Reviews Anticoagulation in Chronic Hemodialysis: Progress Toward an Optimal Approach le Kessler,* Fre de rique Moureau,† and Philippe Nguyen‡ Miche *Department of Nephrology, University Hospital, Vandœuvre-les-Nancy, France, †Baxter-Gambro, Meyzieu, France, and ‡Department of Hematology, University Hospital, Reims, France
ABSTRACT Appropriate anticoagulation for hemodialysis (HD) requires a subtle balance between under- and over-heparinization to prevent extracorporeal circuit (ECC) clotting and bleeding, respectively. We discuss five key issues relating to anticoagulation therapy for chronic HD in adults following a review of relevant literature published since 2002: (i) options for standardization of anticoagulation in HD settings. The major nephrology societies have issued low evidence level recommendations on this subject. Interventional studies have generally investigated novel lowmolecular weight heparins and provided data on safety of dosing regimens that cannot readily be extrapolated to clinical practice; (ii) identification of clinical and biological parameters to aid individualization of anticoagulation
treatment. We find that use of clinical and biological monitoring of anticoagulation during HD sessions is currently not clearly defined in routine clinical practice; (iii) role of ECC elements (dialysis membrane and blood lines), dialysis modalities, and blood flow in clotting development; (iv) options to reduce or suppress systemic heparinization during HD sessions. Alternative strategies have been investigated, especially when the routine mode of anticoagulation was not suitable in patients at high risk of bleeding or was contraindicated; (v) optimization of anticoagulation therapy for the individual patient. We conclude by proposing a standardized approach to deliver anticoagulation treatment for HD based on an individualized prescription prepared according to the patient’s profile and needs.
Maintaining full patency in the extracorporeal circuit (ECC) during hemodialysis (HD) sessions is a prerequisite for optimal HD quality (1–4). A complex disturbance of the coagulation system is commonly encountered in patients at the terminal stage of chronic kidney disease (CKD), leading to considerable morbidity and mortality (5). Although HD reduces the bleeding risk by the removal of uremic toxins, interaction between blood and artificial surfaces contributes to activate coagulation pathways. This nonphysiological environment leads to clotting on these foreign surfaces which reduces HD efficiency, shortens circuit lifetime, and increases patient blood loss, nursing workload, disposable consumption, and thus the cost of treatment (3,4).
Appropriate anticoagulation requires a subtle balance between under- and over-heparinization to prevent ECC clotting and bleeding, respectively. HD patients are prone to prolonged bleeding episodes from dialysis fistula, as well as gastrointestinal and intracranial hemorrhage (5). Conversely, they may develop a prothrombotic status or comorbid conditions requiring oral anticoagulants or antiplatelet agents (1,5). Of interest, the dialysis population represents the only group of patients to receive heparin three times per week, with a potential longterm cumulative effect associated with an increased risk of osteoporosis, aldosterone suppression and hyperkalemia, and a deterioration of lipid profile and endothelial function (2,4,6). The objective of this article was to address the key issues on anticoagulation therapy for chronic HD in adults by presenting an overview of literature published since 2002 with regard to guidelines, clinical practices, assessment procedures, and alternative options. Key topics to be covered include the following: options for the standardization of anticoagulation in HD settings; identification of clinical and biological parameters to aid individualization of anticoagulation treatment; role of ECC elements (dialysis membrane, blood lines), dialysis modalities and blood flow in clotting development; options to reduce or suppress systemic heparinization during HD sessions; and the optimization of anticoagulation therapy for the individual patient.
le Kessler, Address correspondence to: Professor Miche Department of Nephrology, University Hospital, 54511 Vandœuvre-les-Nancy, France, Tel.: +33 3 83 15 31 69, Fax: +33 3 83 15 31 63, or e-mail: [email protected]. Seminars in Dialysis—Vol 28, No 5 (September–October) 2015 pp. 474–489 DOI: 10.1111/sdi.12380 © 2015 The Authors. Seminars in Dialysis published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 474
475
ANTICOAGULATION IN CHRONIC HEMODIALYSIS
Concise Search Strategy The scope of the literature search was to cover clinical data dealing with anticoagulation for chronic HD. The search was limited to references published in English from January 2002 to August 2014. For the search, we used the following bibliographic databases: Ovid MEDLINE, Ovid EMBASE, Ovid Evidence-Based Medicine Reviews – Cochrane Database, ACP Journal Club, Database of Abstracts of Reviews of Effects, PubMed, and Clinical and Current Controlled trials databases. We also searched the Baxter-Gambro Renal Replacement Therapies internal and private database. The main search concepts included were as follows: HD, chronic renal dialysis; anticoagulation; unfractionated or low-molecular-weight heparins (UFH or LMWH); renal therapies guidelines; adverse events; bleeding; dialyzer, dialysis membrane, blood lines, circuit clotting, dialyzer biocompatibility, home HD, nocturnal home HD, priming, vascular access patency, and single needle. Acute renal failure, continuous renal replacement therapies, pediatrics and locking solutions used in vascular access, as well as congress abstracts and posters were excluded. The selection process relied on regular exchanges and meetings among the authors. The articles
Anticoagulation in hemodialysis Records identified through database searching (Medline®, Embase®, Evidence-based Medicine Reviews) (n = 891)
included in this review were selected based on the analysis of the full text. Any disagreements were discussed until a consensus was reached. The flowchart outlining the process for selecting references is presented in Fig. 1. The complete search strategy is detailed in Data S1. Results Options for the Standardization of Anticoagulation in HD Settings Anticoagulation with heparin or its derivatives during HD sessions is not evidence-based and is unlikely to ever be tested in randomized clinical trials (7). The major nephrology societies have issued recommendations or position statements surrounding the prevention of ECC clotting during HD (3,4,8–15). However, observational and interventional studies have since been published; do they provide new approaches or raise new questions? Recommendations by Nephrology Societies Clinical practice guidelines on anticoagulation for chronic HD have been developed by nephrology societies in Europe, United Kingdom, United States, Canada, Australasia, and Japan (3,4,9–15).
Anticoagulation in hemodialysis Additional records identified through other sources (Baxter-Gambro Internal database, Internet) (n = 647)
Records after removing duplicates (n = 534)
Records screened (n = 534) Additional searches: guidelines, clinical trials, bleeding, clotting, priming, vascular access patency, home hemodialysis, single needle, FHN references (n = 951)
Records excluded with reasons (n = 111)
Full-text articles assessed (n = 423)
Full-text articles assessed (n = 1374)
Full-text articles excluded with reasons (n =1331)
References selected for the manuscript (n = 143)
Fig. 1. Flowchart outlining the process for selecting bibliographical references. FNN, Frequent Hemodialysis Network.
476
Kessler et al.
The Canadian Society Hemodialysis Clinical Practice Guidelines have simply stated that adequate anticoagulation may be used to increase urea clearance and possibly dialysis adequacy (14). Recommendations from the European Renal Association – European Dialysis and Transplant Association (ERA– EDTA) (4), the British Renal Association (9), the National Kidney Foundation (10–12), the Japanese Society for Dialysis Therapy (13), and the Caring for Australasians with Renal impairment (CARI) recently expanded to patients with cardiovascular diseases (KHA-CARI) (3,15) are summarized in Table 1. The CARI guidelines have underlined the lack of clear difference between UFH and LMWH regarding HD adequacy and risk of thrombosis and hemorrhage (3). The National Kidney Foundation has highlighted limited data for LMWH in a core curriculum providing clinically relevant practical information in dialysis patients (11). The last update of the European Best Practice Guidelines (EBPG) on anticoagulation for HD advocate the use of LMWH (4), but in contrast, the British Renal Association recommend UFH as the standard anticoagulant and LMWH as an alternative agent (9). Regarding the dosage of heparin in dialysis patients with a normal bleeding risk, the European and UK recommendations are based on a loading dose of UFH followed by a continuous infusion; no detailed dosage information for LMWH is available (many different molecules) (4,9). Some anticoagulation strategies have been recommended for specific populations with increased bleeding risk as detailed in Table 1 (4,9–11,13,15). In Europe, regular saline flushing seems to be the preferred solution with no use of anticoagulant or a minimal dose of UFH (4,9). Regional citrate infusion is considered a complex technique which is unsuitable for routine use or should be limited to intensive care (4,9,12). These recommendations outline the substantial heterogeneity of results available from clinical studies, and thus the low level of underlying evidence for creating clinical practice guidelines. Data From Observational Studies (2002–2014) Anticoagulation practices and extracorporeal thrombosis or bleeding events occurring within HD sessions were analyzed in four observational studies conducted in Germany, Spain, the United States, and China (16–19), as well as two event reports in the United States (20,21). In a large cohort of 781 stable chronic HD patients monitored for 32 weeks in Germany, no clinically relevant clotting was observed macroscopically in 97.1% of 24,117 regular HD treatments performed mainly with a loading dose of enoxaparin (70 IU/kg) (16). In a cross-sectional national survey proposed by the Task Force for Anticoagulation of the Spanish Society of Nephrology, the majority of HD units prescribed both types of heparin: UFH
(intermittent administration) and LMWH (single initial bolus), with a choice based on medical condition and ease of administration (17). Factors to consider for dose adjustment included body weight, coagulation of the dialyzer/lines and bleeding after disconnection. In the week prior to the survey, 4.4% of patients experienced bleeding episodes and 1.9% had thrombotic complications. In a recent US cohort of 17,722 HD patients aged 67 years or older, a variety of heparin dosing schedules reflected a patient-centered decisionmaking process (18). Although most patterns in heparin dosing were linked to clinical characteristics, such as patient weight and duration of HD sessions, some remained unexplained suggesting that heparin dosing could be improved in some individuals (18). Recently, two consecutive surveys in Northern China (2007–2012) showed a favorable evolution in anticoagulation practices toward individualized management following the implementation of national blood purification standard operating procedures (19). In summary, these studies performed on a national scale highlight a large degree of heterogeneity in the criteria used when prescribing anticoagulants for HD. Analysis of US event reports has revealed that clotting in ECC is the second most commonly reported adverse event, and identified that many adverse events and errors observed in HD units are related to omission of heparin administration (20,21). These data suggest that heparin administration should be confirmed before anticoagulant treatment is modified in cases where clotting occurs unexpectedly in a clinically stable patient. Results From Interventional Clinical Studies (2002–2014) A meta-analysis of 11 randomized controlled trials (RCTs) demonstrated equal efficacy and safety of anticoagulation with LMWH and UFH. However, these results should be interpreted with caution as the studies varied in terms of LMWH doses administered and dose adjustment strategies employed (22). Seven clinical trials have evaluated the efficacy and safety of different LMWH with monitoring of ECC clotting by visual inspection, recording of bleeding episodes, and measurement of access compression times (Table 2) (23–29). Three studies including stable HD patients investigated the efficacy and safety of each LMWH with weight-based dosing regimens (tinzaparin, enoxaparin) (23–25). Two additional studies compared tinzaparin with UFH and suggested comparable safety and comparable (26) or superior efficacy of tinzaparin (27). Two other studies which compared tinzaparin with dalteparin (28), and nadroparin with enoxaparin (29), showed no significant difference. In conclusion, most reported interventional studies were phase III or IV clinical trials investigating novel LMWH. Although these studies provided data on the safety of several LMWH dosing
See below
Guideline 7.1: UFH or LMWH (Evidence level 1A) UFH = standard AC loading dose (unspecified) followed by a continuous infusion of 500–1500 units/ hour discontinued ~30 minutes before the end of the session LMWH = alternative AC associated with lower risk of bleeding, less frequent episodes of hyperkalemia and an improved lipid profile compared with standard heparin
Guideline V.2.1: Low-dose of UFH or LMWH (Evidence level A) UFH: in routine, loading dose 50 IU/ kg followed by a continuous infusion 800–1500 IU/hour) LMWH: see suggestions by the manufacturer; reduced dose on an individual basis for patients requiring antiplatelets or antivitamin K Guideline V.2.2: LMWHs over UFH due to Proven safety (Evidence level A) Equal efficacy (Evidence level A) Easy handling (Evidence level C) Other benefits of LMWHs: Improved lipid profile (Evidence level B) Less hyperkalemia (Evidence level B) Less blood loss (Evidence level C)
In patients with low bleeding risk
British Renal Association (9)
See below
European Renal Association–European Dialysis and Transplant Association (ERA-EDTA (4)
UFH or LMWH? Which dosage?
Guidelines on AC in HD Most common AC is systemic heparin (11,12) (bolus and/or incremental administration during HD); occasionally regional administration or saline flushes. In routine clinical practice, intensity of AC is not measured Alternatives: LMWH, direct thrombin inhibitors, regional citrate AC (intensive care), prostacyclin, anticoagulant-free HD with frequent saline flushes. Citrate-containing dialysate solutions (substituting citrate for acetate in the bicarbonate concentrate may reduce heparin requirements).
The National Kidney Foundation (10–12) No recommendation (3) a. No clear differences in HD adequacy results using UFH or LMWH (Evidence level II) b. No differences in dialysis adequacy results using different LMWH (Evidence level II) c. No clear difference in the risk of thrombosis or hemorrhage with LMWHs compared with standard heparins, although results of individuals studies have been quite variable (Evidence level I)
Caring for Australasians with Renal Impairment (CARI) and for cardiovascular disease in dialysis patients (KHA-CARI) (3,15)
TABLE 1. Recommendations on anticoagulation in hemodialysis published by five major national and international nephrology societies
Japanese Society for Dialysis Therapy (13)
ANTICOAGULATION IN CHRONIC HEMODIALYSIS
477
In patients with high bleeding risk
Guidelines on AC in HD
Table 1. (Continued)
Guideline V.3.1: Systemic AC should be avoided (Evidence level A) Strategies (for phase immediately before and after surgery, in case of gastrointestinal blood loss): No use of AC with regular saline flushing (0.9%: 100–300 ml every 30 minutes; removal of all air from the dialyzer during priming, absolute prevention of air introduction in the ECC during HD and high blood flow rate from the beginning of HD) Regional citrate AC (a complex technique, unsuitable for routine HD) Prostacyclin infusion (0.4–0.5 ng/kg/ minute; discontinuation of treatment if flushing, or intradialytic hypotension; disadvantage is cost) Guideline V.3.2: Regional heparinization (i.e., heparin administration into the arterial line and protamine into the venous line) should not be performed (Evidence level A)
European Renal Association–European Dialysis and Transplant Association (ERA-EDTA (4) Guideline 7.2: Systemic AC should be avoided or kept to a minimum using a high blood flow rate, a regular flushing of the ECC with saline every 15–30 minutes or regional citrate infusion. Lowdose UFH may be used with caution in patients with intermediate risk of bleeding (Evidence level 1C). Alternatively heparin may be replaced by: a prostacyclin infusion (risk of hypotension, and expensive) or regional citrate AC (too complex for routine use, reduces the incidence of bleeding complications compared to the use of standard heparin)
British Renal Association (9) Guideline 9.2.a: Cerebrovascular disease – Special considerations in dialysis patients include anticoagulation in nonvalvular atrial fibrillation: dialysis patients are at increased risk for bleeding and careful monitoring should accompany intervention (Evidence level C) (10) AC must be based on comorbid conditions (regional methods, saline flushes, citrate infusion or citrate based dialysate) (11)
The National Kidney Foundation (10–12) All CKD patients (eGFR
ABSTRACT Appropriate anticoagulation for hemodialysis (HD) requires a subtle balance between under- and over-heparinization to prevent extracorporeal circuit (ECC) clotting and bleeding, respectively. We discuss five key issues relating to anticoagulation therapy for chronic HD in adults following a review of relevant literature published since 2002: (i) options for standardization of anticoagulation in HD settings. The major nephrology societies have issued low evidence level recommendations on this subject. Interventional studies have generally investigated novel lowmolecular weight heparins and provided data on safety of dosing regimens that cannot readily be extrapolated to clinical practice; (ii) identification of clinical and biological parameters to aid individualization of anticoagulation
treatment. We find that use of clinical and biological monitoring of anticoagulation during HD sessions is currently not clearly defined in routine clinical practice; (iii) role of ECC elements (dialysis membrane and blood lines), dialysis modalities, and blood flow in clotting development; (iv) options to reduce or suppress systemic heparinization during HD sessions. Alternative strategies have been investigated, especially when the routine mode of anticoagulation was not suitable in patients at high risk of bleeding or was contraindicated; (v) optimization of anticoagulation therapy for the individual patient. We conclude by proposing a standardized approach to deliver anticoagulation treatment for HD based on an individualized prescription prepared according to the patient’s profile and needs.
Maintaining full patency in the extracorporeal circuit (ECC) during hemodialysis (HD) sessions is a prerequisite for optimal HD quality (1–4). A complex disturbance of the coagulation system is commonly encountered in patients at the terminal stage of chronic kidney disease (CKD), leading to considerable morbidity and mortality (5). Although HD reduces the bleeding risk by the removal of uremic toxins, interaction between blood and artificial surfaces contributes to activate coagulation pathways. This nonphysiological environment leads to clotting on these foreign surfaces which reduces HD efficiency, shortens circuit lifetime, and increases patient blood loss, nursing workload, disposable consumption, and thus the cost of treatment (3,4).
Appropriate anticoagulation requires a subtle balance between under- and over-heparinization to prevent ECC clotting and bleeding, respectively. HD patients are prone to prolonged bleeding episodes from dialysis fistula, as well as gastrointestinal and intracranial hemorrhage (5). Conversely, they may develop a prothrombotic status or comorbid conditions requiring oral anticoagulants or antiplatelet agents (1,5). Of interest, the dialysis population represents the only group of patients to receive heparin three times per week, with a potential longterm cumulative effect associated with an increased risk of osteoporosis, aldosterone suppression and hyperkalemia, and a deterioration of lipid profile and endothelial function (2,4,6). The objective of this article was to address the key issues on anticoagulation therapy for chronic HD in adults by presenting an overview of literature published since 2002 with regard to guidelines, clinical practices, assessment procedures, and alternative options. Key topics to be covered include the following: options for the standardization of anticoagulation in HD settings; identification of clinical and biological parameters to aid individualization of anticoagulation treatment; role of ECC elements (dialysis membrane, blood lines), dialysis modalities and blood flow in clotting development; options to reduce or suppress systemic heparinization during HD sessions; and the optimization of anticoagulation therapy for the individual patient.
le Kessler, Address correspondence to: Professor Miche Department of Nephrology, University Hospital, 54511 Vandœuvre-les-Nancy, France, Tel.: +33 3 83 15 31 69, Fax: +33 3 83 15 31 63, or e-mail: [email protected]. Seminars in Dialysis—Vol 28, No 5 (September–October) 2015 pp. 474–489 DOI: 10.1111/sdi.12380 © 2015 The Authors. Seminars in Dialysis published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 474
475
ANTICOAGULATION IN CHRONIC HEMODIALYSIS
Concise Search Strategy The scope of the literature search was to cover clinical data dealing with anticoagulation for chronic HD. The search was limited to references published in English from January 2002 to August 2014. For the search, we used the following bibliographic databases: Ovid MEDLINE, Ovid EMBASE, Ovid Evidence-Based Medicine Reviews – Cochrane Database, ACP Journal Club, Database of Abstracts of Reviews of Effects, PubMed, and Clinical and Current Controlled trials databases. We also searched the Baxter-Gambro Renal Replacement Therapies internal and private database. The main search concepts included were as follows: HD, chronic renal dialysis; anticoagulation; unfractionated or low-molecular-weight heparins (UFH or LMWH); renal therapies guidelines; adverse events; bleeding; dialyzer, dialysis membrane, blood lines, circuit clotting, dialyzer biocompatibility, home HD, nocturnal home HD, priming, vascular access patency, and single needle. Acute renal failure, continuous renal replacement therapies, pediatrics and locking solutions used in vascular access, as well as congress abstracts and posters were excluded. The selection process relied on regular exchanges and meetings among the authors. The articles
Anticoagulation in hemodialysis Records identified through database searching (Medline®, Embase®, Evidence-based Medicine Reviews) (n = 891)
included in this review were selected based on the analysis of the full text. Any disagreements were discussed until a consensus was reached. The flowchart outlining the process for selecting references is presented in Fig. 1. The complete search strategy is detailed in Data S1. Results Options for the Standardization of Anticoagulation in HD Settings Anticoagulation with heparin or its derivatives during HD sessions is not evidence-based and is unlikely to ever be tested in randomized clinical trials (7). The major nephrology societies have issued recommendations or position statements surrounding the prevention of ECC clotting during HD (3,4,8–15). However, observational and interventional studies have since been published; do they provide new approaches or raise new questions? Recommendations by Nephrology Societies Clinical practice guidelines on anticoagulation for chronic HD have been developed by nephrology societies in Europe, United Kingdom, United States, Canada, Australasia, and Japan (3,4,9–15).
Anticoagulation in hemodialysis Additional records identified through other sources (Baxter-Gambro Internal database, Internet) (n = 647)
Records after removing duplicates (n = 534)
Records screened (n = 534) Additional searches: guidelines, clinical trials, bleeding, clotting, priming, vascular access patency, home hemodialysis, single needle, FHN references (n = 951)
Records excluded with reasons (n = 111)
Full-text articles assessed (n = 423)
Full-text articles assessed (n = 1374)
Full-text articles excluded with reasons (n =1331)
References selected for the manuscript (n = 143)
Fig. 1. Flowchart outlining the process for selecting bibliographical references. FNN, Frequent Hemodialysis Network.
476
Kessler et al.
The Canadian Society Hemodialysis Clinical Practice Guidelines have simply stated that adequate anticoagulation may be used to increase urea clearance and possibly dialysis adequacy (14). Recommendations from the European Renal Association – European Dialysis and Transplant Association (ERA– EDTA) (4), the British Renal Association (9), the National Kidney Foundation (10–12), the Japanese Society for Dialysis Therapy (13), and the Caring for Australasians with Renal impairment (CARI) recently expanded to patients with cardiovascular diseases (KHA-CARI) (3,15) are summarized in Table 1. The CARI guidelines have underlined the lack of clear difference between UFH and LMWH regarding HD adequacy and risk of thrombosis and hemorrhage (3). The National Kidney Foundation has highlighted limited data for LMWH in a core curriculum providing clinically relevant practical information in dialysis patients (11). The last update of the European Best Practice Guidelines (EBPG) on anticoagulation for HD advocate the use of LMWH (4), but in contrast, the British Renal Association recommend UFH as the standard anticoagulant and LMWH as an alternative agent (9). Regarding the dosage of heparin in dialysis patients with a normal bleeding risk, the European and UK recommendations are based on a loading dose of UFH followed by a continuous infusion; no detailed dosage information for LMWH is available (many different molecules) (4,9). Some anticoagulation strategies have been recommended for specific populations with increased bleeding risk as detailed in Table 1 (4,9–11,13,15). In Europe, regular saline flushing seems to be the preferred solution with no use of anticoagulant or a minimal dose of UFH (4,9). Regional citrate infusion is considered a complex technique which is unsuitable for routine use or should be limited to intensive care (4,9,12). These recommendations outline the substantial heterogeneity of results available from clinical studies, and thus the low level of underlying evidence for creating clinical practice guidelines. Data From Observational Studies (2002–2014) Anticoagulation practices and extracorporeal thrombosis or bleeding events occurring within HD sessions were analyzed in four observational studies conducted in Germany, Spain, the United States, and China (16–19), as well as two event reports in the United States (20,21). In a large cohort of 781 stable chronic HD patients monitored for 32 weeks in Germany, no clinically relevant clotting was observed macroscopically in 97.1% of 24,117 regular HD treatments performed mainly with a loading dose of enoxaparin (70 IU/kg) (16). In a cross-sectional national survey proposed by the Task Force for Anticoagulation of the Spanish Society of Nephrology, the majority of HD units prescribed both types of heparin: UFH
(intermittent administration) and LMWH (single initial bolus), with a choice based on medical condition and ease of administration (17). Factors to consider for dose adjustment included body weight, coagulation of the dialyzer/lines and bleeding after disconnection. In the week prior to the survey, 4.4% of patients experienced bleeding episodes and 1.9% had thrombotic complications. In a recent US cohort of 17,722 HD patients aged 67 years or older, a variety of heparin dosing schedules reflected a patient-centered decisionmaking process (18). Although most patterns in heparin dosing were linked to clinical characteristics, such as patient weight and duration of HD sessions, some remained unexplained suggesting that heparin dosing could be improved in some individuals (18). Recently, two consecutive surveys in Northern China (2007–2012) showed a favorable evolution in anticoagulation practices toward individualized management following the implementation of national blood purification standard operating procedures (19). In summary, these studies performed on a national scale highlight a large degree of heterogeneity in the criteria used when prescribing anticoagulants for HD. Analysis of US event reports has revealed that clotting in ECC is the second most commonly reported adverse event, and identified that many adverse events and errors observed in HD units are related to omission of heparin administration (20,21). These data suggest that heparin administration should be confirmed before anticoagulant treatment is modified in cases where clotting occurs unexpectedly in a clinically stable patient. Results From Interventional Clinical Studies (2002–2014) A meta-analysis of 11 randomized controlled trials (RCTs) demonstrated equal efficacy and safety of anticoagulation with LMWH and UFH. However, these results should be interpreted with caution as the studies varied in terms of LMWH doses administered and dose adjustment strategies employed (22). Seven clinical trials have evaluated the efficacy and safety of different LMWH with monitoring of ECC clotting by visual inspection, recording of bleeding episodes, and measurement of access compression times (Table 2) (23–29). Three studies including stable HD patients investigated the efficacy and safety of each LMWH with weight-based dosing regimens (tinzaparin, enoxaparin) (23–25). Two additional studies compared tinzaparin with UFH and suggested comparable safety and comparable (26) or superior efficacy of tinzaparin (27). Two other studies which compared tinzaparin with dalteparin (28), and nadroparin with enoxaparin (29), showed no significant difference. In conclusion, most reported interventional studies were phase III or IV clinical trials investigating novel LMWH. Although these studies provided data on the safety of several LMWH dosing
See below
Guideline 7.1: UFH or LMWH (Evidence level 1A) UFH = standard AC loading dose (unspecified) followed by a continuous infusion of 500–1500 units/ hour discontinued ~30 minutes before the end of the session LMWH = alternative AC associated with lower risk of bleeding, less frequent episodes of hyperkalemia and an improved lipid profile compared with standard heparin
Guideline V.2.1: Low-dose of UFH or LMWH (Evidence level A) UFH: in routine, loading dose 50 IU/ kg followed by a continuous infusion 800–1500 IU/hour) LMWH: see suggestions by the manufacturer; reduced dose on an individual basis for patients requiring antiplatelets or antivitamin K Guideline V.2.2: LMWHs over UFH due to Proven safety (Evidence level A) Equal efficacy (Evidence level A) Easy handling (Evidence level C) Other benefits of LMWHs: Improved lipid profile (Evidence level B) Less hyperkalemia (Evidence level B) Less blood loss (Evidence level C)
In patients with low bleeding risk
British Renal Association (9)
See below
European Renal Association–European Dialysis and Transplant Association (ERA-EDTA (4)
UFH or LMWH? Which dosage?
Guidelines on AC in HD Most common AC is systemic heparin (11,12) (bolus and/or incremental administration during HD); occasionally regional administration or saline flushes. In routine clinical practice, intensity of AC is not measured Alternatives: LMWH, direct thrombin inhibitors, regional citrate AC (intensive care), prostacyclin, anticoagulant-free HD with frequent saline flushes. Citrate-containing dialysate solutions (substituting citrate for acetate in the bicarbonate concentrate may reduce heparin requirements).
The National Kidney Foundation (10–12) No recommendation (3) a. No clear differences in HD adequacy results using UFH or LMWH (Evidence level II) b. No differences in dialysis adequacy results using different LMWH (Evidence level II) c. No clear difference in the risk of thrombosis or hemorrhage with LMWHs compared with standard heparins, although results of individuals studies have been quite variable (Evidence level I)
Caring for Australasians with Renal Impairment (CARI) and for cardiovascular disease in dialysis patients (KHA-CARI) (3,15)
TABLE 1. Recommendations on anticoagulation in hemodialysis published by five major national and international nephrology societies
Japanese Society for Dialysis Therapy (13)
ANTICOAGULATION IN CHRONIC HEMODIALYSIS
477
In patients with high bleeding risk
Guidelines on AC in HD
Table 1. (Continued)
Guideline V.3.1: Systemic AC should be avoided (Evidence level A) Strategies (for phase immediately before and after surgery, in case of gastrointestinal blood loss): No use of AC with regular saline flushing (0.9%: 100–300 ml every 30 minutes; removal of all air from the dialyzer during priming, absolute prevention of air introduction in the ECC during HD and high blood flow rate from the beginning of HD) Regional citrate AC (a complex technique, unsuitable for routine HD) Prostacyclin infusion (0.4–0.5 ng/kg/ minute; discontinuation of treatment if flushing, or intradialytic hypotension; disadvantage is cost) Guideline V.3.2: Regional heparinization (i.e., heparin administration into the arterial line and protamine into the venous line) should not be performed (Evidence level A)
European Renal Association–European Dialysis and Transplant Association (ERA-EDTA (4) Guideline 7.2: Systemic AC should be avoided or kept to a minimum using a high blood flow rate, a regular flushing of the ECC with saline every 15–30 minutes or regional citrate infusion. Lowdose UFH may be used with caution in patients with intermediate risk of bleeding (Evidence level 1C). Alternatively heparin may be replaced by: a prostacyclin infusion (risk of hypotension, and expensive) or regional citrate AC (too complex for routine use, reduces the incidence of bleeding complications compared to the use of standard heparin)
British Renal Association (9) Guideline 9.2.a: Cerebrovascular disease – Special considerations in dialysis patients include anticoagulation in nonvalvular atrial fibrillation: dialysis patients are at increased risk for bleeding and careful monitoring should accompany intervention (Evidence level C) (10) AC must be based on comorbid conditions (regional methods, saline flushes, citrate infusion or citrate based dialysate) (11)
The National Kidney Foundation (10–12) All CKD patients (eGFR
