant prophylaxis. The trial result suggests either that a preoperative start for anticoagulant prophylaxis is less important than was previously thought, or that enoxaparin can prevent the extension of small thrombi as well as their formation. Others have also found VT rates of 8-12% after hip replacement in patients given enoxaparin subcutaneously once or twice a day (Planes et al, 1986, 1988), Fragmin (Dechavanne et al, 1989) or Fraxiparine (Bansillon et al, 1987) but they started prophylaxis before surgery in the more usual way. Papers presented at the recent XIIth Congress of the International Society for Haemostasis and Thrombosis (ISTH, in Tokyo, abstracted in Thrombosis and Haemostasis: 62(supplement 1); 1989) strengthened the case for accepting adjusted dose heparin and LMW heparins as the most powerful prophylactic approaches after hip replacement, since one venographically controlled evaluation of adjusted dose heparin yielded a thrombosis rate of 16%, while five studies of various LMW heparins and heparinoids showed VT in 13-31% of treated patients (lower than VT rates

ANTICOAGULANTS IN PREVENTION OF VENOUS THROMBOEMBOLISM

671

found in comparison groups receiving no therapy, heparin/DHE, low-dose heparin, or elastic stockings in four trials, and similar to the VT rate with adjusted-dose heparin in the fifth). There was also support for the proposition that enoxaparin may be effective when the first dose is given after surgery (as proposed by Turpie et al, 1986), since a study by Planes et al (1989) presented to the ISTH found venographically demonstrable postoperative VT in 6.5% of 62 patients having elective hip replacement under general anaesthesia where enoxaparin was begun 12h before surgery, 11.7% of 61 patients starting enoxaparin immediately after surgery because they had spinal anaesthesia, and 16.9% of 65 patients starting prophylaxis 12 h after operation, again under regional anaesthesia. Proximal VT rates were 6.1-6.7% in the three groups, and wound haematoma rates were 1.5-6.7%. For the present, however, until LMW heparins are better evaluated and become more widely available, oral anticoagulants remain the simplest and most practical, easily accessible approach to VT prevention after hip replacement in most countries. There are several possible strategies. 1.

'Low-dose' warfarin therapy is given from the day before surgery, aiming for a PT of 15 s after operation (1.3-1.5 times control measured with a rabbit brain thromboplastin, corresponding to an INR of 2.0-2.5, see above): a randomized comparison with external pneumatic leg compression applied for 10 days after hip replacement found identical VT rates for both methods (12/72, or 0.17, for warfarin, and 11/66, or 0.17, for flow acceleration) and similar bleeding rates (Paiement et al, 1987a). 2. An equally successful but more cumbersome approach has also been reported: the two-step protocol of Francis et al (1983) where 0.5-10 mg/ day warfarin (average 3 mg/day) was given for 10-14 days before hip replacement, aiming for a 1.5-3 s increase in 'Simplastin' PT at the time of operation, and the dose was then increased to prolong the PT ratio to 1.5 (corresponding to an INR of 2.5; Hirsh, 1987). The regimen achieved a VT rate of 11/53 (0.21), compared with 19/37 (0.51) when patients received dextran 40 for 5 days after surgery. 3. The simplest regimen of all is that described by Coventry et al (1973), who delayed starting warfarin until the 4th postoperative day with the intention of preventing fatal PE while avoiding early wound bleeding. Their results in 2012 hip arthroplasties included 5 fatal emboli (0.25%); 2 among the 58 patients with a contraindication to warfarin therapy (3.5%) and 3 in the 1954 patients intended for warfarin therapy (0.15%) (1 before and 2 after starting the drug). There were 3 other deaths, none caused by bleeding. This early study can be criticized for its clinical end-point and lack of appropriate controls, but the small number of deaths with major PE and tow total mortality in patients suitable for warfarin prophylaxis remain impressive. A more recent and nearly as large but also uncontrolled evaluation of postoperative 'low-dose' warfarin prophylaxis has been reported by Balderston et al (1989). They gave 10 mg warfarin on the evening of surgery and then daily from the

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A.S. GALLUS second postoperative day to 1392 patients, aiming for a prothrombin time of 15 s (1.2-1.4 times the control value), found symptomatic nonfatal PE confirmed by 'high-probability' ventilation-perfusion lung scanning during the hospital stay in 1.1%, and lost no patients with fatal embolism. Again, the study has serious deficiencies: we are not told if patients were consecutive or whether some were excluded from prophylaxis, or the overall mortality, and we are left to guess that prothrombin times were measured using a rabbit brain thromboplastin with sensitivity similar to that used by Francis et al (1983, above). Nevertheless, the apparent lack of fatal embolism in over 1000 patients and the relative safety of this approach (2.4% of patients needed drainage of a wound haematoma and 0.4% had a deep wound infection) are again impressive.

Hip fracture Hip fracture warrants separate review because it is far from clear whether the high-risk period for developing VT begins with the initial trauma or during surgery some hours later. If the former, then some otherwise successful preventive measures started at the time of surgery may well be relatively ineffective. In addition, although PE is very frequent in this setting, many aged patients with hip fracture suffer from co-morbid conditions which contribute to their high mortality so that even successful prophylaxis is unlikely to have much impact on their long-term survival. Both the selection of people for prophylaxis and the timing and choice of preventive method therefore need consideration. Clinical trials based on routine venography (Table 9) suggest that oral anticoagulants reduce the VT rate after hip fracture from about 40% to about 25%, confirming the pioneering studies of Sevitt and Gallagher (1959) who found a much reduced incidence of VTE at autopsy of patients given phenindione from the start of their hospital admission. Dextran 70 (with or without aspirin) has a similar level of effect on VT (Table 9) but there is no support for using low-dose heparin (given alone or together with DHE). A recently published randomized placebo controlled trial of warfarin and aspirin (both starting soon after surgery, and with the aspirin-placebo comparison blinded) in 149 patients with hip fracture is of considerable interest: warfarin doses were adjusted to yield an INR of 2.0 by the 5th postoperative day and of 2.0-2.7 thereafter; the aspirin regimen consisted of a 650 mg slow release tablet given twice daily. The diagnosis of VT was based on leg scanning and plethysmography, followed by venography done either when the screening tests suggested proximal VT or routinely after 21 days, while symptomatic PE was confirmed by lung scanning (Powers et al, 1989). The results were fascinating: the incidence of any VTE (proximal or distal VT, or symptomatic PE) was 20% in the warfarin group, 41% in the aspirin group, and 46% in placebo patients, much as in hip replacement (see Table 8), suggesting that warfarin was clearly superior. More detailed analysis, however, showed the clinically important end-points of proximal VT or PE to be significantly less frequent after both warfarin (9%) and aspirin (11%)

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than with placebo (30%) (P = 0.002). Bleeding was not apparently increased by either warfarin or aspirin. The authors speculate that aspirin may selectively prevent proximal VT by interfering with platelet-femoral vein interactions near the site of trauma and surgical injury, but caution that residual calf VT developing in aspirin-treated subjects remain prone to proximal extension and serious embolism (as happened in one of their patients; Powers et al, 1989). The best results of prophylaxis in hip fracture (VT rates of 10-13%) have again been obtained with LMW heparins, although this information derives from studies reported in abstract only: a dose-ranging study of enoxaparin (Rhone-Poulenc) without untreated controls (Barsotti et al, 1987), a routine venography study of Fraxiparine (Sanofi) without a control group (Simon et al, 1989), and a comparison of the heparinoid O R G 10172 (Organon) with dextran prophylaxis (Bergqvist et al, 1989). One large, multicentre trial has tested the relative merits of heparin/DHE and dextran 70 in preventing fatal PE after elective or emergency orthopaedic surgery in patients older than 16 years (Gruber, 1982): 3698 patients received 7 days of heparin/DHE, and 3712 were given three doses of dextran 70 over 24 h; the average age was 46 years, 13.6% had hip replacement, the others a variety of procedures done on the arm, spine, leg or pelvis. Mortality within 40 days of operation was similar in the two groups (28 and 27 deaths), as was the autopsy rate (69%): 6 deaths among those given heparin/DHE (0.16%) and 9 in the dextran group (0.24%) were blamed wholly or partly on pulmonary embolism (Gruber, 1982). Although few deaths were attributed to PE in either group, it is difficult to judge whether prophylaxis was effective, since there were no untreated controls and the literature contains no firm information about the expected mortality from PE in a study group of this age and composition. The trial did, however, show that use of dextran 70 led to more allergic reactions and bleeding than that of heparin/DHE (Gruber, 1982). A subsequent subgroup analysis of results in the 329 patients admitted after hip fracture found fatal embolism in 2.3% of 172 patients given DHE/heparin and 3.8% of those given dextran 70. Total mortality over 3 months was 12% in both groups (Gruber, 1985). As before, the absence of an untreated control group makes it difficult to gauge the value of either intervention. Indeed, the benefit may well have been slight or negligible, given that 3-month mortality among 239 untreated patients was 12.5% in a recent multicentre trial of ancrod prophylaxis after hip fracture, with 2.1% of patients dying of PE (figures almost identical with those above). Ancrod is a defibrinating enzyme obtained from snake venom previously shown to reduce the number and size of VT after hip surgery and the study was reported in abstract by Prentice and Townsend (1987). 6. MEDICAL PATIENTS Most evidence derives from small trials in patients with medical catastrophes like myocardial infarction or hemiplegia, where the problem is analogous to

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that of emergency surgery since the high-risk period for VTE is triggered by an acute event so that preventive measures begun at or soon after its onset should succeed. Information is sparse about the success of preventive measures applied during transient severe exacerbations of chronic illnesses, as in patients admitted to a respiratory intensive care unit.

Myocardial infarction Because both low-dose and full-dose heparin treatment can prevent VT after myocardial infarction (Gallus and Hirsh, 1976), it becomes important to ask which is the more appropriate approach and the answer will (not surprisingly) vary with circumstance. The problem is not simple, because a high risk of VTE is only one possible reason for deciding on preventive anticoagulant therapy soon after myocardial infarction: others which are at least equally important include a fear of systemic embolism and the likelihood of early coronary artery reocclusion in patients given thrombolytic drugs. Since high-dose subcutaneous heparin (12 500 units s.c. 12-hourly) prevents left ventricular mural thrombosis after full thickness myocardial infarction, whereas low-dose heparin (5000 units s.c. 12-hourly) does not (Turpie et al, 1989b), it follows that full dose heparin becomes more appropriate when the risk of systemic embolism is thought to be great. Whether either treatment can prevent coronary artery rethrombosis is not known. There is some overlap between the known risk factors for VTE and systemic embolism: VTE becomes a problem in patients with heart failure or a significant dysrhythmia after myocardial infarction, with age over 60 years, and after transfemoral venous pacemaker insertion, whereas systemic embolism tends to complicate extensive myocardial infarction as indicated by very high peak creatine kinase levels and especially anterior infarction severe enough to cause apical dyskinesia or akinesia (reviewed by Gallus, 1986). As a result, the proper role of low-dose heparin becomes a matter for individual judgment: if routine anticoagulant therapy to prevent systemic embolism is thought to be desirable then use of low-dose heparin becomes restricted t O patients with small or posterior infarcts where it is perhaps not even necessary. In addition, low dose heparin cannot prevent VTE after insertion of a transfemoral temporary pacemaker (Munch and Mombelli, 1980). The matter is complicated further by a recent report that 12500 units calcium-heparin, given 12-hourly s.c. and starting within 24 h of myocardial infarction, significantly reduced in-hospital mortality from 9.9% among 351 control patients to 5.8 % in 360 heparin treated subjects (P = 0.03) in an open, randomized, multicentre trial where 60% of patients also received streptokinase (SCATI Group, 1989). The mechanism for this surprisingly large heparin effect was unclear, although two-dimensional echocardiography showed less mural thrombi after heparin therapy among those patients with anterior infarcts (supporting Turpie et al, 1989b) and there was a trend towards less recurrent ischaemic episodes when streptokinase was followed

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by heparin. Further evidence concerning the role of therapeutic heparin after myocardial infarction (with or without thrombolytic treatment) is urgently needed. Stroke

It is well known that patients with hemiparesis after a recent stroke become prone to VTE (see Table 1), but clinicians are loath to use anticoagulant prophylaxis because they have concerns about the risks of intracranial bleeding. Small randomized trials have found that both low-dose heparin (5000 units s.c. 8-hourly) and twice-daily heparin/DHE can prevent leg scan detectable VT after a recent ischaemic stroke (McCarthy et al, 1977; Czechanowski and Heinrich, 1981), but neither study was large enough to demonstrate safety and these approaches have not become popular. There has, instead, been great recent interest in the use of LMW heparins and heparinoids after ischaemic stroke, because of their presumably greater safety margin. Thus, in a double-blind trial of the heparinoid, O R G 10172, Turpie et al (1987) found leg scan evidence of VT in 7/25 patients given placebo (28%) and 2/50 patients given twice-daily s.c. O R G 10172 (4%) (P = 0.005). As a bonus, they also found a statistically significant decrease in the incidence of proximal VT from 16% to zero and little evidence of increased bleeding (one patient given O R G 10172 developed haemorrhagic infarct extension after a fall). All patients had computed tomographic head scans before trial entry to screen for intracranial bleeding. A striking reduction in VT rate after acute ischaemic stroke by twice daily s.c. injection of 2500 units of the LMW heparin Fragmin has also been reported by Prins et al (1989) who found VT in 6/30 patients given Fragmin and 15/30 controls (P = 0.05). There were, however, trends towards higher mortality and more intracranial bleeding in the Fragmin-treated subjects, which indicate a need for larger studies designed to assess safety as well as efficacy. VT prevention after ischaemic stroke presents several dilemmas. VT is most likely in patients with severe paralysis (Turpie et al, 1987) who also have the worst short- and long-term prognosis. Prophylaxis with low-dose heparin or a heparinoid is simple, but the studies have not excluded a small but significant bleeding risk. Intermittent leg compression, which is effective in the analogous setting of paralysis after cranial trauma, is very safe but cumbersome and inconvenient. Graded pressure elastic stockings alone were no less effective than intermittent leg compression plus elastic stockings in a recent neurosurgery study (Turpie et al, 1989a) and may prove the simplest remedy. More information is needed. Other medical indications

Few recent studies have defined the frequency or clinical importance of VTE among medical patients admitted to hospital for reasons other than myocardial infarction or stroke. A leg scan survey by Kierkegaard et al (1987) found VT in 13/101 bed-

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ridden patients aged over 55 years who were in hospital because of ischaemic heart disease (but not myocardial infarction), pneumonia, or another acute exacerbation of a chronic disorder. VT developed most often during admissions for pneumonia or heart disease (11/56 patients, or 20%; compared with VT in 2/45, or 4%, among patients with other disorders) (Kierkegaard et al, 1987). Both low-dose heparin and LMW heparins appear to work in this setting, achieving substantial risk reductions without causing bleeding other than injection site bruising (Table 10). In addition, a randomized trial of low-dose heparin, graded pressure elastic stockings, and aspirin, found that all gave VT rates of zero to 6% in bedridden patients with lung disease, compared with 26% in a previous (non-randomized) control group (Ibarra-Perez, 1988). A much earlier study of full-dose oral anticoagulant therapy in patients with congestive heart failure had found that Dicumarol prevented clinically suspected PE and also greatly reduced the incidence of PE found at autopsy (Harvey and Finch, 1950). Table 10. Randomized trials of anticoagulant prophylaxis in medical patients (other than trials after myocardial infarction or stroke). Venous thrombosis (VT) detected by leg scanning. VT rate Investigators

Comments

Belch et al (1981)

Age 40-80 years; 8hourly heparin 5000 units s.c. Age >65 years; LMW heparin (Pharmuka) 60mg s.c. daily

Dahan et al (1986)

Method

Control

Relative risk reduction

P value

2/ 50 (0.04) 13/ 50 (0.26)

0.85

<0.05

4/132 (0.03) 12/131 (0.09)

0.67

0.03

LMW, low molecular weight.

One large-scale trial has found that twice-daily 5000 units s.c. heparin, starting within 12 h of admission, significantly reduced in-hospital mortality among 1358 consecutive patients aged over 40 years who were admitted to general medical wards as emergencies during a 6-month period for reasons other than myocardial infarction or stroke (Halkin et al, 1982). Heparin was given if there was no contraindication and the patient had an even numbered medical record, while patients with odd numbered records became controls: 52/669 (7.8%) even numbered patients died (heparin was given to 411), compared with 75/689 controls (10.9%), a 31% difference (P<0.05). The investigators recorded mortality for all treatment group (even numbered) patients, regardless of whether heparin was given or not, in order to minimize the impact of bias in the selection of even numbered patients for preventive heparin that was inherent in their unconventional case-allocation method (Halkin et al, 1982). There is uncertainty about the frequency of VTE among patients admitted to intensive care units, mainly because the relevant studies are small, but two respiratory intensive care unit surveys have been reported: Moser et al (1981b) found few patients with leg scan evidence of VT during their first week under respiratory intensive care (3/23, or 13%) and only

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677

minor PE at autopsy in 2/16 patients who died, while a larger study found PE in 18/66 patients examined post-mortem (27%) (Neuhaus et al, 1978). Cade (1982) reported VT in 29% of critically ill patients aged over 40 years admitted to a general intensive care unit and studied with fibrinogen leg scanning. Information about the value of prophylaxis in intensive care unit patients is limited to the leg scan study of 119 critically ill patients by Cade (1982), where low-dose heparin reduced the incidence of VT from 29 to 13% (e
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A.S. CALLUS

to be treated to prevent one additional VT (1/0.19-0.10), which seems to be an acceptable benefit, especially when the simplicity of LMW heparin prophylaxis is taken into account. SUMMARY

For 50 years, the key to successfully preventing venous thrombosis (VT) or pulmonary embolism (PE) among high-risk patients has been the judicious use of anticoagulants: first through full doses of oral anticoagulants and more recently through low-dose heparin prophylaxis. Low-dose heparin has become the standard of comparison for other preventive methods, since it is relatively safe and simple, its ability to prevent approximately 65% of the subclinical VT found by leg scanning after elective general surgery is well known, and recent meta-analysis of the many pertinent published clinical trials (large and small) strongly suggests a much greater benefit: a 65% reduction in the risk of postoperative death from major PE. In addition, there are trials that have also found low-dose heparin to be effective in general medical patients, although its value in this clinical setting is much less well documented. Although several effective approaches other than low-dose heparin are available, many of these tend to be either more cumbersome (intermittent external leg compression) or probably less powerful (graded pressure elastic stockings). There are situations where low-dose heparin prophylaxis fails, most obviously after orthopaedic surgery where the use of more complex regimens, including adjusted-dose heparin treatment and various schedules of warfarin prophylaxis, becomes appropriate. Recent progress has come from the intensive clinical exploration of various low molecular weight heparin fractions or fragments which appear to be effective after once daily administration to general surgical patients and show great promise of effectiveness and safety after hip surgery. The level of warfarin effect needed for VT prophylaxis has also been reinvestigated, with trials suggesting a need for less warfarin and a lower prothrombin time effect than was previously thought to be appropriate. Given that any attempts to minimize mortality from PE in hospital patients must rely on the widespread and systematic use of simple, safe, and cost-effective preventive methods, it is hoped that these advances will help move anticoagulant prophylaxis further out of the realm of clinical research and into that of common clinical practice.

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