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Three Part Question

In [patients undergoing cardiac surgery], would the use of [Low molecular weight Heparin] result in [a significantly reduced number of DVTs and PEs without bleeding complications].

Clinical Scenario

You are at a weekly hospital lecture meeting and a guest lecturer has come to discuss the current treatment of pulmonary embolus. The discussion turns to prophylaxis protocols for DVTs in your hospital. It becomes evident that the general physicians, and all non-cardiac surgeons are routinely using low-molecular-weight-heparin for all their patients. The lecturer asks one of your colleagues why you do not use it in cardiac surgery, and he replies that the incidence is very low in cardiac surgery due to the clotting derangements post-operatively and anyway we would give all our patients pericardial effusions if we did. You are not sure that he is correct and therefore resolve to look up the answer.

Search Strategy

Medline 1966–May 2006 using the OVID interface
[exp Venous Thrombosis/OR DVT.mp OR exp Pulmonary Embolism/OR PE.mp OR Pulmonary embol$.mp] AND [Cardiac surgical procedures.mp OR exp cardiac surgical procedures/OR exp Coronary Artery Bypass/OR Coronary art$ bypass.mp OR heart surgery.mp OR exp Thoracic surgery/OR Cardiac surgery.mp OR CABG.mp] AND [exp postoperative complications/OR complication$.mp OR adverse event$.mp] limit to humans.

Search Outcome

Altogether 390 papers were identified on Medline. Relevant major guidelines were also searched together with their reference lists. Sixteen papers represented the best evidence on the topic

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Geets et al, 2001, USA	Publication of a guideline following the Sixth ACCP Consensus Conference on Antithrombotic Therapy USA. Recommendations made for all aspects of surgery and also in medical fields. After systematic review and meta-analysis	Meta -analysis (level 1a)	Prevention of DVT after General Surgery	Untreated Controls 54 trials, 4310pts, incidence of DVT-25% Unfractionated Heparin 47 trials, 10339pts, incidence of DVT – 8% Relative risk reduction (RRR) 68% LMWH 21 trials, 9364pts, incidence of DVT 6% RRR76% Elastic stockings 3 trials, 196 pts incidence of DVT – 14% RRR 44%	Some trials used LDUH (Heparin s/c) instead of LMWH. Cancer patients have a greater risk of DVT compared to normal surgical population. Many different ways of measuring outcome (venography, radio-isotope imaging, US, symptoms, Fibrinogen Uptake Test – FUT) Data also given for knee surgery, neurosurgical, trauma, ICU, cancer and medical patients
			Prevention of PE after general surgery	3 large trials have demonstrated risk reduction of 89% for fatal PE with Heparin s/c.
			Prevention of DVT after Gynaecologic Surgery	Untreated controls 12 trials, 945pts incidence of DVT 16% Unfractionated Heparin 11trials, 1,092 pts. incidence of DVT - 7%, RRR 56%. Elastic stockings 1 trial 104 pts , incidence of DVT 0%
			Prevention of DVT after Hip replacement surgery	Placebo or controls 12trials, 626pts, incidence of prox DVT 27% Elastic stockings 4 trials, 290 pts, incidence of prox DVT 25% Low dose Heparin 11 trials 1016 pts, incidence of prox DVT 19% RRR27% LMWH 30 trials 6216pts, incidence of Prox DVT 5.9% RRR 78%
			ACCP guideline for Moderate risk general surgical patients	Moderate risk:minor procedures but have additional thrombosis risk factors, those having non-major surgery between the ages of 40 and 60 years with no additional risk factors, or those undergoing major operations who are younger than 40 years with no additional clinical risk factors Recommended prophylaxis with LDU, LMWH, Elastic Stockings or IPC. Grade 1A recommnendation Heparin 5000iu s/c bd Deltaparin 3500iu od, Enoxaparin 20mg s/c od, Tinzaparin 3500iu s/c od.
			ACCP guideline for High risk general surgical patients	High Risk: those having non-major surgery over the age of 60 years or with additional risk factors or patients undergoing major surgery over the age of 40 years or with additional risk factors. Recommended prophyaxis with LDUH, LMWH or IPC. Heparin 5000iu s/c tds. Deltaparin 5000iu od, Enoxaparin 30-40mg s/c od, Tinzaparin 4500iu s/c od
Gutt et al, 2005, Germany	Systematic review of MEDLINE and EMBASE articles from 1980 to 2003 searching for prophylactic regimes for DVT after general surgery.	Systematic review (level 1a)	Guideline for prophylaxis	LMWH and LDUH are the most effective therapies in reducing the incidence of DVT, providing a 68% to 76% risk reduction.	No significant new studies identified that were not in the ACCP guideline
			Side-effects	Fewer wound haematomas and bleeding complications with LMWH shown by some studies . Other trials showed LMWH caused more bleeding than LDUH. This appears to be dose related across these studies. Doses higher than 3400iu seemed to increase the bleeding risk in comparison to Heparin sc 2-3 times per day
Bergqvist, 2004, Sweden	Systematic review of MEDLINE and EMBASE 1980 to 2003 searching for DVT prophylactic regimes in General surgery Identified 16 comparative studies	Systematic Review (level 1a)	LMWH versus Unfractionated Heparin	9 trials with 8850pts. LMWH is at least as effective as unfractionated heparin and may have a better safety profile.	The variation in the studies meant that no formal assessment of heterogeneity or meta-analysis of the data was attempted.
			Saftey of LMWH	Bleeding complications 4% to 12% Severe bleeding around 1% Incidence of wound haematomas ranged from 1.4 to 4.4%
			Dose Related haemorrhagic complications	Patients who received 5000units of Dalteparin showed 4.6% bleeding complications and 8.5% incidence of DVT. Those treated with 2500units had 3.6% bleeding complications and 14.9% DVT rates.
Ambrosetti et al, 2004, Italy	270 consecutive patients admitted to 3 rehabilitation facilities after CABG surgery from 19 cardiac surgery units. 82% male, age (mean ± SD) 65± 9 years, 4-19 days after operation. 63% received LMWH Or unfractionated heparin DVT, diagnosed by serial venous ultrasound examination	Cohort study (level 2b)	Rates of Venous Thrombo-embolism following CABG surgery.	DVT 47/270 (17.4%) Proximal DVT 7/270 (2.6%) Pulmonary embolus 2/270 (0.7%), one fatal In 23 cases (49% of DVTs) clots were found in the contralateral leg to saphenous vein harvest Risk Factors include: age, prolonged immobility (post-operative complications), female gender.	Heparin prophylaxis was allocated according to surgeons preference.
			Heparin prophylaxis against DVT	No heparin – 21% suffered a DVT. Heparin <3days – 14% suffered a DVT. Heparin >3 days – 17% suffered a DVT
Ramos et al, 1996, USA	2,551 consecutive patients who underwent cardiac surgery over a ten year period. Group A (1196pts) Heparin 5000iu s/c bd. Group B (1355pts) Heparin 5000iu s/c bd and pneumatic compression stockings ( Plastic bilateral 3 chamber plastic stockings ankle to prox thigh, inflated for 11 secs every hour ) Both methods started immediately post-op and continued until ambulant (4-5 days) Diagnosis made by High risk VQ scan , pulmonary angiogram or autopsy.	PRCT (level 1b)	Incidence of PE	Group A – Heparin 4% (48/1196) Group B - Heparin and PCS 1.5% (21/1355) P<0.001	Use of heparin rather than LMWH, but shows that the incidence of PE following cardiac surgery is 2.7% in total Study conducted between 1984 and 1994.
Shammas, 2000, USA	Studies published since 1975 looking at rates of venous thromboembolism following cardiac bypass and/or valve surgery. 10 studies identified with a total patient population of 18.818 pts	Review based on cohort studies (level 2a)	Incidence of DVT	23% (81/359) of ambulating pts have a DVTeven with aspirin and stockings. <2% of patients are actually diagnosed as an inpatient. Incidence of Prox DVT is 15% (12/81) in 2 studies	Various prophylaxis regimens used, only 1 study used LMWH, first studies from 1975. Incidence of HIT reported to be around 3.8%
			Incidence of PE in CABG patients	Seven studies, 2,229 patients of whom 76 (3.4%) patients had a PE, 11 (0.49%) fatal.
			Incidence of PE in CABG + valve surgery	2 studies, 16,332 patients. 73 (0.45%) has a PE, 17 (0.1%) were fatal.
			Incidence of PE in valve surgery	2 studies, 257 patients. 1 (0.4%) PE which was fatal.
Reis, 1991, USA	US examination of lower leg veins of 29 CABG patients before hospital discharge, who had no signs or symptoms of DVT. Exclusion criteria: anticoagulation therapy, concomitant valve replacement or implantable cardiac defibrillator.	Cohort study (level 3b)	Frequency of DVT	14 (48.3%) patients had 20 documented DVTs. 1 popliteal, 19 in calf veins. Of the 20 thrombi, 10 were in the ipsilateral leg to the saphenous vein harvest site, and 10 in the contralateral leg. None of the DVTs were suspected clinically.	Small numbers. Patients selected depending on availablility of a single ultrasonographer.
Kulik et al, 2006, Canada	Systematic review of MEDLINE, EMBASE, CINAHL, BIOSIS, SIGLE, EIC, Cochrane library up to June 2004 searching for early anticoagulation strategies after mechanical waves	Systematic Review (level 1a)	Anticoagulation with LMWH and oral coumadin	4 trials 168 patients Absolute thromboembolism rate 1/168 (0.6%) Bleeding rate 8/168 (4.8%) 4 major bleeds, 1 minor bleed, 3 pleural effusions 20 trials Thromboembolism rate 28/3056 (0.9%)
			Subcut heparin and oral coumadin	Bleeding rate 50/1525 (3.3%) Bleeding mortality rate 77/9798 (0.8%) 3 tamponades
			Intravenous heparin and oral coumadin	7 trials Thromboembolism 28/2535 (1.1%) Bleeding rate 19/263 (7.2%) Bleeding mortality rate19 /2466 (0.8%)
Malouf et al, 1993, Lebanon	141 patients undergoing CABG (56), valve (69) or congenital (16) cardiac surgery postoperatively by 2-D Echocardiography Group 1 (n=74) received full anticoagulation (warfarin 73; heparin 1) Group 2 (n=67) antithrombotics or no treatment	Prospective Cohort Study (level 2b)	Pericardial effusion of any size	Anticoagulated group 43/74 (58%) Controls 27/67 (40%) P=0.043 by Fisher's exact test	41 of the 74 anticoagulations had a period of excessive anticoagulation and these patients had an extensive incidence of effusion Selective cohort of patients
			Large pericardial effusions	Anticoagulated group 24/74 (32%) Controls 3/67 (4%) P<0.005
			Tamponade requiring drainage	Anticoagulated group 12/74 (16%) Controls 0/67 (0%) P<0.001

Comment(s)

There are three main issues when considering the possibility of DVT prophylaxis in patients post-cardiac surgery. Firstly whether there is a significant morbidity and mortality associated with DVTs and PEs in patients post-cardiac surgery. Secondly whether prophylaxis can significantly reduce the incidence of DVT and PE. Thirdly whether DVT prophylaxis might cause an increase in post-operative bleeding complications. Pravalence and morbidity of DVTs and PEs after Cardiac Surgery Shammas in 2000 performed a literature review to obtain an estimate of the incidence of DVTs and PEs after cardiac surgery. They identified 8 studies comprising over 18,000 patients and found that if routine USS or venography was performed the incidence of DVT was 22%, and proximal DVT 15%. In addition the incidence of PE was 0.8% with 29 fatal PEs. Interestingly the clinical detection of DVTs was less than 2% and half of DVTs were in the non-harvested leg. Ambrosettia in 2004 performed serial ultrasound of 270-consecutive patients post CABG attending 3-rehabilitation programmes. They found an incidence of DVT of 17%, an incidence of proximal DVT of 2.6% and 2-patients suffered a pulmonary embolus. Half of DVTs were in the leg where the saphenous vein was not harvested. They also analysed their data for protection of DVT with heparin and found a weak relationship but their numbers were too small to definitively prove this link. Ramos in 1996 performed a large PRCT comparing heparin 5000iu sc bd with heparin and 4-5 days of intermittent compression stockings. They decreased the incidence of PE from 4% to 1.5% with this intervention. This study showed that even with good prophylaxis, the incidence of PE after cardiac surgery around 3%. Risk reduction of DVTs and PEs with heparin. Considering whether prophylaxis significantly reduces the incidence of DVT and PE, we could find no clinical trials that assessed the impact of DVT prophylaxis in patients post-cardiac surgery. However the American College of Chest Physicians(ACCP) in 2001 published a comprehensive systematic review and guideline on DVT prophylaxis in other specialties. In general surgery 68 trials in nearly 20,000patients have shown that either heparin or LMWH reduces the relative risk of DVT by 70%. In hip replacement surgery in over 40-trials with 7000-patients LMWH or heparin reduced the risk by upto 78%. 3-ICU trials showed at least a halving of DVT, and 3-studies post-MI also showed a reduction. The general surgery trials have also demonstrated a reduction in proximal DVT, PE and fatal pulmonary embolus. Thus across the whole range of surgical and medical conditions the incidence of DVT is high and prophylaxis significantly reduces the incidence of DVT and the incidence of its sequelae. Complications of heparin therapy. Gutt in 2005 performed a systematic review of DVT prophylaxis in general surgery. They looked at the increase in bleeding complications and stated that LMWH at doses around 3400iu or lower, reduced bleeding risk compared to heparin but above this, the risk was higher. They did not quantify this risk. Bergqvist in 2003 performed a systematic review in general surgery, and looked at efficacy and safety of LMWH versus unfractionated heparin. They found that the rate of bleeding was 4-12% and severe bleeding was around 1%. Concluded that the safety profile of LMWH was superior to unfractionated heparin at lower doses of LMWH, but this did rise as the dose increased. Malouf assessed the impact of anticoagulation on pericardial effusions. They assessed 141pts with serial echo of patients having warfarinisation post surgery. 67-Controls had an incidence of 4% of large effusions, but warfarinised patients had a 32% incidence, with 12-delayed tamponades. As a caveat, 41-patients had excessive anticoagulation at some stage and this study was in patients receiving full warfarin anticoagulation rather than prophylaxtic heparin. Kulik in 2006 performed a systematic review of early anticoagulation strategies after mechanical valve replacements. They compared commencement of warfarin alone, with subcutaneous heparin and warfarin, LMWH and warfarin and intravenous heparin and warfarin. The bleeding rate was highest with intravenous heparin at 8% and was lower if s/c or LMW heparin was used at around 4%.

Clinical Bottom Line

The incidence of Thromboembolism after cardiac surgery is similar to the incidence in patients undergoing high risk general surgery. The ACCP guidelines recommend heparin prophylaxis for this risk group and we conclude that patients post-cardiac surgery should be treated equivalently, with prophylaxis using heparin or LMWH starting on the first post-operative day.

References

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2. Gutt CN, Oniu T, Wolkener F et al. Prophylaxis and treatment of deep vein thrombosis in general surgery. The American Journal of Surgery 2005;189:14-22.
3. Bergqvist D. Low molecular weight heparin for the prevention of venous thromboembolism after abdominal surgery. British Journal of Surgery 2004; 91: 965-974.
4. Ambrosetti M, Salerno M, Zambelli M et al. Deep Vein Thrombosis Among Patients Entering Cardiac Rehabilitation After Coronary Artery Bypass Surgery. CHEST 2004;125:191-196.
5. Ramos R, Salem BI, De Pawlikowski MP et al. The efficacy of pneumatic compression stockings in the prevention of pulmonary embolism after cardiac surgery. CHEST 1996;109:82-85.
6. Shammas NW. Pulmonary Embolus after Coronary Artery Bypass Surgery: A Review of the Literature. Clinical Cardiology 2000;23:637-644.
7. Reis SE, Polak JF, Hirsch DR et al. Frequency of deep venous thrombosis in asymptomatic patients with coronary artery bypass grafts. American Heart Journal 1991;122(2):478-82.
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11. Wisoff BG, Hartstein ML, Aintablian A et al. Risk of coronary surgery. Two hundred consecutive patients with no hospital deaths. J Thorac Cardiovasc Surg 1975;69:669-673.
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13. Pouplard C, May M-A, Iochmann S et al. Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular weight heparin. Circulation 1999; 99:2530–2536.
14. Kulik A, Rubens FD, Wells PS et al. Early postoperative anticoagulation after mechanical valve replacement: A systematic review. Annals of Thoracic Surgery 2006;81:770-81.
15. Malouf JF, Alam S, Gharzeddine W et al. The role of anticoagulation in the development of pericardial effusion and late tamponade after cardiac surgery. .[erratum appears in Eur Heart J 1994 Apr;15(4):583-4]. Eur. Heart J 1993;14:1451-1457.
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