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
651 Copyright © 1990, by Bailli~re Tindall All rights of reproduction in any form reserved
652
A.S. GALLUS
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
1-3
ANTICOAGULANTS IN PREVENTION OF VENOUS THROMBOEMBOLISM
653
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
654
A.S. GALLUS
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).
656
A.S.
GALLUS
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
ANTICOAGULANTS IN
PREVENTIONOF VENOUS THROMBOEMBOLISM
657
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),
658
4.
A . S . GALLUS
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,
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
651 Copyright © 1990, by Bailli~re Tindall All rights of reproduction in any form reserved
652
A.S. GALLUS
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
1-3
ANTICOAGULANTS IN PREVENTION OF VENOUS THROMBOEMBOLISM
653
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
654
A.S. GALLUS
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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10
11
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
ANTICOAGULANTS IN
PREVENTIONOF VENOUS THROMBOEMBOLISM
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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,
