- Email: [email protected]
Comparison of the Effectiveness and Safety of Low-Molecular Weight Heparin Versus Unfractionated Heparin Anticoagulation After Heart Valve Surgery
Comparison of the Effectiveness and Safety of Low-Molecular Weight Heparin Versus Unfractionated Heparin Anticoagulation After Heart Valve Surgery Claudia Bucci, PharmDa,b,*, William H. Geerts, MDc, Andrew Sinclair BScPhmb, and Stephen E. Fremes, MDd Although unfractionated heparin (UFH) is used routinely after heart valve surgery at many institutions, cardiovascular surgery patients have a particularly high risk for developing heparin-induced thrombocytopenia (HIT). The aim of this study was to compare the efficacy and safety of low-molecular-weight heparin (LMWH) or UFH after heart valve surgery by conducting a retrospective evaluation of consecutive cardiovascular surgery patients in whom the LMWH dalteparin (n ⴝ 100) was used as the postoperative anticoagulant. This group was compared to an earlier group of patients who received UFH (n ⴝ 103). The main outcomes included the efficacy of the anticoagulant regimens (determined by the incidence of valve thrombosis, arterial thromboembolic events, and venous thromboembolic events) and the safety (determined by major bleeding, HIT, thrombotic events in HIT-positive cases, and death). Overall, there were for fewer thrombotic events in the LMWH-treated group (4% vs 11%, p ⴝ 0.11). There was a higher rate of bleeding events in the UFH-treated group (10% vs 3%, p ⴝ 0.08). Six patients in the UFH-treated group developed HIT, 4 of whom had thrombotic events (HIT with thrombosis). In the LMWHtreated group, 3 patients developed HIT, 1 of whom had HIT with thrombosis. In conclusion, in this study, an LMWH regimen after heart valve surgery was effective and safe, with fewer thrombotic, bleeding, HIT, and HIT with thrombosis events. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:591–594) In the past, intravenous unfractionated heparin (UFH) was used routinely at our institution after heart valve replacement surgery to prevent thrombotic complications (Appendix A). LMWH is associated with a substantially
a Department of Pharmacy and bFaculty of Pharmacy, University of Toronto; and cThromboembolism Program, Department of Medicine, and d Division of Cardiovascular Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Manuscript received July 15, 2010; revised manuscript received and accepted October 11, 2010. Dr. Bucci has received research grant support from AstraZeneca, Wilmington, Delaware. Dr. Bucci is a consultant for Sanofi-Aventis, Paris, France; Bristol-Myers Squibb, New York, New York; Bayer Healthcare, Munich, Germany; Boehringer Ingelheim, Ingelheim, Germany; and Eli Lilly & Company, Indianapolis, Indiana. Dr. Geerts has received research grant support from Bayer Healthcare; Pfizer, Inc., New York, New York; and Sanofi-Aventis. Dr. Geerts is a consultant for Bayer Healthcare; Boehringer Ingelheim; GlaxoSmithKline, London, United Kingdom; LEO Pharma A/S, Ballerup, Denmark; Pfizer, Inc.; and Sanofi-Aventis. Dr. Geerts has received honoraria for presentations from Bayer Healthcare, Boehringer Ingelheim, Pfizer, Inc., and Sanofi-Aventis. Dr. Fremes has received honoraria from Sanofi-Aventis; Bayer Healthcare; Astellas Pharma US, Inc., Deerfield, Illinois; Novo Nordisk A/S, Bagsværd, Denmark; Novadaq, Bonita Springs, Florida; Medtronic, Inc., Minneapolis, Minnesota; Edwards Lifesciences, Irvine, California; Sorin Group USA, Inc., Arvada, Colorado; and Merck & Company, Whitehouse Station, New Jersey. Dr. Fremes has received research support from St. Jude Medical, Inc., St. Paul, Minnesota; Aventis; Proctor & Gamble, Cincinnati, Ohio; Medicure, Winnipeg, Manitoba, Canada; and Merck & Company. *Corresponding author: Tel: 416-480-6755; fax: 416-480-5887. E-mail address: [email protected] (C. Bucci).
0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.10.020
lower rate of heparin-induced thrombocytopenia (HIT) and HIT with thrombosis than UFH and may be a safer alternative after heart valve surgery.1 We replaced intravenous and subcutaneous UFH with subcutaneous low-molecularweight heparin (LMWH) in prophylactic or therapeutic doses for early anticoagulation after heart valve replacement surgery (Appendix B). The objective of the study was to assess the efficacy and safety of anticoagulation with LMWH after heart valve surgery compared to UFH. Methods In March 2006, we implemented an “avoid-heparin policy” after cardiovascular surgery (Appendixes A and B). Intraoperative UFH was used in all cases. We conducted a retrospective evaluation of consecutive patients in whom the LMWH dalteparin was used, and we compared this group to an earlier group of patients who received UFH. This study was approved by the ethics review board of Sunnybrook Health Sciences Centre. The main outcome measures included the efficacy (determined by the incidence of valve thrombosis, arterial thromboembolic events, and venous thromboembolic events) and the safety (determined by major bleeding, HIT, thrombotic events in HIT-positive cases, and death) of the 2 anticoagulant regimens. All outcomes collected occurred during the operative hospital admission. Confirmed HIT was defined by 1 of the following: positive serotonin release assay, positive HIT enzyme-linked immunosorbent assay plus high clinical probability for HIT www.ajconline.org
592
The American Journal of Cardiology (www.ajconline.org)
Table 1 Baseline characteristics Characteristic Age (years) Age ⬎75 years Men/women Left ventricular function 1 2 3 4 Atrial fibrillation* Renal dysfunction† Valve replacement Single Mechanical aortic Tissue aortic Mechanical mitral Tissue mitral Mitral annuloplasty Tricuspid repair Double Coronary bypass Length of surgery (hours) Length of stay after surgery (days)
Heparin (n ⫽ 103)
Dalteparin (n ⫽ 100)
65.1 ⫾ 12.6 (31–87) 23 (22%) 72/31
66.1 ⫾ 12.1 (43–84) 24 (24%) 67/33
57 (55%) 22 (21%) 16 (16%) 8 (8%) 66 (64%) 13 (13%)
52 (52%) 28 (28%) 15 (15%) 5 (5%) 68 (68%) 16 (16%)
95 (92%) 27 21 17 14 15 1 8 (8%) 43 (42%) 4.9 ⫾ 1.7 (2.3–10.2) 15.9 ⫾ 9.9 (5–61)
90 (90%) 23 19 21 8 18 1 10 (10%) 32 (32%) 5.3 ⫾ 1.9 (2.7–12.9) 16.1 ⫾ 9.5 (6–64)
p Value 0.57 0.87 0.76 0.65
0.67 0.55 0.63
0.63 0.19 0.09 0.87
Data are expressed as mean ⫾ SD (range) or as number (percentage). * Includes transient and chronic episodes. Transient atrial fibrillation occurred in 49 and 43 patients in the heparin and LMWH groups, respectively (p ⫽ 0.57). Chronic atrial fibrillation was present preoperatively and/or was persistent after surgery and occurred in 17 and 25 patients in the heparin and LMWH groups, respectively (p ⫽ 0.17). † Creatinine clearance ⬍30 ml/min.
or strongly positive HIT enzyme-linked immunosorbent assay (optical density ⱖ1.0). HIT was ruled out in patients with negative results on HIT enzyme-linked immunosorbent assay or serotonin release assay. Major bleeding was defined as any overt bleeding meeting ⱖ1 of the following criteria: proved fatal bleeding, intracranial hemorrhage (computed tomography or magnetic resonance imaging required), retroperitoneal bleeding (ultrasound, computed tomography, or magnetic resonance imaging required), bleeding requiring an intervention (pericardial bleeding requiring reoperation or catheter drainage of blood, pleural bleeding requiring thoracotomy or chest tube, gastrointestinal bleeding requiring surgery or endoscopic treatment, wound bleeding requiring reoperation), other life-threatening bleeding at a critical site, bleeding requiring transfusion of ⱖ2 U of red blood cells, or bleeding that resulted in chronic sequelae or prolongation of the hospital stay. Bleeding requiring pericardiocentesis, thoracentesis, or diagnostic endoscopy alone was not considered major. Nonmajor bleeding was defined as any of the following: epistaxis requiring nasal packing, airway bleeding, hematuria, hematemesis (but not just coffee grounds), or gastrointestinal bleeding (frank blood or melena stools) not requiring an intervention. All analyses were done using InStat version 3 (GraphPad Software, San Diego, California). All statistical tests were 2 sided and used a p value of 0.05 as the threshold for statistical significance. Baseline discrete variables are presented as frequencies or percentages, while continuous variables are presented as mean ⫾ SD or as median (interquartile range).
The frequencies of the clinical end points were compared using a chi-square or Fisher’s exact tests. Results The control group consisted of 103 consecutive patients treated with UFH after heart valve surgery from April 2004 to May 2006. These patients received only UFH in therapeutic (83%) or prophylactic (17%) doses. The control group patients were compared to 100 heart valve patients given therapeutic (73%) or prophylactic (27%) dalteparin postoperatively from March 2006 to August 2007. The 2 groups were similar for a large number of demographic and clinical characteristics (Table 1). The mean age was approximately 65 years, and 68% of patients were men. Thrombotic and bleeding risk factors in the 2 groups were similar apart from greater postoperative aspirin use in the UFH patients (Table 2). Approximately 60% of the study population had ⱖ1 risk factor for thrombosis, and ⬎80% of patients had ⱖ1 risk factor for bleeding. Overall, there were fewer thrombotic events in the LMWH-treated group, although the difference was not statistically significant (4% vs 11%, p ⫽ 0.11; Table 3). In the UFH group, there were 11 thrombotic events (5 strokes, 1 valve thrombosis, 1 ischemic bowel, 2 transient global amnesia, 1 foot embolus, 1 kidney infarction). In the dalteparin group, there were 4 thrombotic events (3 strokes, 1 ischemic bowel). The thromboembolic events are listed in Table 4 . In the UFH-treated group, 4 thrombotic events occurred in
Valvular Heart Disease/ Table 2 Risk factors for thrombosis and bleeding Risk Factor Thrombotic Atrial fibrillation* Grade 4 left ventricle Previous thromboembolism Left atrial enlargement Previous myocardial infarction Bleeding Postoperative aspirin Renal dysfunction Clopidogrel Nonsteroidal antiinflammatory drug Intraoperative stroke International normalized ratio ⬎5 (postoperatively) Coagulation disorder† Therapeutic anticoagulation (postoperative) Warfarin (postoperative)
Heparin (n ⫽ 103)
Dalteparin (n ⫽ 100)
17 (17%) 8 (8%) 6 (6%) 17 (17%) 13 (13%)
26 (26%) 5 (5%) 12 (12%) 12 (12%) 10 (10%)
93 (90%) 13 (13%) 3 (3%) 12 (12%)
32 (32%) 16 (16%) 1 (1%) 27 (27%)
1 (1%) 4 (4%)
— 2 (2%)
— 86 (83%)
3 (3%) 73 (73%)
100 (97%)
97 (97%)
593
bleed. Most of the bleeds occurred in patients receiving therapeutic anticoagulation with UFH or LMWH or with warfarin. Concomitant aspirin increased the risk for bleeding events (odds ratio 7.43, 95% confidence interval 1.85 to 126). Six patients in the UFH-treated group developed HIT, 4 of whom had thrombotic events (HIT with thrombosis). In the LMWH-treated group, 3 patients developed HIT, 1 of whom had HIT with thrombosis. There was 1 death in each group during hospitalization, both related to HIT (Table 3). Discussion
* Represents chronic atrial fibrillation (i.e., present preoperatively or at discharge). † Includes factor VII deficiency (n ⫽ 1) and sickle-cell disease (n ⫽ 2). Table 3 Comparison of efficacy and safety outcomes Outcome
Heparin (n ⫽ 103)
Dalteparin (n ⫽ 100)
p Value
Thrombotic events Stroke Valve thrombosis Ischemic bowel Transient global Amnesia Foot embolus Infarction kidney Bleeding events Pericardial Retroperitoneal Hemothorax Patients with HIT Patients with HIT with thrombosis Death due to HIT
11 (11%) 5 1 1 2
4 (4%) 3 — 1
.11
1 1 10 (10%) 5 4 1 6 (6%) 4 (4%) 1 (1%)
— — 3 (3%) 2 — 1 3 (3%) 1 (1%) 1 (1%)
0.08
0.50 0.37 1.00
HIT-positive patients, while in the LMWH-treated group, 1 thrombotic event occurred in an HIT-positive patient. There was a higher rate of bleeding events in the UFHtreated group (10% vs 3%, p ⫽ 0.08; Table 3). There were 10 major bleeding events in the UFH-treated group (5 pericardial bleeds, 4 retroperitoneal bleeds, and 1 hemothorax; all these patients received concomitant aspirin and/or clopidogrel) and 3 major bleeding events in the LMWH-treated group (2 pericardial bleeds, 1 hemothorax; 2 of these patients received concomitant aspirin and/or clopidogrel). One patient in each group had a nonmajor lower gastrointestinal
Patients who have undergone cardiac surgery routinely receive UFH during and after surgery. The product monographs for LMWHs warn against the use of LMWH for prevention of thromboembolism in patients with prosthetic heart valves, including those who are pregnant.2 This is based on 2 cases of valve thrombosis in pregnant women receiving enoxaparin.3 The Anticoagulation in Prosthetic Valves and Pregnancy Consensus Report Panel concluded that the level of anticoagulation with enoxaparin may not have been optimal in these cases.4 LMWH may be a safer alternative to UFH in cardiac surgery patients because of the lower risk for HIT. However, to date, the safety and efficacy of LMWH after mechanical heart valve surgery has been poorly evaluated. In a nonrandomized case series of 208 patients who underwent heart valve replacement, therapeutic anticoagulation was more rapidly and predictably achieved with LMWH than with UFH.5 In a larger study with no control group, the use of the LMWH enoxaparin as bridging to therapeutic anticoagulation with warfarin after mechanical valve replacement appeared to be safe and effective.6 In a small study, LMWH patients were matched to patients who received UFH after mechanical heart valve implantation.7 Although bridging with LMWH was as safe and effective as bridging with UFH, LMWH was associated with reduced length of hospital stay and costs. In this study, we found that an LMWH regimen after heart valve surgery was effective and safe. In addition, there was a lower risk for thrombosis and bleeding in the LMWHtreated group. No cases of valve thrombosis occurred in the LMWH group of this study. There were also fewer HIT and HIT with thrombosis events in patients receiving LMWH. Our study provides data supporting the use of LMWH in patients with newly implanted heart valves. We believe that this is the first report assessing the development of HIT in this patient population. Our study was retrospective in nature and consisted of a relatively small sample. Although the baseline characteristics were similar, confounding may be present. Confounding from unmeasured factors such as the motivation of the clinical staff and increased attention to postoperative anticoagulation may have been present. We believe that this is the first intervention study to systematically attempt to reduce HIT in cardiac surgery. The results of this preliminary study are important as part of ongoing quality assurance of the protocol implemented at our institution.
594
The American Journal of Cardiology (www.ajconline.org)
Appendix A: Unfractionated Heparin Anticoagulation Protocol After Heart Valve Replacement Valve Position Mechanical valves Aortic
Additional Risk Factors*
Heparin Therapy
No
5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin. 5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin. 500 U/hour IV starting 12 hours postoperatively for 96 hours. If INR ⬍2 on POD 4, start IV heparin. 500 U/hour IV starting 12 hours postoperatively for 96 hours. If INR ⬍2 on POD 4, start IV heparin.
Aortic
Yes
Mitral
No
Mitral
Yes
Tissue valves Aortic Aortic
No Yes
Mitral and mitral annuloplasty
No
Mitral and mitral annuloplasty
Yes
Aspirin Use
None (except for DVT prophylaxis). 5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin. 5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin. 5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin.
Target INR
None
2.0–3.0
ECASA 81 mg/day
2.0–3.0
None
2.5–3.5
ECASA 81 mg/day
2.5–3.5
ECASA 325 mg/day None
No warfarin 2.0–3.0
ECASA 325 mg/day; start after 3 months of warfarin None
2.0–3.0; warfarin only for 3 months 2.0–3.0
* Atrial fibrillation, large left atrium, left atrial thrombus, previous thromboembolism. DVT ⫽ deep venous thrombosis; ECASA ⫽ enteric-coated aspirin; INR ⫽ international normalized ratio; IV ⫽ intravenous; POD ⫽ postoperative day; q12h ⫽ every 12 hours; SC ⫽ subcutaneous.
Appendix B: Low-Molecular-Weight Heparin Anticoagulation Protocol After Heart Valve Replacement Valve Position Mechanical valves Aortic
Mitral
Tissue valves Aortic without risk factors Aortic with risk factors*
Mitral and mitral annuloplasty
LMWH Therapy
Aspirin
Target INR
Dalteparin 2,500 U SC qhs. If INR ⬍2 at 96 hours postoperatively, increase dalteparin dose.* Dalteparin 5,000 U SC qhs. If INR ⬍2 at 96 hours postoperatively, increase dalteparin dose.*
None
2.0–3.0
None
2.5–3.5
None Dalteparin 2,500 U SC qhs. If INR ⬍2 at 96 hours postoperatively, increase dalteparin dose.* Dalteparin 2,500 U SC qhs. If INR ⬍2 at 96 hours postoperatively, increase dalteparin dose.*
ECASA 325 mg/day None
None
None
2.0–3.0 Warfarin for 3 months (unless risk factors are present), then ECASA 325 mg/day is added
2.0–3.0
* Sustained or intermittent atrial fibrillation lasting ⬎48 hours, maze procedure. ECASA ⫽ enteric-coated aspirin; INR ⫽ international normalized ratio; qhs ⫽ at bedtime; SC ⫽ subcutaneous.
1. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated heparin and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;106:2710 –2715. 2. Canadian Pharmacists Association. Product monograph heparins: low molecular weight. In: e-CPS: Compendium of Pharmaceuticals and Specialties. Available at: http://www.pharmacists.ca/content/products/ ecps_english.cfm. Accessed February 4, 2010. 3. Shapira Y, Sagie A, Battler A. Low-molecular-weight heparin for the treatment of patients with mechanical heart valves. Clin Cardiol 2002;25:323–327. 4. Anticoagulation and enoxaparin use in patients with prosthetic heart vavles and/or pregnancy. Clin Cardiol Consensus Rep 2002;3:1–20.
5. Montalescot G, Polle V, Collet JP, Leprince P, Bellanger A, Gandjbakhch I. Low molecular weight heparin after mechanical heart valve replacement. Circulation 2000;101:1083–1086. 6. Meurin P, Tabet JY, Weber H, Renaud N, Ben Driss A. Low-molecularweight heparin as a bridging anticoagulant early after mechanical heart valve replacement. Circulation 2006;113:564 –569. 7. Fanikos J, Tsilimingras K, Kucher N, Rosen AB, Hieblinger MD, Goldhaber SZ. Comparison of efficacy, safety and cost of low-molecular weight heparin with continuous-infusion unfractionated heparin for initiation of anticoagulation after mechanical prosthetic valve implantation. Am J Cardiol 2004;93:247–250.
a Department of Pharmacy and bFaculty of Pharmacy, University of Toronto; and cThromboembolism Program, Department of Medicine, and d Division of Cardiovascular Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Manuscript received July 15, 2010; revised manuscript received and accepted October 11, 2010. Dr. Bucci has received research grant support from AstraZeneca, Wilmington, Delaware. Dr. Bucci is a consultant for Sanofi-Aventis, Paris, France; Bristol-Myers Squibb, New York, New York; Bayer Healthcare, Munich, Germany; Boehringer Ingelheim, Ingelheim, Germany; and Eli Lilly & Company, Indianapolis, Indiana. Dr. Geerts has received research grant support from Bayer Healthcare; Pfizer, Inc., New York, New York; and Sanofi-Aventis. Dr. Geerts is a consultant for Bayer Healthcare; Boehringer Ingelheim; GlaxoSmithKline, London, United Kingdom; LEO Pharma A/S, Ballerup, Denmark; Pfizer, Inc.; and Sanofi-Aventis. Dr. Geerts has received honoraria for presentations from Bayer Healthcare, Boehringer Ingelheim, Pfizer, Inc., and Sanofi-Aventis. Dr. Fremes has received honoraria from Sanofi-Aventis; Bayer Healthcare; Astellas Pharma US, Inc., Deerfield, Illinois; Novo Nordisk A/S, Bagsværd, Denmark; Novadaq, Bonita Springs, Florida; Medtronic, Inc., Minneapolis, Minnesota; Edwards Lifesciences, Irvine, California; Sorin Group USA, Inc., Arvada, Colorado; and Merck & Company, Whitehouse Station, New Jersey. Dr. Fremes has received research support from St. Jude Medical, Inc., St. Paul, Minnesota; Aventis; Proctor & Gamble, Cincinnati, Ohio; Medicure, Winnipeg, Manitoba, Canada; and Merck & Company. *Corresponding author: Tel: 416-480-6755; fax: 416-480-5887. E-mail address: [email protected] (C. Bucci).
0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.10.020
lower rate of heparin-induced thrombocytopenia (HIT) and HIT with thrombosis than UFH and may be a safer alternative after heart valve surgery.1 We replaced intravenous and subcutaneous UFH with subcutaneous low-molecularweight heparin (LMWH) in prophylactic or therapeutic doses for early anticoagulation after heart valve replacement surgery (Appendix B). The objective of the study was to assess the efficacy and safety of anticoagulation with LMWH after heart valve surgery compared to UFH. Methods In March 2006, we implemented an “avoid-heparin policy” after cardiovascular surgery (Appendixes A and B). Intraoperative UFH was used in all cases. We conducted a retrospective evaluation of consecutive patients in whom the LMWH dalteparin was used, and we compared this group to an earlier group of patients who received UFH. This study was approved by the ethics review board of Sunnybrook Health Sciences Centre. The main outcome measures included the efficacy (determined by the incidence of valve thrombosis, arterial thromboembolic events, and venous thromboembolic events) and the safety (determined by major bleeding, HIT, thrombotic events in HIT-positive cases, and death) of the 2 anticoagulant regimens. All outcomes collected occurred during the operative hospital admission. Confirmed HIT was defined by 1 of the following: positive serotonin release assay, positive HIT enzyme-linked immunosorbent assay plus high clinical probability for HIT www.ajconline.org
592
The American Journal of Cardiology (www.ajconline.org)
Table 1 Baseline characteristics Characteristic Age (years) Age ⬎75 years Men/women Left ventricular function 1 2 3 4 Atrial fibrillation* Renal dysfunction† Valve replacement Single Mechanical aortic Tissue aortic Mechanical mitral Tissue mitral Mitral annuloplasty Tricuspid repair Double Coronary bypass Length of surgery (hours) Length of stay after surgery (days)
Heparin (n ⫽ 103)
Dalteparin (n ⫽ 100)
65.1 ⫾ 12.6 (31–87) 23 (22%) 72/31
66.1 ⫾ 12.1 (43–84) 24 (24%) 67/33
57 (55%) 22 (21%) 16 (16%) 8 (8%) 66 (64%) 13 (13%)
52 (52%) 28 (28%) 15 (15%) 5 (5%) 68 (68%) 16 (16%)
95 (92%) 27 21 17 14 15 1 8 (8%) 43 (42%) 4.9 ⫾ 1.7 (2.3–10.2) 15.9 ⫾ 9.9 (5–61)
90 (90%) 23 19 21 8 18 1 10 (10%) 32 (32%) 5.3 ⫾ 1.9 (2.7–12.9) 16.1 ⫾ 9.5 (6–64)
p Value 0.57 0.87 0.76 0.65
0.67 0.55 0.63
0.63 0.19 0.09 0.87
Data are expressed as mean ⫾ SD (range) or as number (percentage). * Includes transient and chronic episodes. Transient atrial fibrillation occurred in 49 and 43 patients in the heparin and LMWH groups, respectively (p ⫽ 0.57). Chronic atrial fibrillation was present preoperatively and/or was persistent after surgery and occurred in 17 and 25 patients in the heparin and LMWH groups, respectively (p ⫽ 0.17). † Creatinine clearance ⬍30 ml/min.
or strongly positive HIT enzyme-linked immunosorbent assay (optical density ⱖ1.0). HIT was ruled out in patients with negative results on HIT enzyme-linked immunosorbent assay or serotonin release assay. Major bleeding was defined as any overt bleeding meeting ⱖ1 of the following criteria: proved fatal bleeding, intracranial hemorrhage (computed tomography or magnetic resonance imaging required), retroperitoneal bleeding (ultrasound, computed tomography, or magnetic resonance imaging required), bleeding requiring an intervention (pericardial bleeding requiring reoperation or catheter drainage of blood, pleural bleeding requiring thoracotomy or chest tube, gastrointestinal bleeding requiring surgery or endoscopic treatment, wound bleeding requiring reoperation), other life-threatening bleeding at a critical site, bleeding requiring transfusion of ⱖ2 U of red blood cells, or bleeding that resulted in chronic sequelae or prolongation of the hospital stay. Bleeding requiring pericardiocentesis, thoracentesis, or diagnostic endoscopy alone was not considered major. Nonmajor bleeding was defined as any of the following: epistaxis requiring nasal packing, airway bleeding, hematuria, hematemesis (but not just coffee grounds), or gastrointestinal bleeding (frank blood or melena stools) not requiring an intervention. All analyses were done using InStat version 3 (GraphPad Software, San Diego, California). All statistical tests were 2 sided and used a p value of 0.05 as the threshold for statistical significance. Baseline discrete variables are presented as frequencies or percentages, while continuous variables are presented as mean ⫾ SD or as median (interquartile range).
The frequencies of the clinical end points were compared using a chi-square or Fisher’s exact tests. Results The control group consisted of 103 consecutive patients treated with UFH after heart valve surgery from April 2004 to May 2006. These patients received only UFH in therapeutic (83%) or prophylactic (17%) doses. The control group patients were compared to 100 heart valve patients given therapeutic (73%) or prophylactic (27%) dalteparin postoperatively from March 2006 to August 2007. The 2 groups were similar for a large number of demographic and clinical characteristics (Table 1). The mean age was approximately 65 years, and 68% of patients were men. Thrombotic and bleeding risk factors in the 2 groups were similar apart from greater postoperative aspirin use in the UFH patients (Table 2). Approximately 60% of the study population had ⱖ1 risk factor for thrombosis, and ⬎80% of patients had ⱖ1 risk factor for bleeding. Overall, there were fewer thrombotic events in the LMWH-treated group, although the difference was not statistically significant (4% vs 11%, p ⫽ 0.11; Table 3). In the UFH group, there were 11 thrombotic events (5 strokes, 1 valve thrombosis, 1 ischemic bowel, 2 transient global amnesia, 1 foot embolus, 1 kidney infarction). In the dalteparin group, there were 4 thrombotic events (3 strokes, 1 ischemic bowel). The thromboembolic events are listed in Table 4 . In the UFH-treated group, 4 thrombotic events occurred in
Valvular Heart Disease/ Table 2 Risk factors for thrombosis and bleeding Risk Factor Thrombotic Atrial fibrillation* Grade 4 left ventricle Previous thromboembolism Left atrial enlargement Previous myocardial infarction Bleeding Postoperative aspirin Renal dysfunction Clopidogrel Nonsteroidal antiinflammatory drug Intraoperative stroke International normalized ratio ⬎5 (postoperatively) Coagulation disorder† Therapeutic anticoagulation (postoperative) Warfarin (postoperative)
Heparin (n ⫽ 103)
Dalteparin (n ⫽ 100)
17 (17%) 8 (8%) 6 (6%) 17 (17%) 13 (13%)
26 (26%) 5 (5%) 12 (12%) 12 (12%) 10 (10%)
93 (90%) 13 (13%) 3 (3%) 12 (12%)
32 (32%) 16 (16%) 1 (1%) 27 (27%)
1 (1%) 4 (4%)
— 2 (2%)
— 86 (83%)
3 (3%) 73 (73%)
100 (97%)
97 (97%)
593
bleed. Most of the bleeds occurred in patients receiving therapeutic anticoagulation with UFH or LMWH or with warfarin. Concomitant aspirin increased the risk for bleeding events (odds ratio 7.43, 95% confidence interval 1.85 to 126). Six patients in the UFH-treated group developed HIT, 4 of whom had thrombotic events (HIT with thrombosis). In the LMWH-treated group, 3 patients developed HIT, 1 of whom had HIT with thrombosis. There was 1 death in each group during hospitalization, both related to HIT (Table 3). Discussion
* Represents chronic atrial fibrillation (i.e., present preoperatively or at discharge). † Includes factor VII deficiency (n ⫽ 1) and sickle-cell disease (n ⫽ 2). Table 3 Comparison of efficacy and safety outcomes Outcome
Heparin (n ⫽ 103)
Dalteparin (n ⫽ 100)
p Value
Thrombotic events Stroke Valve thrombosis Ischemic bowel Transient global Amnesia Foot embolus Infarction kidney Bleeding events Pericardial Retroperitoneal Hemothorax Patients with HIT Patients with HIT with thrombosis Death due to HIT
11 (11%) 5 1 1 2
4 (4%) 3 — 1
.11
1 1 10 (10%) 5 4 1 6 (6%) 4 (4%) 1 (1%)
— — 3 (3%) 2 — 1 3 (3%) 1 (1%) 1 (1%)
0.08
0.50 0.37 1.00
HIT-positive patients, while in the LMWH-treated group, 1 thrombotic event occurred in an HIT-positive patient. There was a higher rate of bleeding events in the UFHtreated group (10% vs 3%, p ⫽ 0.08; Table 3). There were 10 major bleeding events in the UFH-treated group (5 pericardial bleeds, 4 retroperitoneal bleeds, and 1 hemothorax; all these patients received concomitant aspirin and/or clopidogrel) and 3 major bleeding events in the LMWH-treated group (2 pericardial bleeds, 1 hemothorax; 2 of these patients received concomitant aspirin and/or clopidogrel). One patient in each group had a nonmajor lower gastrointestinal
Patients who have undergone cardiac surgery routinely receive UFH during and after surgery. The product monographs for LMWHs warn against the use of LMWH for prevention of thromboembolism in patients with prosthetic heart valves, including those who are pregnant.2 This is based on 2 cases of valve thrombosis in pregnant women receiving enoxaparin.3 The Anticoagulation in Prosthetic Valves and Pregnancy Consensus Report Panel concluded that the level of anticoagulation with enoxaparin may not have been optimal in these cases.4 LMWH may be a safer alternative to UFH in cardiac surgery patients because of the lower risk for HIT. However, to date, the safety and efficacy of LMWH after mechanical heart valve surgery has been poorly evaluated. In a nonrandomized case series of 208 patients who underwent heart valve replacement, therapeutic anticoagulation was more rapidly and predictably achieved with LMWH than with UFH.5 In a larger study with no control group, the use of the LMWH enoxaparin as bridging to therapeutic anticoagulation with warfarin after mechanical valve replacement appeared to be safe and effective.6 In a small study, LMWH patients were matched to patients who received UFH after mechanical heart valve implantation.7 Although bridging with LMWH was as safe and effective as bridging with UFH, LMWH was associated with reduced length of hospital stay and costs. In this study, we found that an LMWH regimen after heart valve surgery was effective and safe. In addition, there was a lower risk for thrombosis and bleeding in the LMWHtreated group. No cases of valve thrombosis occurred in the LMWH group of this study. There were also fewer HIT and HIT with thrombosis events in patients receiving LMWH. Our study provides data supporting the use of LMWH in patients with newly implanted heart valves. We believe that this is the first report assessing the development of HIT in this patient population. Our study was retrospective in nature and consisted of a relatively small sample. Although the baseline characteristics were similar, confounding may be present. Confounding from unmeasured factors such as the motivation of the clinical staff and increased attention to postoperative anticoagulation may have been present. We believe that this is the first intervention study to systematically attempt to reduce HIT in cardiac surgery. The results of this preliminary study are important as part of ongoing quality assurance of the protocol implemented at our institution.
594
The American Journal of Cardiology (www.ajconline.org)
Appendix A: Unfractionated Heparin Anticoagulation Protocol After Heart Valve Replacement Valve Position Mechanical valves Aortic
Additional Risk Factors*
Heparin Therapy
No
5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin. 5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin. 500 U/hour IV starting 12 hours postoperatively for 96 hours. If INR ⬍2 on POD 4, start IV heparin. 500 U/hour IV starting 12 hours postoperatively for 96 hours. If INR ⬍2 on POD 4, start IV heparin.
Aortic
Yes
Mitral
No
Mitral
Yes
Tissue valves Aortic Aortic
No Yes
Mitral and mitral annuloplasty
No
Mitral and mitral annuloplasty
Yes
Aspirin Use
None (except for DVT prophylaxis). 5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin. 5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin. 5,000 U SC q12h until INR ⬎2. If INR ⬍2 on POD 4, start IV heparin.
Target INR
None
2.0–3.0
ECASA 81 mg/day
2.0–3.0
None
2.5–3.5
ECASA 81 mg/day
2.5–3.5
ECASA 325 mg/day None
No warfarin 2.0–3.0
ECASA 325 mg/day; start after 3 months of warfarin None
2.0–3.0; warfarin only for 3 months 2.0–3.0
* Atrial fibrillation, large left atrium, left atrial thrombus, previous thromboembolism. DVT ⫽ deep venous thrombosis; ECASA ⫽ enteric-coated aspirin; INR ⫽ international normalized ratio; IV ⫽ intravenous; POD ⫽ postoperative day; q12h ⫽ every 12 hours; SC ⫽ subcutaneous.
Appendix B: Low-Molecular-Weight Heparin Anticoagulation Protocol After Heart Valve Replacement Valve Position Mechanical valves Aortic
Mitral
Tissue valves Aortic without risk factors Aortic with risk factors*
Mitral and mitral annuloplasty
LMWH Therapy
Aspirin
Target INR
Dalteparin 2,500 U SC qhs. If INR ⬍2 at 96 hours postoperatively, increase dalteparin dose.* Dalteparin 5,000 U SC qhs. If INR ⬍2 at 96 hours postoperatively, increase dalteparin dose.*
None
2.0–3.0
None
2.5–3.5
None Dalteparin 2,500 U SC qhs. If INR ⬍2 at 96 hours postoperatively, increase dalteparin dose.* Dalteparin 2,500 U SC qhs. If INR ⬍2 at 96 hours postoperatively, increase dalteparin dose.*
ECASA 325 mg/day None
None
None
2.0–3.0 Warfarin for 3 months (unless risk factors are present), then ECASA 325 mg/day is added
2.0–3.0
* Sustained or intermittent atrial fibrillation lasting ⬎48 hours, maze procedure. ECASA ⫽ enteric-coated aspirin; INR ⫽ international normalized ratio; qhs ⫽ at bedtime; SC ⫽ subcutaneous.
1. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated heparin and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;106:2710 –2715. 2. Canadian Pharmacists Association. Product monograph heparins: low molecular weight. In: e-CPS: Compendium of Pharmaceuticals and Specialties. Available at: http://www.pharmacists.ca/content/products/ ecps_english.cfm. Accessed February 4, 2010. 3. Shapira Y, Sagie A, Battler A. Low-molecular-weight heparin for the treatment of patients with mechanical heart valves. Clin Cardiol 2002;25:323–327. 4. Anticoagulation and enoxaparin use in patients with prosthetic heart vavles and/or pregnancy. Clin Cardiol Consensus Rep 2002;3:1–20.
5. Montalescot G, Polle V, Collet JP, Leprince P, Bellanger A, Gandjbakhch I. Low molecular weight heparin after mechanical heart valve replacement. Circulation 2000;101:1083–1086. 6. Meurin P, Tabet JY, Weber H, Renaud N, Ben Driss A. Low-molecularweight heparin as a bridging anticoagulant early after mechanical heart valve replacement. Circulation 2006;113:564 –569. 7. Fanikos J, Tsilimingras K, Kucher N, Rosen AB, Hieblinger MD, Goldhaber SZ. Comparison of efficacy, safety and cost of low-molecular weight heparin with continuous-infusion unfractionated heparin for initiation of anticoagulation after mechanical prosthetic valve implantation. Am J Cardiol 2004;93:247–250.