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Antithrombotic Therapy Management
The periprocedural management of antithrombotic medications is a common challenge for hospitalists, for which there is limited high‐quality evidence to guide clinical decision making. The introduction of third‐generation antiplatelet agents (prasugrel and ticagrelor) and the new oral anticoagulants (rivaroxaban, apixaban, and dabigatran), has added an additional layer of complexity to clinical management.
This article will provide a conceptual framework for the periprocedural management of antithrombotic therapy, with a particular focus on procedures that are considered core competencies by the Society of Hospital Medicine; these include: arthrocentesis, lumbar puncture, paracentesis, thoracentesis, and central line placement (Table 1).[1, 2] The recommendations in this article are based on a review of published guidelines and consensus statements and their supporting literature.[3, 4, 5, 6, 7, 8] Additional articles were identified by performing a PubMed keyword search using the terms perioperative management or periprocedural management and anticoagulation or antithrombotic or antiplatelet in combination with keywords relevant to the content areas (eg, arthrocentesis, lumbar puncture). Articles for inclusion were chosen based on methodological quality and relevance to hospital medicine.
There are several questions that must be addressed when developing a periprocedural antithrombotic management strategy:
- What is the patient's risk of bleeding if antithrombotic therapy is continued?
- What is the patient's risk of thromboembolism if antithrombotic therapy is interrupted?
- Are there interventions that can decrease the risk of periprocedural bleeding and/or thromboembolism?
WHAT IS THE PATIENT'S RISK OF BLEEDING IF ANTITHROMBOTIC THERAPY IS CONTINUED?
Although the risk of bleeding is well described for many procedures, there are limited data on how that risk is affected by coagulopathy in general and antithrombotic medications in particular. When these data are available, they are largely derived from case series or bridging registries, which include heterogeneous patient populations and nonstandardized definitions of bleeding.[8, 9, 10] As such, few procedural or surgical professional societies have published guidelines on the periprocedural management of antithrombotic therapy,[3, 4, 5, 11]and guidelines from the American College of Chest Physicians (ACCP), the American College of Cardiology (ACC), and American Heart Association (AHA) only provide specific recommendations regarding minor ambulatory procedures.[6, 7, 8]
Procedures can be categorized as low or high risk for bleeding based on the following considerations: the extent of associated tissue injury, proximity to vital organs or vascular structures, the ability to readily detect and control bleeding, and the morbidity associated with a bleeding complication (eg, a small bleed into the epidural space is potentially catastrophic, whereas a large bleed from the colon often results in no permanent harm). For procedures with a high risk or consequence of bleeding, anticoagulants must be stopped, whereas in some cases antiplatelet agents can be safely continued. For procedures with a low risk or consequence of bleeding, it may be possible to continue both anticoagulant and antiplatelet agents.
Procedure | Antithrombotic Therapy | |||||
---|---|---|---|---|---|---|
Aspirin | Thienopyridines | Prophylactic UFH or LWMH | Therapeutic UFH or LMWH | Warfarin | NOACs | |
| ||||||
Arthrocentesis[12, 13, 14, 15] | + | + | + | + | + | + |
Lumbar puncture[3] | + | 5000 units UFH BID | ||||
Paracentesis[28, 29, 30] | + | + | + | |||
Thoracentesis[37, 38, 39, 40, 41, 42] | + | + | + | |||
Central venous catheter insertion[48, 49, 50, 51, 52, 53] | + | + | + |
Because procedures in hospitalized patients are most often performed for the purpose of diagnosing or treating an emergent condition, the risk of delaying the procedure while antithrombotic medications are held must be part of the overall risk‐benefit calculation.
Arthrocentesis
Bleeding complications from arthrocentesis are very rare, and there are few data on the additional risk associated with antithrombotic therapy.[12, 13, 14] In a retrospective cohort study, investigators determined the incidence of clinically significant bleeding (defined as bleeding requiring reversal of anticoagulation, prolonged manual pressure, surgical intervention, hospital admission, or delay in hospital discharge) and procedure‐related pain among 514 patients on antithrombotic therapy referred for arthrocentesis or injection of the hip, shoulder, or knee. Four hundred fifty‐six procedures were performed in patients without interrupting warfarin therapy, all of whom maintained an international normalized ratio (INR)2, and 184 procedures were performed in patients who had stopped their warfarin to achieve an INR <2. Antiplatelet therapy was routinely continued in both groups, with 48% of patients taking aspirin and 9% clopidogrel. There was 1 bleeding complication (0.2%) in a patient with an INR of 2.3 who was also taking aspirin, and 2 patients developed procedure‐related pain (INR 3.3 and 5.3, neither taking antiplatelet medications).[15]
Based on the available evidence, arthrocentesis appears to be safe in patients on therapeutic warfarin, with or without aspirin and/or clopidogrel. At present, there are no published studies that address the risk of arthrocentesis in patients taking other antiplatelet or anticoagulant medications, but given the low overall risk of this procedure, it is reasonable to infer that these medications can also be safely continued.
Lumbar Puncture
The incidence of bleeding complications from diagnostic lumbar puncture is unknown, but is likely similar to that seen with spinal anesthesia, where in a large retrospective observational study, spinal hematoma occurred in 1:165,000 spinal block procedures.[16] Factors associated with an increased risk of spinal hematoma include traumatic tap, advanced age, female gender, spinal cord or vertebral column abnormalities, coagulopathy, and not allowing sufficient time between stopping and restarting antithrombotic therapy.[3, 17, 18, 19, 20]
Therapeutic anticoagulation must be stopped and prophylactic anticoagulation delayed before performing a lumbar puncture. The 1 exception is low‐dose unfractionated heparin (UFH), which the American Society for Regional Anesthesia (ARSA) recommends continuing in patients undergoing neuraxial procedures, provided the total dose is 5000 U twice daily. This assessment is based on observational data, surveys of practice patterns, and decades of use without evidence of complications; in fact, there are only 5 case reports of spinal hematomas in this population.[3] However, because these data are from surgical populations, in which heparin thromboprophylaxis is typically dosed at 5000 units twice daily, there are limited data on the safety of higher or more frequent doses of heparin. In a retrospective cohort study of 928 patients who received thoracic epidural analgesia in conjunction with UFH dosed at 5000 U, 3 times daily, there were no cases of neuraxial bleeding, but given the rarity of neuraxial hematoma, it is not possible to draw any conclusions from this relatively small sample size.[21]
In November 2013, based on surveillance data showing increased risk for spinal or epidural hematoma associated with low‐molecular‐weight heparin (LMWH), the US Food and Drug Administration (FDA) issued a drug safety communication recommending that neuraxial procedures be delayed for 12 hours after prophylactic LMWH and 24 hours after therapeutic LMWH, and that LMWH not be restarted for at least 4 hours after catheter removal.[20] These recommendations are largely consistent with existing guidelines[3, 22] but are not explicitly stated in the package insert for any of the LMWHs available in the United States,[23, 24, 25] and the FDA is working with the manufacturers to add this information.
Nonsteroidal anti‐inflammatory drugs (NSAIDs), dipyridamole, and aspirin do not appear to increase the risk of spinal hematoma and are considered safe to continue.[11, 26] There are limited data on the safety of thienopyridine medications in neuraxial anesthesia, but based on case reports and increased bleeding rates seen in surgical populations, it is generally recommended that these medications be discontinued before performing a lumbar puncture.[3, 22, 27]
The optimal time to restart anticoagulation after a lumbar puncture is unknown. The ARSA recommends a minimum of 1 hour for UFH and 2 hours for LMWH after neuraxial catheter removal, and provides no specific guidance about other anticoagulants,[3] whereas the European Society of Anesthesiology recommends a minimum of 1 hour for UFH, 4 hours for LMWH, 4 to 6 hours for rivaroxaban and apixiban, and 6 hours for dabigatran and fondaparinux.[22] Longer time periods should be considered after a traumatic tap, and postprocedure monitoring of neurological function is recommended for all patients.
The available evidence suggests that lumbar puncture can be safely performed in patients being treated with aspirin, NSAIDs, and UFH dosed at 5000 U twice daily; the safety of higher or more frequent doses of UFH is not known. Lumbar puncture should be delayed 12 hours after prophylactic LMWH and 24 hours after therapeutic LMWH, and LMWH should not be restarted for at least 4 hours after the procedure.[20] There are limited data on the safety of thienopyridines, but they should generally be discontinued, and all other prophylactic or therapeutic anticoagulation must be stopped prior to the procedure.
Paracentesis
Bleeding complications from paracentesis are uncommon, with abdominal wall hematoma and hemoperitoneum complicating 1% and 0.01% of procedures, respectively.[28, 29, 30] Whether antithrombotic therapy increases the risk of bleeding during paracentesis is unknown, primarily because most patients for whom the procedure is indicated have coagulopathy and thrombocytopenia from liver disease, and are therefore rarely treated with these medications.
Although patients with liver disease often have an elevated INR due to impaired hepatic synthesis of clotting factors, it is incorrect to generalize the observed rate of bleeding in this population to patients with an elevated INR from warfarin therapy who may require paracentesis for reasons unrelated to liver disease (eg, malignancy or infection). The coagulopathy of liver disease reflects deficiencies in the hepatic production of both pro‐ and anticoagulant proteins, and these patients develop both thrombotic and hemorrhagic complications irrespective of their in vitro coagulation indices.[31]
Although the available evidence suggests that paracentesis can be safely performed in patients with coagulopathy from liver disease, regardless of the INR,[30] little is known about the bleeding risk in other patients, with or without antithrombotic therapy. Based on indirect evidence, it is reasonable to assume that prophylactic UFH or LWMH or antiplatelet therapy would confer minimal additional risk, whereas the safety of continuing therapeutic anticoagulation is unknown.
Thoracentesis
Bleeding complications from thoracentesis are uncommon, generally occurring in <1% of procedures.[32, 33, 34] Factors associated with increased risk of overall complications include operator inexperience, large volume drainage, and lack of ultrasound guidance.[34, 35, 36] There are no studies that specifically address the risk of bleeding in patients on anticoagulant therapy, but such patients are included in studies on the risk of bleeding with coagulopathy.[37, 38, 39, 40]
In a retrospective cohort study of 1076 ultrasound‐guided thoracenteses performed by radiologists on patients with coagulopathy (defined as thrombocytopenia or an elevated INR from any cause), there were no bleeding complications (defined as anything other than minimal symptoms not requiring intervention). Among the patients in this study, 497 (46%) patients had a preprocedure INR >1.5; 198 (24%) had an INR between 2 and 3, and 32 (4%) had an INR >3.[39]
A similar study, which compared outcomes in patients with corrected and uncorrected coagulopathy, included 744 patients with an INR >1.6 (from any cause), of which 167 received preprocedural fresh‐frozen plasma (FFP) and 577 did not. There was 1 (0.1%) bleeding complication in a patient who received prophylactic FFP and none in the group that was not transfused.[38]
In a prospective cohort of 312 patients at increased risk for bleeding (from coagulopathy or antithrombotic medications) who underwent ultrasound‐guided thoracentesis by a pulmonologist or physician's assistant, 44 (34%) had an INR >1.5 (secondary to liver disease or warfarin therapy), 15 (12%) were taking clopidogrel, and 14 (11%) were treated with therapeutic LMWH within 12 hours or therapeutic UFH within 4.5 hours of the procedure. There were no bleeding complications in any of the patients (defined as mean change in hematocrit, chest x‐ray abnormalities, hemothorax, or requirement for transfusion).[37]
Although there are no studies that specifically address the use of aspirin and bleeding complications in thoracentesis, it is generally considered safe to continue this medication,[5] and there are small studies that show that thoracentesis and small‐bore chest tubes can be safely placed in patients taking clopidogrel.[41, 42]
Thoracentesis is associated with a low rate of bleeding complications, and when performed by an experienced operator using ultrasound, warfarin does not appear to increase this risk. However, given the low overall complication rate, it is not known whether patients on warfarin would have worse outcomes in the event of more serious complications (eg, intercostal artery laceration). At present, there are no published studies that address the risk of thoracentesis in patients taking new oral anticoagulants (NOACs).
Central Venous Catheter Insertion
The incidence of bleeding complications from central venous catheter (CVC) placement varies depending on the site of insertion and definition of bleeding, with hematoma and hemothorax occurring in 0.1% to 6.9%, and 0.4% to 1.3% of procedures, respectively.[43, 44, 45] Factors that increase the likelihood of complications include operator inexperience, multiple needle passes, and lack of ultrasound guidance.[46, 47] There are no studies that specifically address the risk of bleeding from CVC placement in patients on anticoagulant therapy, but such patients are included in studies of CVC placement in patients with coagulopathy, which report similar complication rates as seen in patients with normal hemostasis.[48, 49, 50, 51, 52, 53]
In a retrospective cohort study, investigators collected information on CVC‐associated bleeding complications in 281 medical and surgical intensive care patients with coagulopathy (INR 1.5 from any cause) after they adopted a more conservative approach to plasma transfusion in their intensive care unit; specifically, the routine use of prophylactic FFP to correct coagulopathy was discouraged for patients with an INR <3 (vs usual practice using an INR cutoff of 1.5), but the final decision was left to the discretion of the attending performing or supervising the procedure. Bleeding was defined as insertion‐site hematoma, interventions other than local manual pressure, and the need for blood transfusion. One case of bleeding (hematoma) was observed in a patient with an INR of 3.9, who received FFP before the procedure. There were no complications among those with uncorrected coagulopathy, including 66 patients with an INR between 1.5 and 2.9, and 6 with an INR 3.0. Ultrasound guidance was used in 50% of CVCs placed in the internal jugular vein.[54]
Although there are no studies that specifically address the use of antiplatelet drugs and bleeding complications in CVC placement, aspirin is generally considered safe to continue,[5] and by inference, thienopyridines are expected to add minimal additional risk.
CVC placement is associated with a variable rate of bleeding complications, with hematoma being relatively common. Based on the available literature, warfarin does not appear to increase this risk, but there are limited data from which to draw firm conclusions. A femoral or jugular approach may be preferable because they allow for ultrasound visualization and are amenable to manual compression. There are no published studies that address the risk of CVC placement in patients taking NOACs, and although the risk of bleeding is probably similar to patients receiving warfarin, the lack of effective reversal agents for these medications should be part of any risk‐benefit calculation.[55]
WHAT IS THE PATIENT'S RISK OF THROMBOEMBOLISM IF ANTITHROMBOTIC THERAPY IS INTERRUPTED?
Anticoagulants
If it is determined that a procedure cannot safely be performed while continuing antithrombotic therapy, one must then consider the patient's risk of thromboembolism if these therapies are temporarily interrupted. Unfortunately, there are few robust clinical studies from which to make this assessment, and therefore most clinicians rely on the risk stratification model proposed by the ACCP, which divides patients into 3 tiers (low, moderate, high), based on their indication for anticoagulation and risk factors for thromboembolism (Table 2)[8]. The ACCP model is largely based on indirect evidence from antithrombotic therapy trials in nonoperative patients, and its application to perioperative patients necessitates several assumptions that may not hold true in practice.
Indication for Anticoagulant Therapy | |||
---|---|---|---|
Risk Stratum | Mechanical Heart Valve | Atrial Fibrillation | VTE |
| |||
High Thrombotic Risk |
|
|
|
Moderate Thrombotic Risk |
|
|
|
Low Thrombotic Risk |
|
|
|
First, it assumes that the annualized risk of a thrombotic event in nonoperative patients can be prorated to determine the short‐term risk of discontinuing antithrombotic therapy in the perioperative period. For example, it has been estimated that the risk for perioperative stroke in a patient with atrial fibrillation who temporarily interrupts anticoagulation for 1 week would be 0.1% (5% per year 52 weeks),[56, 57]and yet we know from observational data that the actual risk of perioperative stroke in similar patients is 5 to 7 times higher.[58, 59] Second, it assumes that bridging therapy will decrease the risk of thromboembolism in high‐risk patients when warfarin therapy is interrupted, a premise that is logical but has not been subject to randomized controlled trials.[60] Third, it does not take into account the surgery‐specific risk for thromboembolism, which varies significantly, with arterial thromboembolism being more common in cardiac valve, vascular, and neurologic procedures, and venous thromboembolism (VTE) being more likely in orthopedic, trauma, and cancer surgery.[61, 62] These limitations notwithstanding, the ACCP model still offers the best available framework for thrombotic risk assessment and a reasonable starting point for clinical decision making.
Antiplatelet Agents
Patients with coronary artery stents who undergo noncardiac surgery are at increased risk for adverse cardiovascular events, including acute stent thrombosis, which carries a risk of myocardial infarction and death of 70% and 30%, respectively.[63] This risk is highest during the period between stent implantation and endothelialization, a process that takes 4 to 6 weeks for bare‐metal stents (BMS) and 6 to 12 months for drug‐eluting stents (DES). Premature discontinuation of dual antiplatelet therapy is the most important risk factor for stent thrombosis during this time.[64] Although the optimal perioperative strategy for these patients is unknown, there is general agreement that elective surgery should be delayed for at least 4 weeks in patients with a BMS and 12 months for patients with a DES. If a procedure or surgery is required during this time period, every effort should be made to continue dual antiplatelet therapy; if this is not possible, aspirin should be continued, and thienopyridine therapy should be interrupted as briefly as possible (Table 3).
Recommended Interval Between Last Dose of Medication and Procedure | Recommended Interval Between Procedure and First Dose of Medication, h | ||
---|---|---|---|
Low Risk or Consequence of Postprocedure Bleeding | High Risk or Consequence of Postprocedure Bleeding | ||
| |||
Antiplatelet Medicationsa | |||
Aspirin (81325 mg dailydipyridamole) | 710 days (skip 69 doses) | 24 | 48 |
Ticlodipine (250 mg twice daily) | 1014 days (skip 1926 doses) | 24 | 48 |
Clopidogrel (75 mg once daily) | 710 days (skip 69 doses)b | 24 | 48 |
Prasugrel (10 mg once daily) | 710 days (skip 69 dose)c | 24 | 48 |
Ticagrelor (90 mg twice daily; t =8 hours) | 5 days (skip 8 doses) | 24 | 48 |
Cilostazol (100 mg twice daily; t =11 hours) | 3 days (skip 4 doses) | 24 | 48 |
Anticoagulant Medicationse | |||
Warfarin (t =3642 hours, but highly variable) | 6 days (skip 5 doses)f | 12 | 24 |
Intravenous UFH (t 60 minutes) | 46 hours | 24 | 4872 |
LMWH (t =37 hours) | |||
Prophylactic dosing | 12 hours# | 12 | 2436 |
Therapeutic dosing | |||
Once daily | 24 hours (give 50% of last total dose)# | 24 | 4872 |
Twice daily | 24 hours (skip 1 dose)# | 24 | 4872 |
Fondaparinux (t =17 hours, any dose) | 34 days (skip 23 doses)h | 24 | 4872 |
Dabigatran (150 mg twice daily) | |||
CrCl>50 mL/min (t =1417 hours) | 3 days (skip 4 doses) | 24 | 4872 |
CrCl 3050 mL/min (t =1618 hours) | 45 days (skip 68 doses) | 24 | 4872 |
CrCl 1530 mL/min (t =1618 hours)i | 45 days (skip 68 doses) | 24 | 4872 |
Rivaroxaban (20 mg once daily) | |||
CrCl>50 mL/min (t =89 hours) | 3 days (skip 2 doses) | 24 | 4872 |
CrCl 3050 mL/min (t =9 hours) | 3 days (skip 2 doses) | 24 | 4872 |
CrCl 1529.9 mL/min (t =910 hours)j | 4 days (skip 3 doses) | 24 | 4872 |
Apixiban (5 mg twice daily) | |||
CrCl>50 mL/min (t =78 hours) | 3 days (skip 4 doses) | 24 | 4872 |
CrCl 3050 mL/min (t =1718 hours) | 4 days (skip 6 doses) | 24 | 4872 |
ARE THERE INTERVENTIONS THAT CAN DECREASE THE RISK OF PERIPROCEDURAL BLEEDING AND/OR THROMBOEMBOLISM?
Mitigating the Risk of Bleeding
Bleeding complications can be reduced by allowing a sufficient time for the effects of antithrombotic medications to wear off before performing a procedure. This requires an understanding of the pharmacology of these medications, with particular attention to patients in whom these medications are less well studied, including the elderly, patients with renal insufficiency, and those with very high or low body mass index. Table 3 provides recommendations for when to stop antithrombotic therapy prior to an invasive procedure. The intervals are based on the time needed to achieve a minimal antithrombotic effect, which is generally 4 to 5 half‐lives for anticoagulants and 7 to 10 days for irreversible antiplatelet agents. Shorter intervals may be appropriate for procedures with low risk or consequence of bleeding, but there are insufficient data to make specific recommendations regarding this strategy.
It is equally important to ensure that there is adequate time for postoperative hemostasis prior to restarting antithrombotic therapy. Data from VTE prophylaxis trials and bridging studies consistently show that bleeding complications occur more frequently when anticoagulation is started too early, and antithrombotic therapy should generally be delayed 24 hours in patients at average risk and 48 to 72 hours in patients at high risk or consequence for postoperative bleeding.[8, 60, 65]
Aspirin increases the risk of surgical blood loss and transfusion by up to 20%, and by up to 50% when given in combination with clopidogrel, but with the exception of intracranial surgery, there does not appear to be an increase in perioperative morbidity or mortality with either of these agents.[66]
Mitigating the Risk of Thromboembolism
Once the decision has been made to temporarily discontinue warfarin, the next consideration is whether to bridge with a short acting anticoagulant (typically subcutaneous LMWH or intravenous UFH) during the period of time when the INR is subtherapeutic. Conceptually, one would expect this strategy would minimize the risk of thromboembolism, but its efficacy has never been clearly demonstrated. In fact, in a systematic review and meta‐analysis of 34 studies that compared the rates of thromboembolism among bridged and nonbridged patients, heparin therapy did not reduce the risk of thromboembolic events (odds ratio: 0.80; 95% confidence interval: 0.421.54), but did result in higher rates of periprocedural bleeding.[60]
The applicability of these results to clinical practice are limited by the heterogeneity of the data used in the analysis; specifically, bridging strategies varied (including therapeutic, intermediate, and prophylactic dose regimens), there was wide variation in the types of surgery (and therefore bleeding risk), and because the majority of studies were observational, there is a significant likelihood of confounding by indication (ie, patients at high risk for thromboembolism are more likely to receive bridging therapy), and thus the benefit of this strategy may be underestimated. It is also important to note that in the majority studies anticoagulation was restarted <24 hours after the procedure, which likely contributed to the increased rate of bleeding.
Therefore, although bridging therapy is not indicated for patients at low risk, it is premature to conclude that it should be avoided in patients at moderate or high risk for thromboembolism. The results of 2 ongoing, randomized, placebo‐controlled trials of bridging therapy in patients taking warfarin for atrial fibrillation (Effectiveness of Bridging Anticoagulation for Surgery [BRIDGE]) or mechanical heart values (A Double Blind Randomized Control Trial of Post‐Operative Low Molecular Weight Heparin Bridging Therapy Versus Placebo Bridging Therapy for Patients Who Are at High Risk for Arterial Thromboembolism [PERIOP‐2]) should help to answer this question.[67, 68]
The uncertainty regarding the benefits of bridging therapy is reflected in the changes to the most recent ACCP guidelines. In 2008, the ACCP recommended low‐dose LMWH or no bridging for patients at low risk (grade 2C), therapeutic‐dose bridging for patients at moderate risk (grade 2C), and therapeutic‐dose bridging for patients at high risk for thromboembolism (Grade 1C).[56] In 2012, the ACCP recommended against bridging for low‐risk patients (grade 2C), made no specific recommendation regarding moderate‐risk patients, and offered a less robust recommendation for bridging in high‐risk patients (grade 2C).[8]
Until the results of the BRIDGE and PERIOP‐2 trials are available, the author still favors therapeutic bridging for patients at high risk and selected patients at moderate risk for thromboembolism, provided sufficient time is allowed for postoperative hemostasis before anticoagulation is restarted. For procedures with a high risk or consequence of bleeding, intravenous UFH (without a bolus) is a reasonable initial postoperative strategy to insure that anticoagulation is tolerated before committing to LMWH. Indirect evidence supports the use of prophylactic or intermediate‐dose bridging regimens in patients for whom the primary consideration is the prevention of recurrent VTE, but data to show that this strategy is effective for the prevention of arterial thromboembolism are lacking.
Intravenous glycoprotein IIb/IIIa inhibitors are sometimes used to bridge high‐risk patients with coronary artery stents who must stop antiplatelet therapy prior to a procedure, but the data to support this practice are limited and observational in nature.[69, 70]
STARTING AND STOPPING ANTITHROMBOTIC THERAPY
Warfarin
For patients on warfarin, the INR at which it is safe to perform invasive procedures is unknown. Normal hemostasis requires clotting factor levels of approximately 20% to 40% of normal,[71] which generally corresponds to an INR of <1.5, whereas for most indications, therapeutic anticoagulation is achieved when the INR is between 2.0 and 3.5. However, because the relationship between the INR and the levels of clotting factors is nonlinear, for a given patient, the INR may be abnormal (ie, >1) despite levels of clotting factors that are sufficient for periprocedural hemostasis.[72, 73, 74, 75] Because of its relatively long half‐life (3642 hours), warfarin should be stopped 6 days (skip 5 doses) prior to a procedure to achieve an INR of <1.5, but can safely be restarted the same day in most patients.
Heparins
The half‐life of intravenous heparin is dose dependent, and at therapeutic levels is approximately 60 minutes; therefore, it should be discontinued 4 to 6 hours (5 half‐lives) before performing an invasive procedure.[76] The half‐life of subcutaneous LMWHs ranges from 3 to 7 hours in healthy volunteers,[23, 24, 25] and is often longer in patients for whom these medications are commonly prescribed.[77, 78] Therefore, when administered at therapeutic doses twice daily, the last dose should be given in the morning the day before the procedure, and for therapeutic once‐daily regimens, the last dose should be reduced by 50%.[8] The optimal time to discontinue prophylactic doses of LWMH prior to an invasive procedure is unclear, but a minimum of 12 hours is recommended.[22, 79] Because LWMHs are renally cleared, longer intervals are needed for patients with impaired renal function.[76, 80]
New Oral Anticoagulants
The manufacturer of rivaroxaban recommends that if anticoagulation must be discontinued, it be stopped at least 24 hours before the procedure.[81] Although this may be sufficient for procedures with a low risk or consequence of bleeding, the half‐life of rivaroxaban is between 8 and 10 hours, and therefore 48 hours (45 half‐lives) is required to ensure minimal residual anticoagulant effect.
Apixaban has a clearance half‐life of 6 hours, but displays prolonged absorption such that its effective half‐life is 12 hours after repeated dosing. The manufacturer recommends that it be stopped at least 24 hours prior to a procedure with a low risk or consequence of bleeding, and 48 hours prior to a procedure with a high risk or consequence of bleeding.[82]
The manufacturer of dabigatran recommends that the drug be discontinued 1 to 2 days (creatinine clearance (CrCl) 50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures, and that longer times be considered when complete hemostasis is required.[83] Given that the half‐life of dabigatran is 14 to 17 hours, the author recommends that it be stopped at least 2 days (3 half‐lives) prior to a procedure with a low risk or consequence of bleeding, and 3 days (45 half‐lives) prior to a procedure with a high risk or consequence of bleeding.
The clearance of all the NOACs is significantly prolonged in patients with renal impairment, and a longer interval between the last dose and the procedure is necessary in patients with renal failure to ensure normal hemostasis (Table 3).
The effect of the NOACs on the standard clotting assays are complex and vary depending on drug dose, the type of reagents used, and the calibration of the equipment. For dabigatran, the activated partial thromboplastin time (aPTT) and the thrombin time (TT) are sufficiently sensitive to allow for a qualitative assessment of drug effect, such that a normal aPTT indicates the absence, or a very low level of an anticoagulant effect, and a normal TT essentially rules out an effect. Accurate quantitative testing of dabigatran requires an appropriately calibrated dilute thrombin test or ecarin clotting time assay.[84, 85]
Depending on the thromboplastin reagent used, the prothrombin time (PT) may be sufficiently sensitive to rivaroxaban that a normal level rules out a residual drug effect,[86] but this does not hold true for apixaban, which has minimal effect on the PT at therapeutic concentrations. The aPTT is insensitive to both rivaroxaban and apixaban and cannot be used for assessing residual drug effect. Accurate quantitative testing of rivaroxaban or apixaban requires an anti‐factor Xa assay calibrated for use with these agents.[84]
Antiplatelet Agents
Aspirin irreversibly inhibits platelet cyclooxygenase activity, and the thienopyridines clopidogrel and prasugrel, irreversibly inhibit the platelet P2Y12 receptor. As such, the biological effects of these medications persist until the platelet pool has turned over, a process that occurs at 10% to 12% per day and takes 7 to 10 days to complete.[87] The minimum number of functional platelets required to ensure adequate periprocedural hemostasis is unknown, but is likely between 50 and 100,000/L.[88] Therefore, assuming a platelet pool of 200,000/L, most patients will regenerate an adequate number of functional platelets by 5 days after discontinuing therapy, and nearly all will have normal platelet function by 10 days. Determining the risk of bleeding prior to complete turnover of the platelet pool is further complicated by genetic variability between patients in drug metabolism and the degree of platelet inhibition by these agents.[89]
Owing to this complexity, guidelines and prescribing recommendations are inconsistent. The ACCP recommends stopping antiplatelet agents 7 to 10 days prior to an invasive procedure, and the ACC/AHA makes no specific recommendations at all.[90] Based on data from patients undergoing cardiac bypass surgery, it is recommended that clopidogrel be stopped 5 days, and prasugrel 7 days, prior to an invasive procedure.[91, 92] The elimination half‐life of ticlodipine is sufficiently long (up to 96 hours after repeated dosing) that it should be stopped 10 to 14 days prior to an invasive procedure.[87] Ticagrelor is a reversible P2Y12 receptor inhibitor with a half‐life of approximately 8 hours and should therefore have minimal effect by 3 days after discontinuation; however, the manufacturer recommends that it be stopped 5 days prior to an invasive procedure.[93]
The optimal time to restart antiplatelet agents after an invasive procedure is also unknown. The 2008 ACCP guidelines recommended restarting aspirin and/or clopidogrel in 24 hours, or as hemostasis allows,[56] whereas neither the 2007 or 2009 ACC/AHA guidelines,[90] or the most recent 2012 ACCP guidelines,[8] offer specific recommendations. Aspirin, prasugrel, and ticagrelor have a rapid onset of action, whereas the full antiplatelet effect of clopidogrel does not occur for several days, and for patients in whom more rapid platelet inhibition is desired, a loading dose (300600 mg) may be appropriate.[87]
CONCLUSIONS
Deciding on an optimal periprocedural antithrombotic management strategy is a common challenge for hospitalists that requires careful consideration of both patient and procedure related‐risk factors for bleeding and thrombosis, as well as the consequences of delaying or forgoing the procedure altogether. For many procedures, there is evidence that antithrombotic therapy can be safely continued, thereby obviating the risk associated with interrupting therapy. When antithrombotic therapy must be stopped, it should be done in a manner that appropriately balances the risks and consequence of periprocedural bleeding and thromboembolism. Strategies to decrease the risk of perioperative bleeding include allowing sufficient time for the effects of antithrombotic therapy to subside before starting the procedure, and ensuring adequate time for hemostasis before restarting antithrombotic therapy. Bridging therapy may provide net clinical benefit for patients at moderate to high risk for thromboembolism, but this will not be clear until the results of several ongoing bridging trials are available. The periprocedural antithrombotic management strategy should be developed in collaboration with the relevant providers and with active participation by the patient in all decisions and treatment plans. Standardized protocols and documentation can help to minimize unintended variation in practice and improve information transfer during transitions of care.
Acknowledgements
The author would like to thank Shoshana and Lola Herzig for their support in the design and preparation of the manuscript.
Disclosure: Nothing to report.
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The periprocedural management of antithrombotic medications is a common challenge for hospitalists, for which there is limited high‐quality evidence to guide clinical decision making. The introduction of third‐generation antiplatelet agents (prasugrel and ticagrelor) and the new oral anticoagulants (rivaroxaban, apixaban, and dabigatran), has added an additional layer of complexity to clinical management.
This article will provide a conceptual framework for the periprocedural management of antithrombotic therapy, with a particular focus on procedures that are considered core competencies by the Society of Hospital Medicine; these include: arthrocentesis, lumbar puncture, paracentesis, thoracentesis, and central line placement (Table 1).[1, 2] The recommendations in this article are based on a review of published guidelines and consensus statements and their supporting literature.[3, 4, 5, 6, 7, 8] Additional articles were identified by performing a PubMed keyword search using the terms perioperative management or periprocedural management and anticoagulation or antithrombotic or antiplatelet in combination with keywords relevant to the content areas (eg, arthrocentesis, lumbar puncture). Articles for inclusion were chosen based on methodological quality and relevance to hospital medicine.
There are several questions that must be addressed when developing a periprocedural antithrombotic management strategy:
- What is the patient's risk of bleeding if antithrombotic therapy is continued?
- What is the patient's risk of thromboembolism if antithrombotic therapy is interrupted?
- Are there interventions that can decrease the risk of periprocedural bleeding and/or thromboembolism?
WHAT IS THE PATIENT'S RISK OF BLEEDING IF ANTITHROMBOTIC THERAPY IS CONTINUED?
Although the risk of bleeding is well described for many procedures, there are limited data on how that risk is affected by coagulopathy in general and antithrombotic medications in particular. When these data are available, they are largely derived from case series or bridging registries, which include heterogeneous patient populations and nonstandardized definitions of bleeding.[8, 9, 10] As such, few procedural or surgical professional societies have published guidelines on the periprocedural management of antithrombotic therapy,[3, 4, 5, 11]and guidelines from the American College of Chest Physicians (ACCP), the American College of Cardiology (ACC), and American Heart Association (AHA) only provide specific recommendations regarding minor ambulatory procedures.[6, 7, 8]
Procedures can be categorized as low or high risk for bleeding based on the following considerations: the extent of associated tissue injury, proximity to vital organs or vascular structures, the ability to readily detect and control bleeding, and the morbidity associated with a bleeding complication (eg, a small bleed into the epidural space is potentially catastrophic, whereas a large bleed from the colon often results in no permanent harm). For procedures with a high risk or consequence of bleeding, anticoagulants must be stopped, whereas in some cases antiplatelet agents can be safely continued. For procedures with a low risk or consequence of bleeding, it may be possible to continue both anticoagulant and antiplatelet agents.
Procedure | Antithrombotic Therapy | |||||
---|---|---|---|---|---|---|
Aspirin | Thienopyridines | Prophylactic UFH or LWMH | Therapeutic UFH or LMWH | Warfarin | NOACs | |
| ||||||
Arthrocentesis[12, 13, 14, 15] | + | + | + | + | + | + |
Lumbar puncture[3] | + | 5000 units UFH BID | ||||
Paracentesis[28, 29, 30] | + | + | + | |||
Thoracentesis[37, 38, 39, 40, 41, 42] | + | + | + | |||
Central venous catheter insertion[48, 49, 50, 51, 52, 53] | + | + | + |
Because procedures in hospitalized patients are most often performed for the purpose of diagnosing or treating an emergent condition, the risk of delaying the procedure while antithrombotic medications are held must be part of the overall risk‐benefit calculation.
Arthrocentesis
Bleeding complications from arthrocentesis are very rare, and there are few data on the additional risk associated with antithrombotic therapy.[12, 13, 14] In a retrospective cohort study, investigators determined the incidence of clinically significant bleeding (defined as bleeding requiring reversal of anticoagulation, prolonged manual pressure, surgical intervention, hospital admission, or delay in hospital discharge) and procedure‐related pain among 514 patients on antithrombotic therapy referred for arthrocentesis or injection of the hip, shoulder, or knee. Four hundred fifty‐six procedures were performed in patients without interrupting warfarin therapy, all of whom maintained an international normalized ratio (INR)2, and 184 procedures were performed in patients who had stopped their warfarin to achieve an INR <2. Antiplatelet therapy was routinely continued in both groups, with 48% of patients taking aspirin and 9% clopidogrel. There was 1 bleeding complication (0.2%) in a patient with an INR of 2.3 who was also taking aspirin, and 2 patients developed procedure‐related pain (INR 3.3 and 5.3, neither taking antiplatelet medications).[15]
Based on the available evidence, arthrocentesis appears to be safe in patients on therapeutic warfarin, with or without aspirin and/or clopidogrel. At present, there are no published studies that address the risk of arthrocentesis in patients taking other antiplatelet or anticoagulant medications, but given the low overall risk of this procedure, it is reasonable to infer that these medications can also be safely continued.
Lumbar Puncture
The incidence of bleeding complications from diagnostic lumbar puncture is unknown, but is likely similar to that seen with spinal anesthesia, where in a large retrospective observational study, spinal hematoma occurred in 1:165,000 spinal block procedures.[16] Factors associated with an increased risk of spinal hematoma include traumatic tap, advanced age, female gender, spinal cord or vertebral column abnormalities, coagulopathy, and not allowing sufficient time between stopping and restarting antithrombotic therapy.[3, 17, 18, 19, 20]
Therapeutic anticoagulation must be stopped and prophylactic anticoagulation delayed before performing a lumbar puncture. The 1 exception is low‐dose unfractionated heparin (UFH), which the American Society for Regional Anesthesia (ARSA) recommends continuing in patients undergoing neuraxial procedures, provided the total dose is 5000 U twice daily. This assessment is based on observational data, surveys of practice patterns, and decades of use without evidence of complications; in fact, there are only 5 case reports of spinal hematomas in this population.[3] However, because these data are from surgical populations, in which heparin thromboprophylaxis is typically dosed at 5000 units twice daily, there are limited data on the safety of higher or more frequent doses of heparin. In a retrospective cohort study of 928 patients who received thoracic epidural analgesia in conjunction with UFH dosed at 5000 U, 3 times daily, there were no cases of neuraxial bleeding, but given the rarity of neuraxial hematoma, it is not possible to draw any conclusions from this relatively small sample size.[21]
In November 2013, based on surveillance data showing increased risk for spinal or epidural hematoma associated with low‐molecular‐weight heparin (LMWH), the US Food and Drug Administration (FDA) issued a drug safety communication recommending that neuraxial procedures be delayed for 12 hours after prophylactic LMWH and 24 hours after therapeutic LMWH, and that LMWH not be restarted for at least 4 hours after catheter removal.[20] These recommendations are largely consistent with existing guidelines[3, 22] but are not explicitly stated in the package insert for any of the LMWHs available in the United States,[23, 24, 25] and the FDA is working with the manufacturers to add this information.
Nonsteroidal anti‐inflammatory drugs (NSAIDs), dipyridamole, and aspirin do not appear to increase the risk of spinal hematoma and are considered safe to continue.[11, 26] There are limited data on the safety of thienopyridine medications in neuraxial anesthesia, but based on case reports and increased bleeding rates seen in surgical populations, it is generally recommended that these medications be discontinued before performing a lumbar puncture.[3, 22, 27]
The optimal time to restart anticoagulation after a lumbar puncture is unknown. The ARSA recommends a minimum of 1 hour for UFH and 2 hours for LMWH after neuraxial catheter removal, and provides no specific guidance about other anticoagulants,[3] whereas the European Society of Anesthesiology recommends a minimum of 1 hour for UFH, 4 hours for LMWH, 4 to 6 hours for rivaroxaban and apixiban, and 6 hours for dabigatran and fondaparinux.[22] Longer time periods should be considered after a traumatic tap, and postprocedure monitoring of neurological function is recommended for all patients.
The available evidence suggests that lumbar puncture can be safely performed in patients being treated with aspirin, NSAIDs, and UFH dosed at 5000 U twice daily; the safety of higher or more frequent doses of UFH is not known. Lumbar puncture should be delayed 12 hours after prophylactic LMWH and 24 hours after therapeutic LMWH, and LMWH should not be restarted for at least 4 hours after the procedure.[20] There are limited data on the safety of thienopyridines, but they should generally be discontinued, and all other prophylactic or therapeutic anticoagulation must be stopped prior to the procedure.
Paracentesis
Bleeding complications from paracentesis are uncommon, with abdominal wall hematoma and hemoperitoneum complicating 1% and 0.01% of procedures, respectively.[28, 29, 30] Whether antithrombotic therapy increases the risk of bleeding during paracentesis is unknown, primarily because most patients for whom the procedure is indicated have coagulopathy and thrombocytopenia from liver disease, and are therefore rarely treated with these medications.
Although patients with liver disease often have an elevated INR due to impaired hepatic synthesis of clotting factors, it is incorrect to generalize the observed rate of bleeding in this population to patients with an elevated INR from warfarin therapy who may require paracentesis for reasons unrelated to liver disease (eg, malignancy or infection). The coagulopathy of liver disease reflects deficiencies in the hepatic production of both pro‐ and anticoagulant proteins, and these patients develop both thrombotic and hemorrhagic complications irrespective of their in vitro coagulation indices.[31]
Although the available evidence suggests that paracentesis can be safely performed in patients with coagulopathy from liver disease, regardless of the INR,[30] little is known about the bleeding risk in other patients, with or without antithrombotic therapy. Based on indirect evidence, it is reasonable to assume that prophylactic UFH or LWMH or antiplatelet therapy would confer minimal additional risk, whereas the safety of continuing therapeutic anticoagulation is unknown.
Thoracentesis
Bleeding complications from thoracentesis are uncommon, generally occurring in <1% of procedures.[32, 33, 34] Factors associated with increased risk of overall complications include operator inexperience, large volume drainage, and lack of ultrasound guidance.[34, 35, 36] There are no studies that specifically address the risk of bleeding in patients on anticoagulant therapy, but such patients are included in studies on the risk of bleeding with coagulopathy.[37, 38, 39, 40]
In a retrospective cohort study of 1076 ultrasound‐guided thoracenteses performed by radiologists on patients with coagulopathy (defined as thrombocytopenia or an elevated INR from any cause), there were no bleeding complications (defined as anything other than minimal symptoms not requiring intervention). Among the patients in this study, 497 (46%) patients had a preprocedure INR >1.5; 198 (24%) had an INR between 2 and 3, and 32 (4%) had an INR >3.[39]
A similar study, which compared outcomes in patients with corrected and uncorrected coagulopathy, included 744 patients with an INR >1.6 (from any cause), of which 167 received preprocedural fresh‐frozen plasma (FFP) and 577 did not. There was 1 (0.1%) bleeding complication in a patient who received prophylactic FFP and none in the group that was not transfused.[38]
In a prospective cohort of 312 patients at increased risk for bleeding (from coagulopathy or antithrombotic medications) who underwent ultrasound‐guided thoracentesis by a pulmonologist or physician's assistant, 44 (34%) had an INR >1.5 (secondary to liver disease or warfarin therapy), 15 (12%) were taking clopidogrel, and 14 (11%) were treated with therapeutic LMWH within 12 hours or therapeutic UFH within 4.5 hours of the procedure. There were no bleeding complications in any of the patients (defined as mean change in hematocrit, chest x‐ray abnormalities, hemothorax, or requirement for transfusion).[37]
Although there are no studies that specifically address the use of aspirin and bleeding complications in thoracentesis, it is generally considered safe to continue this medication,[5] and there are small studies that show that thoracentesis and small‐bore chest tubes can be safely placed in patients taking clopidogrel.[41, 42]
Thoracentesis is associated with a low rate of bleeding complications, and when performed by an experienced operator using ultrasound, warfarin does not appear to increase this risk. However, given the low overall complication rate, it is not known whether patients on warfarin would have worse outcomes in the event of more serious complications (eg, intercostal artery laceration). At present, there are no published studies that address the risk of thoracentesis in patients taking new oral anticoagulants (NOACs).
Central Venous Catheter Insertion
The incidence of bleeding complications from central venous catheter (CVC) placement varies depending on the site of insertion and definition of bleeding, with hematoma and hemothorax occurring in 0.1% to 6.9%, and 0.4% to 1.3% of procedures, respectively.[43, 44, 45] Factors that increase the likelihood of complications include operator inexperience, multiple needle passes, and lack of ultrasound guidance.[46, 47] There are no studies that specifically address the risk of bleeding from CVC placement in patients on anticoagulant therapy, but such patients are included in studies of CVC placement in patients with coagulopathy, which report similar complication rates as seen in patients with normal hemostasis.[48, 49, 50, 51, 52, 53]
In a retrospective cohort study, investigators collected information on CVC‐associated bleeding complications in 281 medical and surgical intensive care patients with coagulopathy (INR 1.5 from any cause) after they adopted a more conservative approach to plasma transfusion in their intensive care unit; specifically, the routine use of prophylactic FFP to correct coagulopathy was discouraged for patients with an INR <3 (vs usual practice using an INR cutoff of 1.5), but the final decision was left to the discretion of the attending performing or supervising the procedure. Bleeding was defined as insertion‐site hematoma, interventions other than local manual pressure, and the need for blood transfusion. One case of bleeding (hematoma) was observed in a patient with an INR of 3.9, who received FFP before the procedure. There were no complications among those with uncorrected coagulopathy, including 66 patients with an INR between 1.5 and 2.9, and 6 with an INR 3.0. Ultrasound guidance was used in 50% of CVCs placed in the internal jugular vein.[54]
Although there are no studies that specifically address the use of antiplatelet drugs and bleeding complications in CVC placement, aspirin is generally considered safe to continue,[5] and by inference, thienopyridines are expected to add minimal additional risk.
CVC placement is associated with a variable rate of bleeding complications, with hematoma being relatively common. Based on the available literature, warfarin does not appear to increase this risk, but there are limited data from which to draw firm conclusions. A femoral or jugular approach may be preferable because they allow for ultrasound visualization and are amenable to manual compression. There are no published studies that address the risk of CVC placement in patients taking NOACs, and although the risk of bleeding is probably similar to patients receiving warfarin, the lack of effective reversal agents for these medications should be part of any risk‐benefit calculation.[55]
WHAT IS THE PATIENT'S RISK OF THROMBOEMBOLISM IF ANTITHROMBOTIC THERAPY IS INTERRUPTED?
Anticoagulants
If it is determined that a procedure cannot safely be performed while continuing antithrombotic therapy, one must then consider the patient's risk of thromboembolism if these therapies are temporarily interrupted. Unfortunately, there are few robust clinical studies from which to make this assessment, and therefore most clinicians rely on the risk stratification model proposed by the ACCP, which divides patients into 3 tiers (low, moderate, high), based on their indication for anticoagulation and risk factors for thromboembolism (Table 2)[8]. The ACCP model is largely based on indirect evidence from antithrombotic therapy trials in nonoperative patients, and its application to perioperative patients necessitates several assumptions that may not hold true in practice.
Indication for Anticoagulant Therapy | |||
---|---|---|---|
Risk Stratum | Mechanical Heart Valve | Atrial Fibrillation | VTE |
| |||
High Thrombotic Risk |
|
|
|
Moderate Thrombotic Risk |
|
|
|
Low Thrombotic Risk |
|
|
|
First, it assumes that the annualized risk of a thrombotic event in nonoperative patients can be prorated to determine the short‐term risk of discontinuing antithrombotic therapy in the perioperative period. For example, it has been estimated that the risk for perioperative stroke in a patient with atrial fibrillation who temporarily interrupts anticoagulation for 1 week would be 0.1% (5% per year 52 weeks),[56, 57]and yet we know from observational data that the actual risk of perioperative stroke in similar patients is 5 to 7 times higher.[58, 59] Second, it assumes that bridging therapy will decrease the risk of thromboembolism in high‐risk patients when warfarin therapy is interrupted, a premise that is logical but has not been subject to randomized controlled trials.[60] Third, it does not take into account the surgery‐specific risk for thromboembolism, which varies significantly, with arterial thromboembolism being more common in cardiac valve, vascular, and neurologic procedures, and venous thromboembolism (VTE) being more likely in orthopedic, trauma, and cancer surgery.[61, 62] These limitations notwithstanding, the ACCP model still offers the best available framework for thrombotic risk assessment and a reasonable starting point for clinical decision making.
Antiplatelet Agents
Patients with coronary artery stents who undergo noncardiac surgery are at increased risk for adverse cardiovascular events, including acute stent thrombosis, which carries a risk of myocardial infarction and death of 70% and 30%, respectively.[63] This risk is highest during the period between stent implantation and endothelialization, a process that takes 4 to 6 weeks for bare‐metal stents (BMS) and 6 to 12 months for drug‐eluting stents (DES). Premature discontinuation of dual antiplatelet therapy is the most important risk factor for stent thrombosis during this time.[64] Although the optimal perioperative strategy for these patients is unknown, there is general agreement that elective surgery should be delayed for at least 4 weeks in patients with a BMS and 12 months for patients with a DES. If a procedure or surgery is required during this time period, every effort should be made to continue dual antiplatelet therapy; if this is not possible, aspirin should be continued, and thienopyridine therapy should be interrupted as briefly as possible (Table 3).
Recommended Interval Between Last Dose of Medication and Procedure | Recommended Interval Between Procedure and First Dose of Medication, h | ||
---|---|---|---|
Low Risk or Consequence of Postprocedure Bleeding | High Risk or Consequence of Postprocedure Bleeding | ||
| |||
Antiplatelet Medicationsa | |||
Aspirin (81325 mg dailydipyridamole) | 710 days (skip 69 doses) | 24 | 48 |
Ticlodipine (250 mg twice daily) | 1014 days (skip 1926 doses) | 24 | 48 |
Clopidogrel (75 mg once daily) | 710 days (skip 69 doses)b | 24 | 48 |
Prasugrel (10 mg once daily) | 710 days (skip 69 dose)c | 24 | 48 |
Ticagrelor (90 mg twice daily; t =8 hours) | 5 days (skip 8 doses) | 24 | 48 |
Cilostazol (100 mg twice daily; t =11 hours) | 3 days (skip 4 doses) | 24 | 48 |
Anticoagulant Medicationse | |||
Warfarin (t =3642 hours, but highly variable) | 6 days (skip 5 doses)f | 12 | 24 |
Intravenous UFH (t 60 minutes) | 46 hours | 24 | 4872 |
LMWH (t =37 hours) | |||
Prophylactic dosing | 12 hours# | 12 | 2436 |
Therapeutic dosing | |||
Once daily | 24 hours (give 50% of last total dose)# | 24 | 4872 |
Twice daily | 24 hours (skip 1 dose)# | 24 | 4872 |
Fondaparinux (t =17 hours, any dose) | 34 days (skip 23 doses)h | 24 | 4872 |
Dabigatran (150 mg twice daily) | |||
CrCl>50 mL/min (t =1417 hours) | 3 days (skip 4 doses) | 24 | 4872 |
CrCl 3050 mL/min (t =1618 hours) | 45 days (skip 68 doses) | 24 | 4872 |
CrCl 1530 mL/min (t =1618 hours)i | 45 days (skip 68 doses) | 24 | 4872 |
Rivaroxaban (20 mg once daily) | |||
CrCl>50 mL/min (t =89 hours) | 3 days (skip 2 doses) | 24 | 4872 |
CrCl 3050 mL/min (t =9 hours) | 3 days (skip 2 doses) | 24 | 4872 |
CrCl 1529.9 mL/min (t =910 hours)j | 4 days (skip 3 doses) | 24 | 4872 |
Apixiban (5 mg twice daily) | |||
CrCl>50 mL/min (t =78 hours) | 3 days (skip 4 doses) | 24 | 4872 |
CrCl 3050 mL/min (t =1718 hours) | 4 days (skip 6 doses) | 24 | 4872 |
ARE THERE INTERVENTIONS THAT CAN DECREASE THE RISK OF PERIPROCEDURAL BLEEDING AND/OR THROMBOEMBOLISM?
Mitigating the Risk of Bleeding
Bleeding complications can be reduced by allowing a sufficient time for the effects of antithrombotic medications to wear off before performing a procedure. This requires an understanding of the pharmacology of these medications, with particular attention to patients in whom these medications are less well studied, including the elderly, patients with renal insufficiency, and those with very high or low body mass index. Table 3 provides recommendations for when to stop antithrombotic therapy prior to an invasive procedure. The intervals are based on the time needed to achieve a minimal antithrombotic effect, which is generally 4 to 5 half‐lives for anticoagulants and 7 to 10 days for irreversible antiplatelet agents. Shorter intervals may be appropriate for procedures with low risk or consequence of bleeding, but there are insufficient data to make specific recommendations regarding this strategy.
It is equally important to ensure that there is adequate time for postoperative hemostasis prior to restarting antithrombotic therapy. Data from VTE prophylaxis trials and bridging studies consistently show that bleeding complications occur more frequently when anticoagulation is started too early, and antithrombotic therapy should generally be delayed 24 hours in patients at average risk and 48 to 72 hours in patients at high risk or consequence for postoperative bleeding.[8, 60, 65]
Aspirin increases the risk of surgical blood loss and transfusion by up to 20%, and by up to 50% when given in combination with clopidogrel, but with the exception of intracranial surgery, there does not appear to be an increase in perioperative morbidity or mortality with either of these agents.[66]
Mitigating the Risk of Thromboembolism
Once the decision has been made to temporarily discontinue warfarin, the next consideration is whether to bridge with a short acting anticoagulant (typically subcutaneous LMWH or intravenous UFH) during the period of time when the INR is subtherapeutic. Conceptually, one would expect this strategy would minimize the risk of thromboembolism, but its efficacy has never been clearly demonstrated. In fact, in a systematic review and meta‐analysis of 34 studies that compared the rates of thromboembolism among bridged and nonbridged patients, heparin therapy did not reduce the risk of thromboembolic events (odds ratio: 0.80; 95% confidence interval: 0.421.54), but did result in higher rates of periprocedural bleeding.[60]
The applicability of these results to clinical practice are limited by the heterogeneity of the data used in the analysis; specifically, bridging strategies varied (including therapeutic, intermediate, and prophylactic dose regimens), there was wide variation in the types of surgery (and therefore bleeding risk), and because the majority of studies were observational, there is a significant likelihood of confounding by indication (ie, patients at high risk for thromboembolism are more likely to receive bridging therapy), and thus the benefit of this strategy may be underestimated. It is also important to note that in the majority studies anticoagulation was restarted <24 hours after the procedure, which likely contributed to the increased rate of bleeding.
Therefore, although bridging therapy is not indicated for patients at low risk, it is premature to conclude that it should be avoided in patients at moderate or high risk for thromboembolism. The results of 2 ongoing, randomized, placebo‐controlled trials of bridging therapy in patients taking warfarin for atrial fibrillation (Effectiveness of Bridging Anticoagulation for Surgery [BRIDGE]) or mechanical heart values (A Double Blind Randomized Control Trial of Post‐Operative Low Molecular Weight Heparin Bridging Therapy Versus Placebo Bridging Therapy for Patients Who Are at High Risk for Arterial Thromboembolism [PERIOP‐2]) should help to answer this question.[67, 68]
The uncertainty regarding the benefits of bridging therapy is reflected in the changes to the most recent ACCP guidelines. In 2008, the ACCP recommended low‐dose LMWH or no bridging for patients at low risk (grade 2C), therapeutic‐dose bridging for patients at moderate risk (grade 2C), and therapeutic‐dose bridging for patients at high risk for thromboembolism (Grade 1C).[56] In 2012, the ACCP recommended against bridging for low‐risk patients (grade 2C), made no specific recommendation regarding moderate‐risk patients, and offered a less robust recommendation for bridging in high‐risk patients (grade 2C).[8]
Until the results of the BRIDGE and PERIOP‐2 trials are available, the author still favors therapeutic bridging for patients at high risk and selected patients at moderate risk for thromboembolism, provided sufficient time is allowed for postoperative hemostasis before anticoagulation is restarted. For procedures with a high risk or consequence of bleeding, intravenous UFH (without a bolus) is a reasonable initial postoperative strategy to insure that anticoagulation is tolerated before committing to LMWH. Indirect evidence supports the use of prophylactic or intermediate‐dose bridging regimens in patients for whom the primary consideration is the prevention of recurrent VTE, but data to show that this strategy is effective for the prevention of arterial thromboembolism are lacking.
Intravenous glycoprotein IIb/IIIa inhibitors are sometimes used to bridge high‐risk patients with coronary artery stents who must stop antiplatelet therapy prior to a procedure, but the data to support this practice are limited and observational in nature.[69, 70]
STARTING AND STOPPING ANTITHROMBOTIC THERAPY
Warfarin
For patients on warfarin, the INR at which it is safe to perform invasive procedures is unknown. Normal hemostasis requires clotting factor levels of approximately 20% to 40% of normal,[71] which generally corresponds to an INR of <1.5, whereas for most indications, therapeutic anticoagulation is achieved when the INR is between 2.0 and 3.5. However, because the relationship between the INR and the levels of clotting factors is nonlinear, for a given patient, the INR may be abnormal (ie, >1) despite levels of clotting factors that are sufficient for periprocedural hemostasis.[72, 73, 74, 75] Because of its relatively long half‐life (3642 hours), warfarin should be stopped 6 days (skip 5 doses) prior to a procedure to achieve an INR of <1.5, but can safely be restarted the same day in most patients.
Heparins
The half‐life of intravenous heparin is dose dependent, and at therapeutic levels is approximately 60 minutes; therefore, it should be discontinued 4 to 6 hours (5 half‐lives) before performing an invasive procedure.[76] The half‐life of subcutaneous LMWHs ranges from 3 to 7 hours in healthy volunteers,[23, 24, 25] and is often longer in patients for whom these medications are commonly prescribed.[77, 78] Therefore, when administered at therapeutic doses twice daily, the last dose should be given in the morning the day before the procedure, and for therapeutic once‐daily regimens, the last dose should be reduced by 50%.[8] The optimal time to discontinue prophylactic doses of LWMH prior to an invasive procedure is unclear, but a minimum of 12 hours is recommended.[22, 79] Because LWMHs are renally cleared, longer intervals are needed for patients with impaired renal function.[76, 80]
New Oral Anticoagulants
The manufacturer of rivaroxaban recommends that if anticoagulation must be discontinued, it be stopped at least 24 hours before the procedure.[81] Although this may be sufficient for procedures with a low risk or consequence of bleeding, the half‐life of rivaroxaban is between 8 and 10 hours, and therefore 48 hours (45 half‐lives) is required to ensure minimal residual anticoagulant effect.
Apixaban has a clearance half‐life of 6 hours, but displays prolonged absorption such that its effective half‐life is 12 hours after repeated dosing. The manufacturer recommends that it be stopped at least 24 hours prior to a procedure with a low risk or consequence of bleeding, and 48 hours prior to a procedure with a high risk or consequence of bleeding.[82]
The manufacturer of dabigatran recommends that the drug be discontinued 1 to 2 days (creatinine clearance (CrCl) 50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures, and that longer times be considered when complete hemostasis is required.[83] Given that the half‐life of dabigatran is 14 to 17 hours, the author recommends that it be stopped at least 2 days (3 half‐lives) prior to a procedure with a low risk or consequence of bleeding, and 3 days (45 half‐lives) prior to a procedure with a high risk or consequence of bleeding.
The clearance of all the NOACs is significantly prolonged in patients with renal impairment, and a longer interval between the last dose and the procedure is necessary in patients with renal failure to ensure normal hemostasis (Table 3).
The effect of the NOACs on the standard clotting assays are complex and vary depending on drug dose, the type of reagents used, and the calibration of the equipment. For dabigatran, the activated partial thromboplastin time (aPTT) and the thrombin time (TT) are sufficiently sensitive to allow for a qualitative assessment of drug effect, such that a normal aPTT indicates the absence, or a very low level of an anticoagulant effect, and a normal TT essentially rules out an effect. Accurate quantitative testing of dabigatran requires an appropriately calibrated dilute thrombin test or ecarin clotting time assay.[84, 85]
Depending on the thromboplastin reagent used, the prothrombin time (PT) may be sufficiently sensitive to rivaroxaban that a normal level rules out a residual drug effect,[86] but this does not hold true for apixaban, which has minimal effect on the PT at therapeutic concentrations. The aPTT is insensitive to both rivaroxaban and apixaban and cannot be used for assessing residual drug effect. Accurate quantitative testing of rivaroxaban or apixaban requires an anti‐factor Xa assay calibrated for use with these agents.[84]
Antiplatelet Agents
Aspirin irreversibly inhibits platelet cyclooxygenase activity, and the thienopyridines clopidogrel and prasugrel, irreversibly inhibit the platelet P2Y12 receptor. As such, the biological effects of these medications persist until the platelet pool has turned over, a process that occurs at 10% to 12% per day and takes 7 to 10 days to complete.[87] The minimum number of functional platelets required to ensure adequate periprocedural hemostasis is unknown, but is likely between 50 and 100,000/L.[88] Therefore, assuming a platelet pool of 200,000/L, most patients will regenerate an adequate number of functional platelets by 5 days after discontinuing therapy, and nearly all will have normal platelet function by 10 days. Determining the risk of bleeding prior to complete turnover of the platelet pool is further complicated by genetic variability between patients in drug metabolism and the degree of platelet inhibition by these agents.[89]
Owing to this complexity, guidelines and prescribing recommendations are inconsistent. The ACCP recommends stopping antiplatelet agents 7 to 10 days prior to an invasive procedure, and the ACC/AHA makes no specific recommendations at all.[90] Based on data from patients undergoing cardiac bypass surgery, it is recommended that clopidogrel be stopped 5 days, and prasugrel 7 days, prior to an invasive procedure.[91, 92] The elimination half‐life of ticlodipine is sufficiently long (up to 96 hours after repeated dosing) that it should be stopped 10 to 14 days prior to an invasive procedure.[87] Ticagrelor is a reversible P2Y12 receptor inhibitor with a half‐life of approximately 8 hours and should therefore have minimal effect by 3 days after discontinuation; however, the manufacturer recommends that it be stopped 5 days prior to an invasive procedure.[93]
The optimal time to restart antiplatelet agents after an invasive procedure is also unknown. The 2008 ACCP guidelines recommended restarting aspirin and/or clopidogrel in 24 hours, or as hemostasis allows,[56] whereas neither the 2007 or 2009 ACC/AHA guidelines,[90] or the most recent 2012 ACCP guidelines,[8] offer specific recommendations. Aspirin, prasugrel, and ticagrelor have a rapid onset of action, whereas the full antiplatelet effect of clopidogrel does not occur for several days, and for patients in whom more rapid platelet inhibition is desired, a loading dose (300600 mg) may be appropriate.[87]
CONCLUSIONS
Deciding on an optimal periprocedural antithrombotic management strategy is a common challenge for hospitalists that requires careful consideration of both patient and procedure related‐risk factors for bleeding and thrombosis, as well as the consequences of delaying or forgoing the procedure altogether. For many procedures, there is evidence that antithrombotic therapy can be safely continued, thereby obviating the risk associated with interrupting therapy. When antithrombotic therapy must be stopped, it should be done in a manner that appropriately balances the risks and consequence of periprocedural bleeding and thromboembolism. Strategies to decrease the risk of perioperative bleeding include allowing sufficient time for the effects of antithrombotic therapy to subside before starting the procedure, and ensuring adequate time for hemostasis before restarting antithrombotic therapy. Bridging therapy may provide net clinical benefit for patients at moderate to high risk for thromboembolism, but this will not be clear until the results of several ongoing bridging trials are available. The periprocedural antithrombotic management strategy should be developed in collaboration with the relevant providers and with active participation by the patient in all decisions and treatment plans. Standardized protocols and documentation can help to minimize unintended variation in practice and improve information transfer during transitions of care.
Acknowledgements
The author would like to thank Shoshana and Lola Herzig for their support in the design and preparation of the manuscript.
Disclosure: Nothing to report.
The periprocedural management of antithrombotic medications is a common challenge for hospitalists, for which there is limited high‐quality evidence to guide clinical decision making. The introduction of third‐generation antiplatelet agents (prasugrel and ticagrelor) and the new oral anticoagulants (rivaroxaban, apixaban, and dabigatran), has added an additional layer of complexity to clinical management.
This article will provide a conceptual framework for the periprocedural management of antithrombotic therapy, with a particular focus on procedures that are considered core competencies by the Society of Hospital Medicine; these include: arthrocentesis, lumbar puncture, paracentesis, thoracentesis, and central line placement (Table 1).[1, 2] The recommendations in this article are based on a review of published guidelines and consensus statements and their supporting literature.[3, 4, 5, 6, 7, 8] Additional articles were identified by performing a PubMed keyword search using the terms perioperative management or periprocedural management and anticoagulation or antithrombotic or antiplatelet in combination with keywords relevant to the content areas (eg, arthrocentesis, lumbar puncture). Articles for inclusion were chosen based on methodological quality and relevance to hospital medicine.
There are several questions that must be addressed when developing a periprocedural antithrombotic management strategy:
- What is the patient's risk of bleeding if antithrombotic therapy is continued?
- What is the patient's risk of thromboembolism if antithrombotic therapy is interrupted?
- Are there interventions that can decrease the risk of periprocedural bleeding and/or thromboembolism?
WHAT IS THE PATIENT'S RISK OF BLEEDING IF ANTITHROMBOTIC THERAPY IS CONTINUED?
Although the risk of bleeding is well described for many procedures, there are limited data on how that risk is affected by coagulopathy in general and antithrombotic medications in particular. When these data are available, they are largely derived from case series or bridging registries, which include heterogeneous patient populations and nonstandardized definitions of bleeding.[8, 9, 10] As such, few procedural or surgical professional societies have published guidelines on the periprocedural management of antithrombotic therapy,[3, 4, 5, 11]and guidelines from the American College of Chest Physicians (ACCP), the American College of Cardiology (ACC), and American Heart Association (AHA) only provide specific recommendations regarding minor ambulatory procedures.[6, 7, 8]
Procedures can be categorized as low or high risk for bleeding based on the following considerations: the extent of associated tissue injury, proximity to vital organs or vascular structures, the ability to readily detect and control bleeding, and the morbidity associated with a bleeding complication (eg, a small bleed into the epidural space is potentially catastrophic, whereas a large bleed from the colon often results in no permanent harm). For procedures with a high risk or consequence of bleeding, anticoagulants must be stopped, whereas in some cases antiplatelet agents can be safely continued. For procedures with a low risk or consequence of bleeding, it may be possible to continue both anticoagulant and antiplatelet agents.
Procedure | Antithrombotic Therapy | |||||
---|---|---|---|---|---|---|
Aspirin | Thienopyridines | Prophylactic UFH or LWMH | Therapeutic UFH or LMWH | Warfarin | NOACs | |
| ||||||
Arthrocentesis[12, 13, 14, 15] | + | + | + | + | + | + |
Lumbar puncture[3] | + | 5000 units UFH BID | ||||
Paracentesis[28, 29, 30] | + | + | + | |||
Thoracentesis[37, 38, 39, 40, 41, 42] | + | + | + | |||
Central venous catheter insertion[48, 49, 50, 51, 52, 53] | + | + | + |
Because procedures in hospitalized patients are most often performed for the purpose of diagnosing or treating an emergent condition, the risk of delaying the procedure while antithrombotic medications are held must be part of the overall risk‐benefit calculation.
Arthrocentesis
Bleeding complications from arthrocentesis are very rare, and there are few data on the additional risk associated with antithrombotic therapy.[12, 13, 14] In a retrospective cohort study, investigators determined the incidence of clinically significant bleeding (defined as bleeding requiring reversal of anticoagulation, prolonged manual pressure, surgical intervention, hospital admission, or delay in hospital discharge) and procedure‐related pain among 514 patients on antithrombotic therapy referred for arthrocentesis or injection of the hip, shoulder, or knee. Four hundred fifty‐six procedures were performed in patients without interrupting warfarin therapy, all of whom maintained an international normalized ratio (INR)2, and 184 procedures were performed in patients who had stopped their warfarin to achieve an INR <2. Antiplatelet therapy was routinely continued in both groups, with 48% of patients taking aspirin and 9% clopidogrel. There was 1 bleeding complication (0.2%) in a patient with an INR of 2.3 who was also taking aspirin, and 2 patients developed procedure‐related pain (INR 3.3 and 5.3, neither taking antiplatelet medications).[15]
Based on the available evidence, arthrocentesis appears to be safe in patients on therapeutic warfarin, with or without aspirin and/or clopidogrel. At present, there are no published studies that address the risk of arthrocentesis in patients taking other antiplatelet or anticoagulant medications, but given the low overall risk of this procedure, it is reasonable to infer that these medications can also be safely continued.
Lumbar Puncture
The incidence of bleeding complications from diagnostic lumbar puncture is unknown, but is likely similar to that seen with spinal anesthesia, where in a large retrospective observational study, spinal hematoma occurred in 1:165,000 spinal block procedures.[16] Factors associated with an increased risk of spinal hematoma include traumatic tap, advanced age, female gender, spinal cord or vertebral column abnormalities, coagulopathy, and not allowing sufficient time between stopping and restarting antithrombotic therapy.[3, 17, 18, 19, 20]
Therapeutic anticoagulation must be stopped and prophylactic anticoagulation delayed before performing a lumbar puncture. The 1 exception is low‐dose unfractionated heparin (UFH), which the American Society for Regional Anesthesia (ARSA) recommends continuing in patients undergoing neuraxial procedures, provided the total dose is 5000 U twice daily. This assessment is based on observational data, surveys of practice patterns, and decades of use without evidence of complications; in fact, there are only 5 case reports of spinal hematomas in this population.[3] However, because these data are from surgical populations, in which heparin thromboprophylaxis is typically dosed at 5000 units twice daily, there are limited data on the safety of higher or more frequent doses of heparin. In a retrospective cohort study of 928 patients who received thoracic epidural analgesia in conjunction with UFH dosed at 5000 U, 3 times daily, there were no cases of neuraxial bleeding, but given the rarity of neuraxial hematoma, it is not possible to draw any conclusions from this relatively small sample size.[21]
In November 2013, based on surveillance data showing increased risk for spinal or epidural hematoma associated with low‐molecular‐weight heparin (LMWH), the US Food and Drug Administration (FDA) issued a drug safety communication recommending that neuraxial procedures be delayed for 12 hours after prophylactic LMWH and 24 hours after therapeutic LMWH, and that LMWH not be restarted for at least 4 hours after catheter removal.[20] These recommendations are largely consistent with existing guidelines[3, 22] but are not explicitly stated in the package insert for any of the LMWHs available in the United States,[23, 24, 25] and the FDA is working with the manufacturers to add this information.
Nonsteroidal anti‐inflammatory drugs (NSAIDs), dipyridamole, and aspirin do not appear to increase the risk of spinal hematoma and are considered safe to continue.[11, 26] There are limited data on the safety of thienopyridine medications in neuraxial anesthesia, but based on case reports and increased bleeding rates seen in surgical populations, it is generally recommended that these medications be discontinued before performing a lumbar puncture.[3, 22, 27]
The optimal time to restart anticoagulation after a lumbar puncture is unknown. The ARSA recommends a minimum of 1 hour for UFH and 2 hours for LMWH after neuraxial catheter removal, and provides no specific guidance about other anticoagulants,[3] whereas the European Society of Anesthesiology recommends a minimum of 1 hour for UFH, 4 hours for LMWH, 4 to 6 hours for rivaroxaban and apixiban, and 6 hours for dabigatran and fondaparinux.[22] Longer time periods should be considered after a traumatic tap, and postprocedure monitoring of neurological function is recommended for all patients.
The available evidence suggests that lumbar puncture can be safely performed in patients being treated with aspirin, NSAIDs, and UFH dosed at 5000 U twice daily; the safety of higher or more frequent doses of UFH is not known. Lumbar puncture should be delayed 12 hours after prophylactic LMWH and 24 hours after therapeutic LMWH, and LMWH should not be restarted for at least 4 hours after the procedure.[20] There are limited data on the safety of thienopyridines, but they should generally be discontinued, and all other prophylactic or therapeutic anticoagulation must be stopped prior to the procedure.
Paracentesis
Bleeding complications from paracentesis are uncommon, with abdominal wall hematoma and hemoperitoneum complicating 1% and 0.01% of procedures, respectively.[28, 29, 30] Whether antithrombotic therapy increases the risk of bleeding during paracentesis is unknown, primarily because most patients for whom the procedure is indicated have coagulopathy and thrombocytopenia from liver disease, and are therefore rarely treated with these medications.
Although patients with liver disease often have an elevated INR due to impaired hepatic synthesis of clotting factors, it is incorrect to generalize the observed rate of bleeding in this population to patients with an elevated INR from warfarin therapy who may require paracentesis for reasons unrelated to liver disease (eg, malignancy or infection). The coagulopathy of liver disease reflects deficiencies in the hepatic production of both pro‐ and anticoagulant proteins, and these patients develop both thrombotic and hemorrhagic complications irrespective of their in vitro coagulation indices.[31]
Although the available evidence suggests that paracentesis can be safely performed in patients with coagulopathy from liver disease, regardless of the INR,[30] little is known about the bleeding risk in other patients, with or without antithrombotic therapy. Based on indirect evidence, it is reasonable to assume that prophylactic UFH or LWMH or antiplatelet therapy would confer minimal additional risk, whereas the safety of continuing therapeutic anticoagulation is unknown.
Thoracentesis
Bleeding complications from thoracentesis are uncommon, generally occurring in <1% of procedures.[32, 33, 34] Factors associated with increased risk of overall complications include operator inexperience, large volume drainage, and lack of ultrasound guidance.[34, 35, 36] There are no studies that specifically address the risk of bleeding in patients on anticoagulant therapy, but such patients are included in studies on the risk of bleeding with coagulopathy.[37, 38, 39, 40]
In a retrospective cohort study of 1076 ultrasound‐guided thoracenteses performed by radiologists on patients with coagulopathy (defined as thrombocytopenia or an elevated INR from any cause), there were no bleeding complications (defined as anything other than minimal symptoms not requiring intervention). Among the patients in this study, 497 (46%) patients had a preprocedure INR >1.5; 198 (24%) had an INR between 2 and 3, and 32 (4%) had an INR >3.[39]
A similar study, which compared outcomes in patients with corrected and uncorrected coagulopathy, included 744 patients with an INR >1.6 (from any cause), of which 167 received preprocedural fresh‐frozen plasma (FFP) and 577 did not. There was 1 (0.1%) bleeding complication in a patient who received prophylactic FFP and none in the group that was not transfused.[38]
In a prospective cohort of 312 patients at increased risk for bleeding (from coagulopathy or antithrombotic medications) who underwent ultrasound‐guided thoracentesis by a pulmonologist or physician's assistant, 44 (34%) had an INR >1.5 (secondary to liver disease or warfarin therapy), 15 (12%) were taking clopidogrel, and 14 (11%) were treated with therapeutic LMWH within 12 hours or therapeutic UFH within 4.5 hours of the procedure. There were no bleeding complications in any of the patients (defined as mean change in hematocrit, chest x‐ray abnormalities, hemothorax, or requirement for transfusion).[37]
Although there are no studies that specifically address the use of aspirin and bleeding complications in thoracentesis, it is generally considered safe to continue this medication,[5] and there are small studies that show that thoracentesis and small‐bore chest tubes can be safely placed in patients taking clopidogrel.[41, 42]
Thoracentesis is associated with a low rate of bleeding complications, and when performed by an experienced operator using ultrasound, warfarin does not appear to increase this risk. However, given the low overall complication rate, it is not known whether patients on warfarin would have worse outcomes in the event of more serious complications (eg, intercostal artery laceration). At present, there are no published studies that address the risk of thoracentesis in patients taking new oral anticoagulants (NOACs).
Central Venous Catheter Insertion
The incidence of bleeding complications from central venous catheter (CVC) placement varies depending on the site of insertion and definition of bleeding, with hematoma and hemothorax occurring in 0.1% to 6.9%, and 0.4% to 1.3% of procedures, respectively.[43, 44, 45] Factors that increase the likelihood of complications include operator inexperience, multiple needle passes, and lack of ultrasound guidance.[46, 47] There are no studies that specifically address the risk of bleeding from CVC placement in patients on anticoagulant therapy, but such patients are included in studies of CVC placement in patients with coagulopathy, which report similar complication rates as seen in patients with normal hemostasis.[48, 49, 50, 51, 52, 53]
In a retrospective cohort study, investigators collected information on CVC‐associated bleeding complications in 281 medical and surgical intensive care patients with coagulopathy (INR 1.5 from any cause) after they adopted a more conservative approach to plasma transfusion in their intensive care unit; specifically, the routine use of prophylactic FFP to correct coagulopathy was discouraged for patients with an INR <3 (vs usual practice using an INR cutoff of 1.5), but the final decision was left to the discretion of the attending performing or supervising the procedure. Bleeding was defined as insertion‐site hematoma, interventions other than local manual pressure, and the need for blood transfusion. One case of bleeding (hematoma) was observed in a patient with an INR of 3.9, who received FFP before the procedure. There were no complications among those with uncorrected coagulopathy, including 66 patients with an INR between 1.5 and 2.9, and 6 with an INR 3.0. Ultrasound guidance was used in 50% of CVCs placed in the internal jugular vein.[54]
Although there are no studies that specifically address the use of antiplatelet drugs and bleeding complications in CVC placement, aspirin is generally considered safe to continue,[5] and by inference, thienopyridines are expected to add minimal additional risk.
CVC placement is associated with a variable rate of bleeding complications, with hematoma being relatively common. Based on the available literature, warfarin does not appear to increase this risk, but there are limited data from which to draw firm conclusions. A femoral or jugular approach may be preferable because they allow for ultrasound visualization and are amenable to manual compression. There are no published studies that address the risk of CVC placement in patients taking NOACs, and although the risk of bleeding is probably similar to patients receiving warfarin, the lack of effective reversal agents for these medications should be part of any risk‐benefit calculation.[55]
WHAT IS THE PATIENT'S RISK OF THROMBOEMBOLISM IF ANTITHROMBOTIC THERAPY IS INTERRUPTED?
Anticoagulants
If it is determined that a procedure cannot safely be performed while continuing antithrombotic therapy, one must then consider the patient's risk of thromboembolism if these therapies are temporarily interrupted. Unfortunately, there are few robust clinical studies from which to make this assessment, and therefore most clinicians rely on the risk stratification model proposed by the ACCP, which divides patients into 3 tiers (low, moderate, high), based on their indication for anticoagulation and risk factors for thromboembolism (Table 2)[8]. The ACCP model is largely based on indirect evidence from antithrombotic therapy trials in nonoperative patients, and its application to perioperative patients necessitates several assumptions that may not hold true in practice.
Indication for Anticoagulant Therapy | |||
---|---|---|---|
Risk Stratum | Mechanical Heart Valve | Atrial Fibrillation | VTE |
| |||
High Thrombotic Risk |
|
|
|
Moderate Thrombotic Risk |
|
|
|
Low Thrombotic Risk |
|
|
|
First, it assumes that the annualized risk of a thrombotic event in nonoperative patients can be prorated to determine the short‐term risk of discontinuing antithrombotic therapy in the perioperative period. For example, it has been estimated that the risk for perioperative stroke in a patient with atrial fibrillation who temporarily interrupts anticoagulation for 1 week would be 0.1% (5% per year 52 weeks),[56, 57]and yet we know from observational data that the actual risk of perioperative stroke in similar patients is 5 to 7 times higher.[58, 59] Second, it assumes that bridging therapy will decrease the risk of thromboembolism in high‐risk patients when warfarin therapy is interrupted, a premise that is logical but has not been subject to randomized controlled trials.[60] Third, it does not take into account the surgery‐specific risk for thromboembolism, which varies significantly, with arterial thromboembolism being more common in cardiac valve, vascular, and neurologic procedures, and venous thromboembolism (VTE) being more likely in orthopedic, trauma, and cancer surgery.[61, 62] These limitations notwithstanding, the ACCP model still offers the best available framework for thrombotic risk assessment and a reasonable starting point for clinical decision making.
Antiplatelet Agents
Patients with coronary artery stents who undergo noncardiac surgery are at increased risk for adverse cardiovascular events, including acute stent thrombosis, which carries a risk of myocardial infarction and death of 70% and 30%, respectively.[63] This risk is highest during the period between stent implantation and endothelialization, a process that takes 4 to 6 weeks for bare‐metal stents (BMS) and 6 to 12 months for drug‐eluting stents (DES). Premature discontinuation of dual antiplatelet therapy is the most important risk factor for stent thrombosis during this time.[64] Although the optimal perioperative strategy for these patients is unknown, there is general agreement that elective surgery should be delayed for at least 4 weeks in patients with a BMS and 12 months for patients with a DES. If a procedure or surgery is required during this time period, every effort should be made to continue dual antiplatelet therapy; if this is not possible, aspirin should be continued, and thienopyridine therapy should be interrupted as briefly as possible (Table 3).
Recommended Interval Between Last Dose of Medication and Procedure | Recommended Interval Between Procedure and First Dose of Medication, h | ||
---|---|---|---|
Low Risk or Consequence of Postprocedure Bleeding | High Risk or Consequence of Postprocedure Bleeding | ||
| |||
Antiplatelet Medicationsa | |||
Aspirin (81325 mg dailydipyridamole) | 710 days (skip 69 doses) | 24 | 48 |
Ticlodipine (250 mg twice daily) | 1014 days (skip 1926 doses) | 24 | 48 |
Clopidogrel (75 mg once daily) | 710 days (skip 69 doses)b | 24 | 48 |
Prasugrel (10 mg once daily) | 710 days (skip 69 dose)c | 24 | 48 |
Ticagrelor (90 mg twice daily; t =8 hours) | 5 days (skip 8 doses) | 24 | 48 |
Cilostazol (100 mg twice daily; t =11 hours) | 3 days (skip 4 doses) | 24 | 48 |
Anticoagulant Medicationse | |||
Warfarin (t =3642 hours, but highly variable) | 6 days (skip 5 doses)f | 12 | 24 |
Intravenous UFH (t 60 minutes) | 46 hours | 24 | 4872 |
LMWH (t =37 hours) | |||
Prophylactic dosing | 12 hours# | 12 | 2436 |
Therapeutic dosing | |||
Once daily | 24 hours (give 50% of last total dose)# | 24 | 4872 |
Twice daily | 24 hours (skip 1 dose)# | 24 | 4872 |
Fondaparinux (t =17 hours, any dose) | 34 days (skip 23 doses)h | 24 | 4872 |
Dabigatran (150 mg twice daily) | |||
CrCl>50 mL/min (t =1417 hours) | 3 days (skip 4 doses) | 24 | 4872 |
CrCl 3050 mL/min (t =1618 hours) | 45 days (skip 68 doses) | 24 | 4872 |
CrCl 1530 mL/min (t =1618 hours)i | 45 days (skip 68 doses) | 24 | 4872 |
Rivaroxaban (20 mg once daily) | |||
CrCl>50 mL/min (t =89 hours) | 3 days (skip 2 doses) | 24 | 4872 |
CrCl 3050 mL/min (t =9 hours) | 3 days (skip 2 doses) | 24 | 4872 |
CrCl 1529.9 mL/min (t =910 hours)j | 4 days (skip 3 doses) | 24 | 4872 |
Apixiban (5 mg twice daily) | |||
CrCl>50 mL/min (t =78 hours) | 3 days (skip 4 doses) | 24 | 4872 |
CrCl 3050 mL/min (t =1718 hours) | 4 days (skip 6 doses) | 24 | 4872 |
ARE THERE INTERVENTIONS THAT CAN DECREASE THE RISK OF PERIPROCEDURAL BLEEDING AND/OR THROMBOEMBOLISM?
Mitigating the Risk of Bleeding
Bleeding complications can be reduced by allowing a sufficient time for the effects of antithrombotic medications to wear off before performing a procedure. This requires an understanding of the pharmacology of these medications, with particular attention to patients in whom these medications are less well studied, including the elderly, patients with renal insufficiency, and those with very high or low body mass index. Table 3 provides recommendations for when to stop antithrombotic therapy prior to an invasive procedure. The intervals are based on the time needed to achieve a minimal antithrombotic effect, which is generally 4 to 5 half‐lives for anticoagulants and 7 to 10 days for irreversible antiplatelet agents. Shorter intervals may be appropriate for procedures with low risk or consequence of bleeding, but there are insufficient data to make specific recommendations regarding this strategy.
It is equally important to ensure that there is adequate time for postoperative hemostasis prior to restarting antithrombotic therapy. Data from VTE prophylaxis trials and bridging studies consistently show that bleeding complications occur more frequently when anticoagulation is started too early, and antithrombotic therapy should generally be delayed 24 hours in patients at average risk and 48 to 72 hours in patients at high risk or consequence for postoperative bleeding.[8, 60, 65]
Aspirin increases the risk of surgical blood loss and transfusion by up to 20%, and by up to 50% when given in combination with clopidogrel, but with the exception of intracranial surgery, there does not appear to be an increase in perioperative morbidity or mortality with either of these agents.[66]
Mitigating the Risk of Thromboembolism
Once the decision has been made to temporarily discontinue warfarin, the next consideration is whether to bridge with a short acting anticoagulant (typically subcutaneous LMWH or intravenous UFH) during the period of time when the INR is subtherapeutic. Conceptually, one would expect this strategy would minimize the risk of thromboembolism, but its efficacy has never been clearly demonstrated. In fact, in a systematic review and meta‐analysis of 34 studies that compared the rates of thromboembolism among bridged and nonbridged patients, heparin therapy did not reduce the risk of thromboembolic events (odds ratio: 0.80; 95% confidence interval: 0.421.54), but did result in higher rates of periprocedural bleeding.[60]
The applicability of these results to clinical practice are limited by the heterogeneity of the data used in the analysis; specifically, bridging strategies varied (including therapeutic, intermediate, and prophylactic dose regimens), there was wide variation in the types of surgery (and therefore bleeding risk), and because the majority of studies were observational, there is a significant likelihood of confounding by indication (ie, patients at high risk for thromboembolism are more likely to receive bridging therapy), and thus the benefit of this strategy may be underestimated. It is also important to note that in the majority studies anticoagulation was restarted <24 hours after the procedure, which likely contributed to the increased rate of bleeding.
Therefore, although bridging therapy is not indicated for patients at low risk, it is premature to conclude that it should be avoided in patients at moderate or high risk for thromboembolism. The results of 2 ongoing, randomized, placebo‐controlled trials of bridging therapy in patients taking warfarin for atrial fibrillation (Effectiveness of Bridging Anticoagulation for Surgery [BRIDGE]) or mechanical heart values (A Double Blind Randomized Control Trial of Post‐Operative Low Molecular Weight Heparin Bridging Therapy Versus Placebo Bridging Therapy for Patients Who Are at High Risk for Arterial Thromboembolism [PERIOP‐2]) should help to answer this question.[67, 68]
The uncertainty regarding the benefits of bridging therapy is reflected in the changes to the most recent ACCP guidelines. In 2008, the ACCP recommended low‐dose LMWH or no bridging for patients at low risk (grade 2C), therapeutic‐dose bridging for patients at moderate risk (grade 2C), and therapeutic‐dose bridging for patients at high risk for thromboembolism (Grade 1C).[56] In 2012, the ACCP recommended against bridging for low‐risk patients (grade 2C), made no specific recommendation regarding moderate‐risk patients, and offered a less robust recommendation for bridging in high‐risk patients (grade 2C).[8]
Until the results of the BRIDGE and PERIOP‐2 trials are available, the author still favors therapeutic bridging for patients at high risk and selected patients at moderate risk for thromboembolism, provided sufficient time is allowed for postoperative hemostasis before anticoagulation is restarted. For procedures with a high risk or consequence of bleeding, intravenous UFH (without a bolus) is a reasonable initial postoperative strategy to insure that anticoagulation is tolerated before committing to LMWH. Indirect evidence supports the use of prophylactic or intermediate‐dose bridging regimens in patients for whom the primary consideration is the prevention of recurrent VTE, but data to show that this strategy is effective for the prevention of arterial thromboembolism are lacking.
Intravenous glycoprotein IIb/IIIa inhibitors are sometimes used to bridge high‐risk patients with coronary artery stents who must stop antiplatelet therapy prior to a procedure, but the data to support this practice are limited and observational in nature.[69, 70]
STARTING AND STOPPING ANTITHROMBOTIC THERAPY
Warfarin
For patients on warfarin, the INR at which it is safe to perform invasive procedures is unknown. Normal hemostasis requires clotting factor levels of approximately 20% to 40% of normal,[71] which generally corresponds to an INR of <1.5, whereas for most indications, therapeutic anticoagulation is achieved when the INR is between 2.0 and 3.5. However, because the relationship between the INR and the levels of clotting factors is nonlinear, for a given patient, the INR may be abnormal (ie, >1) despite levels of clotting factors that are sufficient for periprocedural hemostasis.[72, 73, 74, 75] Because of its relatively long half‐life (3642 hours), warfarin should be stopped 6 days (skip 5 doses) prior to a procedure to achieve an INR of <1.5, but can safely be restarted the same day in most patients.
Heparins
The half‐life of intravenous heparin is dose dependent, and at therapeutic levels is approximately 60 minutes; therefore, it should be discontinued 4 to 6 hours (5 half‐lives) before performing an invasive procedure.[76] The half‐life of subcutaneous LMWHs ranges from 3 to 7 hours in healthy volunteers,[23, 24, 25] and is often longer in patients for whom these medications are commonly prescribed.[77, 78] Therefore, when administered at therapeutic doses twice daily, the last dose should be given in the morning the day before the procedure, and for therapeutic once‐daily regimens, the last dose should be reduced by 50%.[8] The optimal time to discontinue prophylactic doses of LWMH prior to an invasive procedure is unclear, but a minimum of 12 hours is recommended.[22, 79] Because LWMHs are renally cleared, longer intervals are needed for patients with impaired renal function.[76, 80]
New Oral Anticoagulants
The manufacturer of rivaroxaban recommends that if anticoagulation must be discontinued, it be stopped at least 24 hours before the procedure.[81] Although this may be sufficient for procedures with a low risk or consequence of bleeding, the half‐life of rivaroxaban is between 8 and 10 hours, and therefore 48 hours (45 half‐lives) is required to ensure minimal residual anticoagulant effect.
Apixaban has a clearance half‐life of 6 hours, but displays prolonged absorption such that its effective half‐life is 12 hours after repeated dosing. The manufacturer recommends that it be stopped at least 24 hours prior to a procedure with a low risk or consequence of bleeding, and 48 hours prior to a procedure with a high risk or consequence of bleeding.[82]
The manufacturer of dabigatran recommends that the drug be discontinued 1 to 2 days (creatinine clearance (CrCl) 50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures, and that longer times be considered when complete hemostasis is required.[83] Given that the half‐life of dabigatran is 14 to 17 hours, the author recommends that it be stopped at least 2 days (3 half‐lives) prior to a procedure with a low risk or consequence of bleeding, and 3 days (45 half‐lives) prior to a procedure with a high risk or consequence of bleeding.
The clearance of all the NOACs is significantly prolonged in patients with renal impairment, and a longer interval between the last dose and the procedure is necessary in patients with renal failure to ensure normal hemostasis (Table 3).
The effect of the NOACs on the standard clotting assays are complex and vary depending on drug dose, the type of reagents used, and the calibration of the equipment. For dabigatran, the activated partial thromboplastin time (aPTT) and the thrombin time (TT) are sufficiently sensitive to allow for a qualitative assessment of drug effect, such that a normal aPTT indicates the absence, or a very low level of an anticoagulant effect, and a normal TT essentially rules out an effect. Accurate quantitative testing of dabigatran requires an appropriately calibrated dilute thrombin test or ecarin clotting time assay.[84, 85]
Depending on the thromboplastin reagent used, the prothrombin time (PT) may be sufficiently sensitive to rivaroxaban that a normal level rules out a residual drug effect,[86] but this does not hold true for apixaban, which has minimal effect on the PT at therapeutic concentrations. The aPTT is insensitive to both rivaroxaban and apixaban and cannot be used for assessing residual drug effect. Accurate quantitative testing of rivaroxaban or apixaban requires an anti‐factor Xa assay calibrated for use with these agents.[84]
Antiplatelet Agents
Aspirin irreversibly inhibits platelet cyclooxygenase activity, and the thienopyridines clopidogrel and prasugrel, irreversibly inhibit the platelet P2Y12 receptor. As such, the biological effects of these medications persist until the platelet pool has turned over, a process that occurs at 10% to 12% per day and takes 7 to 10 days to complete.[87] The minimum number of functional platelets required to ensure adequate periprocedural hemostasis is unknown, but is likely between 50 and 100,000/L.[88] Therefore, assuming a platelet pool of 200,000/L, most patients will regenerate an adequate number of functional platelets by 5 days after discontinuing therapy, and nearly all will have normal platelet function by 10 days. Determining the risk of bleeding prior to complete turnover of the platelet pool is further complicated by genetic variability between patients in drug metabolism and the degree of platelet inhibition by these agents.[89]
Owing to this complexity, guidelines and prescribing recommendations are inconsistent. The ACCP recommends stopping antiplatelet agents 7 to 10 days prior to an invasive procedure, and the ACC/AHA makes no specific recommendations at all.[90] Based on data from patients undergoing cardiac bypass surgery, it is recommended that clopidogrel be stopped 5 days, and prasugrel 7 days, prior to an invasive procedure.[91, 92] The elimination half‐life of ticlodipine is sufficiently long (up to 96 hours after repeated dosing) that it should be stopped 10 to 14 days prior to an invasive procedure.[87] Ticagrelor is a reversible P2Y12 receptor inhibitor with a half‐life of approximately 8 hours and should therefore have minimal effect by 3 days after discontinuation; however, the manufacturer recommends that it be stopped 5 days prior to an invasive procedure.[93]
The optimal time to restart antiplatelet agents after an invasive procedure is also unknown. The 2008 ACCP guidelines recommended restarting aspirin and/or clopidogrel in 24 hours, or as hemostasis allows,[56] whereas neither the 2007 or 2009 ACC/AHA guidelines,[90] or the most recent 2012 ACCP guidelines,[8] offer specific recommendations. Aspirin, prasugrel, and ticagrelor have a rapid onset of action, whereas the full antiplatelet effect of clopidogrel does not occur for several days, and for patients in whom more rapid platelet inhibition is desired, a loading dose (300600 mg) may be appropriate.[87]
CONCLUSIONS
Deciding on an optimal periprocedural antithrombotic management strategy is a common challenge for hospitalists that requires careful consideration of both patient and procedure related‐risk factors for bleeding and thrombosis, as well as the consequences of delaying or forgoing the procedure altogether. For many procedures, there is evidence that antithrombotic therapy can be safely continued, thereby obviating the risk associated with interrupting therapy. When antithrombotic therapy must be stopped, it should be done in a manner that appropriately balances the risks and consequence of periprocedural bleeding and thromboembolism. Strategies to decrease the risk of perioperative bleeding include allowing sufficient time for the effects of antithrombotic therapy to subside before starting the procedure, and ensuring adequate time for hemostasis before restarting antithrombotic therapy. Bridging therapy may provide net clinical benefit for patients at moderate to high risk for thromboembolism, but this will not be clear until the results of several ongoing bridging trials are available. The periprocedural antithrombotic management strategy should be developed in collaboration with the relevant providers and with active participation by the patient in all decisions and treatment plans. Standardized protocols and documentation can help to minimize unintended variation in practice and improve information transfer during transitions of care.
Acknowledgements
The author would like to thank Shoshana and Lola Herzig for their support in the design and preparation of the manuscript.
Disclosure: Nothing to report.
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- Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College Of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):e24S–e43S. , , , .
- Bridging anticoagulation with low‐molecular‐weight heparin after interruption of warfarin therapy is associated with a residual anticoagulant effect prior to surgery. Thromb Haemost. 2005;94(3):528–531. , , , .
- Brief communication: Preoperative anticoagulant activity after bridging low‐molecular‐weight heparin for temporary interruption of warfarin. Ann Intern Med. 2007;146(3):184–187. , , , et al.
- Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107(suppl 1):i96–i106. .
- Meta‐analysis: low‐molecular‐weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med. 2006;144(9):673–684. , , , .
- Janssen Pharmaceuticals, Inc. Xarelto (rivaroxaban) full prescribing information. 2013. Available at: http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100. Accessed October 1, 2013.
- Bristol Meyers Squibb, Inc. Eliquis (apixaban) full prescribing information. 2013. Available at: http://packageinserts.bms.com/pi/pi_eliquis.pdf. Accessed October 1, 2013.
- Boehringer Ingelheim Pharmaceuticals I. Pradaxa (dabigatran etexilate mesylate) full prescribing information. Available at: http://bidocs.boehringer‐ingelheim.com/BIWebAccess/ViewServlet.ser?docBase= renetnt11(2):245–252.
- The laboratory and the direct oral anticoagulants. Blood. 2013;121(20):4032–4035. .
- Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thromb Res. 2012;130(6):956–966. , , , , , .
- Antiplatelet drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):e89S–119S. , , , , .
- Evidence‐based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program. 2007:172–178. .
- Platelet function testing and prediction of procedural bleeding risk. Thromb Haemost. 2013;109(5):817–824. , , .
- Perioperative management of antiplatelet therapy in patients with a coronary stent who need non‐cardiac surgery: a systematic review of clinical practice guidelines. Chest. 2013;144(6):1848–1856. , , , .
- Eli Lilly Pharmaceuticals, Inc. Effient (prasugrel) full prescribing information. 2012. Available at: http://pi.lilly.com/us/effient.pdf. Accessed October 1, 2013.
- Antiplatelet therapy and cardiac surgery: review of recent evidence and clinical implications. Can J Cardiol. 2013;29(9):1042–1047. , , , .
- AstraZeneca. Brilinta (ticagrelor) full prescribing information. 2013. Available at: http://www1.astrazeneca‐us.com/pi/brilinta.pdf. Accessed October 1, 2013.
- 2012 update to the Society of Thoracic Surgeons guideline on use of antiplatelet drugs in patients having cardiac and noncardiac operations. Ann Thorac Surg. 2012;94(5):1761–1781. , , , et al.
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- Abnormal preprocedural international normalized ratio and platelet counts are not associated with increased bleeding complications after ultrasound‐guided thoracentesis. AJR Am J Roentgenol. 2011;197(1):W164–W168. , .
- Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities. Transfusion. 1991;31(2):164–171. , .
- Safety of ultrasound‐guided small‐bore chest tube insertion in patients on clopidogrel. J Bronchology Interv Pulmonol. 2013;20(1):16–20. , , .
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- Preventing complications of central venous catheterization. N Engl J Med. 2003;348(12):1123–1133. , .
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- Real‐time two‐dimensional ultrasound guidance for central venous cannulation: a meta‐analysis. Anesthesiology. 2013;118(2):361–375. , , , , , .
- Central venous catheter placement in patients with disorders of hemostasis. Chest. 1996;110(1):185–188. , , .
- Invasive line placement in critically ill patients: do hemostatic defects matter? Transfusion. 1996;36(9):827–831. , , , .
- Bleeding complications after central line insertions: relevance of pre‐procedure coagulation tests and institutional transfusion policy. Acta Anaesthesiol Scand. 2013;57(5):573–579. , , , , , .
- Low levels of prothrombin time (INR) and platelets do not increase the risk of significant bleeding when placing central venous catheters. Med Klin (Munich). 2009;104(5):331–335. , , , et al.
- Coagulation disorders in patients with cancer: nontunneled central venous catheter placement with US guidance—a single‐institution retrospective analysis. Radiology. 2009;253(1):249–252. , , , et al.
- US‐guided placement of central vein catheters in patients with disorders of hemostasis. Eur J Radiol. 2008;65(2):253–256. , , .
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- How I treat: target specific oral anticoagulant associated bleeding [published online ahead of print January 2, 2014]. Blood. doi: 10.1182/blood‐2013‐09‐529784. , , .
- The perioperative management of antithrombotic therapy: American College of Chest Physicians evidence‐based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):299S–339S. , , , et al.
- Management of anticoagulation before and after elective surgery. N Engl J Med. 1997;336(21):1506–1511. , .
- RIsk of thromboembolism with short‐term interruption of warfarin therapy. Arch Intern Med. 2008;168(1):63–69. , , , et al.
- Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long‐Term Anticoagulation Therapy (RE‐LY) randomized trial. Circulation. 2012;126(3):343–348. , , , et al.
- Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta‐analysis of bleeding and thromboembolic rates. Circulation. 2012;126(13):1630–1639. , , , , , .
- Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 Suppl):e227S–277S. , , , et al.
- Periprocedural anticoagulation management of patients with venous thromboembolism. Arterioscler Thromb Vasc Biol. 2010;30(3):442–448. , , , et al.
- Late coronary stent thrombosis. Circulation. 2007;116(17):1952–1965. , .
- Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry. J Am Coll Cardiol. 2009;53(16):1399–1409. , , , et al.
- Predictors of major bleeding in peri‐procedural anticoagulation management. J Thromb Haemost. 2012;10(2):261–267. , , , et al.
- Perioperative antiplatelet therapy: the case for continuing therapy in patients at risk of myocardial infarction. Br J Anaesth. 2007;99(3):316–328. , , .
- Effectiveness of bridging anticoagulation for surgery (the BRIDGE Study). Available at: www.ClinicalTrials.gov. Identifier: NCT00786474. Accessed October 22, 2013. , .
- A safety and effectiveness study of LMWH bridging therapy versus placebo bridging therapy for patients on long term warfarin and require temporary interruption of their warfarin (PERIOP2). Available at: www.ClinicalTrials.gov. Identifier: NCT00432796. Accessed October 20, 2013. .
- Outcomes of a preoperative “bridging” strategy with glycoprotein IIb/IIIa inhibitors to prevent perioperative stent thrombosis in patients with drug‐eluting stents who undergo surgery necessitating interruption of thienopyridine administration. EuroIntervention. 2013;9(2):204–211. , , , et al.
- Safety of “bridging” with eptifibatide for patients with coronary stents before cardiac and non‐cardiac surgery. Am J Cardiol. 2012;110(4):485–490. , , , et al.
- Hemostatic problems in surgical patients. In: Colman RW HJ, Marder VJ, Clowes AW, George JN, ed. Hemostasis and Thrombosis. 4th ed. Philadelphia, PA: Lippincott Williams 2001:1033. .
- Reversal of drug‐induced anticoagulation: old solutions and new problems. Transfusion. 2012;52:45S–55S. .
- A feasibility study of continuing dose‐reduced warfarin for invasive procedures in patients with high thromboembolic risk. Chest. 2005;127(3):922–927. , , .
- A simple and safe nomogram for the management of oral anticoagulation prior to minor surgery. Clin Lab Haematol. 2003;25(2):127–130. , , , et al.
- International normalized ratio versus plasma levels of coagulation factors in patients on vitamin K antagonist therapy. Arch Pathol Lab Med. 2011;135(4):490–494. , , , , .
- Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College Of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):e24S–e43S. , , , .
- Bridging anticoagulation with low‐molecular‐weight heparin after interruption of warfarin therapy is associated with a residual anticoagulant effect prior to surgery. Thromb Haemost. 2005;94(3):528–531. , , , .
- Brief communication: Preoperative anticoagulant activity after bridging low‐molecular‐weight heparin for temporary interruption of warfarin. Ann Intern Med. 2007;146(3):184–187. , , , et al.
- Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107(suppl 1):i96–i106. .
- Meta‐analysis: low‐molecular‐weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med. 2006;144(9):673–684. , , , .
- Janssen Pharmaceuticals, Inc. Xarelto (rivaroxaban) full prescribing information. 2013. Available at: http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100. Accessed October 1, 2013.
- Bristol Meyers Squibb, Inc. Eliquis (apixaban) full prescribing information. 2013. Available at: http://packageinserts.bms.com/pi/pi_eliquis.pdf. Accessed October 1, 2013.
- Boehringer Ingelheim Pharmaceuticals I. Pradaxa (dabigatran etexilate mesylate) full prescribing information. Available at: http://bidocs.boehringer‐ingelheim.com/BIWebAccess/ViewServlet.ser?docBase= renetnt11(2):245–252.
- The laboratory and the direct oral anticoagulants. Blood. 2013;121(20):4032–4035. .
- Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thromb Res. 2012;130(6):956–966. , , , , , .
- Antiplatelet drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):e89S–119S. , , , , .
- Evidence‐based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program. 2007:172–178. .
- Platelet function testing and prediction of procedural bleeding risk. Thromb Haemost. 2013;109(5):817–824. , , .
- Perioperative management of antiplatelet therapy in patients with a coronary stent who need non‐cardiac surgery: a systematic review of clinical practice guidelines. Chest. 2013;144(6):1848–1856. , , , .
- Eli Lilly Pharmaceuticals, Inc. Effient (prasugrel) full prescribing information. 2012. Available at: http://pi.lilly.com/us/effient.pdf. Accessed October 1, 2013.
- Antiplatelet therapy and cardiac surgery: review of recent evidence and clinical implications. Can J Cardiol. 2013;29(9):1042–1047. , , , .
- AstraZeneca. Brilinta (ticagrelor) full prescribing information. 2013. Available at: http://www1.astrazeneca‐us.com/pi/brilinta.pdf. Accessed October 1, 2013.
- 2012 update to the Society of Thoracic Surgeons guideline on use of antiplatelet drugs in patients having cardiac and noncardiac operations. Ann Thorac Surg. 2012;94(5):1761–1781. , , , et al.
- How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120(15):2954–2962. , .
- American College of Chest Physicians. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):e24S–e43S. , , , ,
SHM Member in the Spotlight
SHM member David Feinbloom, MD, testified before the Massachusetts Joint Committee on Healthcare Financing and Economic Development and Emerging Technologies on May 5, 2005. Dr. Feinbloom was part of a panel of Massachusetts’ healthcare and information systems leaders advocating for additional funding of a statewide initiative to install Computerized Physician Order Entry (CPOE) systems and other advanced information technologies in each hospital across Massachusetts. Dr. Feinbloom is the director of clinical resource management, Department of Medicine, and physician liaison for Clinical Information Systems Development at Beth Israel Deaconess Medical Center in Boston. Under the leadership of John Halamka, MD, MS, and chief information office of Harvard Medical School and BIDMC, the medical center is a nationally recognized leader in medical information technology.
“The goal of the hearing was to share views about the implementation of advanced technologies like CPOE, one of a series of initiatives to create a statewide medical information technology infrastructure,” says Dr. Feinbloom. “Ultimately, this will include applications such as e-prescribing, online physician-patient communications, and regional data sharing networks, which will improve quality, patient satisfaction, and reduce costs.” He says that currently a parallel initiative for related technologies has a $50 million commitment from Blue Cross and Blue Shield. An additional $210 million is needed to bring inpatient CPOE to all of the hospitals in the state. “We wanted to make sure that the committee understood that despite the seemingly high initial outlay of capital, there is a projected savings of $275 million annually.” The dramatic savings, Dr. Feinbloom says, come from efficiencies in patient throughput, reductions in medication errors and adverse drug events, and improved utilization of inpatient resources. The Massachusetts Technology Collaborative and New England Healthcare Institute are coordinating statewide efforts to remove barriers to inpatient CPOE.
Currently, only 5% to 10% percent of hospitals nationwide have CPOE systems, but that is destined to change, says Dr. Feinbloom, especially if hospitalists lead the charge. “Hospitalists are the natural choice to champion these initiatives,” Dr. Feinbloom says. “We are the experts on inpatient care and hospital systems, and we understand how important information technology is for managing complicated patients during an acute hospitalization. In addition, these technologies have proven indispensable for communicating among care providers and managing the transition from the inpatient to the outpatient setting—a process that is notorious for errors.”
For more information on CPOE implementation or funding, contact Dr. Feinbloom at [email protected].
SHM member David Feinbloom, MD, testified before the Massachusetts Joint Committee on Healthcare Financing and Economic Development and Emerging Technologies on May 5, 2005. Dr. Feinbloom was part of a panel of Massachusetts’ healthcare and information systems leaders advocating for additional funding of a statewide initiative to install Computerized Physician Order Entry (CPOE) systems and other advanced information technologies in each hospital across Massachusetts. Dr. Feinbloom is the director of clinical resource management, Department of Medicine, and physician liaison for Clinical Information Systems Development at Beth Israel Deaconess Medical Center in Boston. Under the leadership of John Halamka, MD, MS, and chief information office of Harvard Medical School and BIDMC, the medical center is a nationally recognized leader in medical information technology.
“The goal of the hearing was to share views about the implementation of advanced technologies like CPOE, one of a series of initiatives to create a statewide medical information technology infrastructure,” says Dr. Feinbloom. “Ultimately, this will include applications such as e-prescribing, online physician-patient communications, and regional data sharing networks, which will improve quality, patient satisfaction, and reduce costs.” He says that currently a parallel initiative for related technologies has a $50 million commitment from Blue Cross and Blue Shield. An additional $210 million is needed to bring inpatient CPOE to all of the hospitals in the state. “We wanted to make sure that the committee understood that despite the seemingly high initial outlay of capital, there is a projected savings of $275 million annually.” The dramatic savings, Dr. Feinbloom says, come from efficiencies in patient throughput, reductions in medication errors and adverse drug events, and improved utilization of inpatient resources. The Massachusetts Technology Collaborative and New England Healthcare Institute are coordinating statewide efforts to remove barriers to inpatient CPOE.
Currently, only 5% to 10% percent of hospitals nationwide have CPOE systems, but that is destined to change, says Dr. Feinbloom, especially if hospitalists lead the charge. “Hospitalists are the natural choice to champion these initiatives,” Dr. Feinbloom says. “We are the experts on inpatient care and hospital systems, and we understand how important information technology is for managing complicated patients during an acute hospitalization. In addition, these technologies have proven indispensable for communicating among care providers and managing the transition from the inpatient to the outpatient setting—a process that is notorious for errors.”
For more information on CPOE implementation or funding, contact Dr. Feinbloom at [email protected].
SHM member David Feinbloom, MD, testified before the Massachusetts Joint Committee on Healthcare Financing and Economic Development and Emerging Technologies on May 5, 2005. Dr. Feinbloom was part of a panel of Massachusetts’ healthcare and information systems leaders advocating for additional funding of a statewide initiative to install Computerized Physician Order Entry (CPOE) systems and other advanced information technologies in each hospital across Massachusetts. Dr. Feinbloom is the director of clinical resource management, Department of Medicine, and physician liaison for Clinical Information Systems Development at Beth Israel Deaconess Medical Center in Boston. Under the leadership of John Halamka, MD, MS, and chief information office of Harvard Medical School and BIDMC, the medical center is a nationally recognized leader in medical information technology.
“The goal of the hearing was to share views about the implementation of advanced technologies like CPOE, one of a series of initiatives to create a statewide medical information technology infrastructure,” says Dr. Feinbloom. “Ultimately, this will include applications such as e-prescribing, online physician-patient communications, and regional data sharing networks, which will improve quality, patient satisfaction, and reduce costs.” He says that currently a parallel initiative for related technologies has a $50 million commitment from Blue Cross and Blue Shield. An additional $210 million is needed to bring inpatient CPOE to all of the hospitals in the state. “We wanted to make sure that the committee understood that despite the seemingly high initial outlay of capital, there is a projected savings of $275 million annually.” The dramatic savings, Dr. Feinbloom says, come from efficiencies in patient throughput, reductions in medication errors and adverse drug events, and improved utilization of inpatient resources. The Massachusetts Technology Collaborative and New England Healthcare Institute are coordinating statewide efforts to remove barriers to inpatient CPOE.
Currently, only 5% to 10% percent of hospitals nationwide have CPOE systems, but that is destined to change, says Dr. Feinbloom, especially if hospitalists lead the charge. “Hospitalists are the natural choice to champion these initiatives,” Dr. Feinbloom says. “We are the experts on inpatient care and hospital systems, and we understand how important information technology is for managing complicated patients during an acute hospitalization. In addition, these technologies have proven indispensable for communicating among care providers and managing the transition from the inpatient to the outpatient setting—a process that is notorious for errors.”
For more information on CPOE implementation or funding, contact Dr. Feinbloom at [email protected].
In the Literature
Coronary-Artery Revascularization Before Elective Major Vascular Sugery
McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med. 2004;351:2861-3.
Cardiac risk stratification and treatment prior to non-cardiac surgery is a frequent reason for medical consultation, and yet the optimal approach to managing these patients remains controversial. National guidelines, based on expert opinion and inferred from published data, suggest that preoperative cardiac revascularization be reserved for patients with unstable coronary syndromes or for whom coronary artery bypass grad ing has been shown to improve mortality. Despite these recommendations, there remains considerable variability in clinical practice, which is compounded by a paucity of prospective randomized trials to validate one approach over another.
In this multicenter randomized controlled trial, McFalls et al. studied whether coronary artery revascularization prior to elective vascular surgery would reduce mortality among a cohort of patients with angiographically documented stable coronary artery disease. The investigators evaluated 5859 patients from 18 centers scheduled for abdominal aortic aneurysm or lower extremity vascular surgery. Patients felt to be at high risk for perioperative cardiac complications based on cardiology consultation, established clinical criteria, or the presence of ischemia on stress imaging studies were referred for coronary angiography. Of this cohort, 4669 (80%) were excluded due to subsequent determination of insufficient cardiac risk (28%), urgent need for vascular surgery (18%), severe comorbid illness (13%), patient preference (11%), or prior revascularization without new ischemia (11%). Of the 1190 patients who underwent angiography, 680 were excluded due to protocol criteria including: the absence of obstructive coronary artery disease (54%), coronary disease not amenable to revascularization (32%), led main artery stenosis ≥ 50% (8%), led ventricular ejection fraction <20% (2%), or severe aortic stenosis (AVA<1.0 cm2) (1%).
Of the 510 patients who remained, 252 were randomized to proceed with vascular surgery with optimal medical management, of which 9 crossed over due to the need for urgent cardiac revascularization. Two hundred fifty-eight patients were randomized to elective preoperative revascularization; 99 underwent CABG, 141 underwent PCI, and 18 were excluded due to need for urgent vascular surgery, patient preference, or in one case, stroke. Both groups were similar with respect to baseline clinical variables, including the incidence of previous myocardial infarction, congestive heart failure, diabetes mellitus, led ventricular ejection fraction, and 3vessel coronary artery disease. They were also similar in the use of perioperative betablockers (~ 85%), statins, and aspirin.
At 2.7 years after randomization, mortality was 22% in the revascularization group and 22% in the medical management group, the relative risk was 0.98 (95% CI 0.7-1.37; p=.92), which was not statistically significant. The median time from randomization to vascular surgery was 54 days in the revascularization group and 18 days in the medical management group not undergoing revascularization (p<.001). Although not designed to address short-term outcomes, there were no differences in the rates of early postoperative myocardial infarction, death, or hospital length of stay. It is also worth noting that 316 of the 510 patients who were ultimately randomized had undergone nuclear imaging studies, of which 226 (72%) had moderate to large reversible perfusion defects detected. These outcome data suggest that the presence of reversible perfusions defects is not in itself a reason for preoperative revascularization.
This well-designed study demonstrates that in the absence of unstable coronary syndromes, led main disease, severe aortic stenosis, or severely depressed led ventricular ejection fraction, there is no morbidity or mortality benefit to revascularization among patients with stable coronary artery disease prior to vascular surgery. Because vascular surgery is the highest risk category among non-cardiac procedures, it may be reasonable to extend these findings to lower risk surgeries as well, and in this sense this study is particularly relevant to consultative practice. While this study provides clear evidence on how to manage this cohort of patients, it remains unclear what the optimal strategy is to identify and manage those patients who were excluded from the trial. (DF)
Amiodarone or a Implantable Cardioverter-Defibrilator for Congestive Heart Failure
Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005 20;352:225-37.
Ventricular arrhythmias are the leading cause of sudden cardiac death in patients with systolic heart failure. Treatment with antiarrhythmic drug therapy has failed to improve survival in these patients, due to their proarrhythmic effects. Unlike other antiarrhythmics, amiodarone is a drug with low proarrhythmic effects. Some studies have suggested that amiodarone may be beneficial in patients with systolic heart failure. Conversely, several primary and secondary prevention trials have demonstrated that placement of an implantable cardioverter-defibrillator (ICD) confers a survival benefit in patients with ischemic cardiomyopathy. However, the role of ICDs in nonischemic heart failure remained unproven.
Bardy and colleagues developed the Sudden Cardiac Death in Heart Failure Trial (SCDHeFT) to evaluate the hypothesis that treatment with amiodarone or a shock-only, single-lead ICD would decrease death from any cause in a population of patients with mild to moderate heart failure. They randomly assigned 2521 patients with New York Heart Association (NYHA) class II or II heart failure (and a led ventricular ejection fraction (LVEF) of 35% or less to conventional medical therapy plus placebo, conventional therapy plus treatment with amiodarone or conventional therapy plus a conservatively programmed, shock-only, single-lead ICD.
Fifty-two percent of patients had ischemic heart failure and 48% had nonischemic heart failure. Placebo and amiodarone were given in double-blind fashion. The primary endpoint was death from any cause with a median followup of 45.5 months. The results were as follows:
Placebo Group - 244 deaths (29% Death Rate)
Amiodarone Group - 240 deaths (28% Death Rate)
ICD Group - 182 deaths (22% Death Rate)
Patients treated with amiodarone had a similar risk of death as those who received placebo (hazard ratio, 1.06; 97.5% CI: 0.86–1.30; p=0.53). Patients implanted with an ICD had a 23% decreased risk of death when compared with those who received placebo (0.77; 97.5% CI: 0.62–0.96; p=.007). This resulted in an absolute risk reduction of 7.2% at 5 years. The authors concluded that in patients with NYHA class II or III heart failure and a LVEF of 35% or less, implantation of a single-lead, shock-only ICD reduced overall mortality by 23%, while treatment with amiodarone had no effect on survival. The benefit of ICD placement reached or approached significance in both the ischemic (hazard ratio .79, CI: 0.60–1.04, p= .05) and nonischemic (hazard ratio 0.73, CI: 0.50–1.07, p= 0.06) subgroups.
It is important to note that an additional subgroup analysis showed that ICD therapy had a significant survival benefit only in NYHA class II patients but not in NYHA class III patients. Amiodarone therapy had no benefit in class II patients and actually decreased survival in class III patients compared to those receiving placebo. In light of results from previous trials that demonstrated a greater survival benefit from ICD placement with worsening ejection fraction in patients with ischemic heart failure, the authors were unable to explain whether the differences in subclasses were biologically plausible.
This study is important for several reasons. First, it suggested that patients with systolic heart failure due to either ischemic or non ischemic causes would benefit from placement of an ICD. Second, these results support the conclusions of previous trials that demonstrate a survival advantage of ICD placement in patients with ischemic heart failure. Finally, this study also demonstrates that amiodarone therapy offers no survival benefit in this population of patients. (JL)
Clopidogrel versus Aspirin and Esomeprazole to Prevent Recurrent Ulcer Bleeding
Chan F, Ching J, Hung L, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352:238-44.
The optimal choice of antiplatelet therapy for patients with coronary heart disease who have had a recent upper gastrointestinal hemorrhage has not been well studied. Clopidogrel has been shown to cause fewer episodes of gastrointestinal hemorrhage than aspirin, but it is unknown whether clopidogrel monotherapy is in fact superior to aspirin plus a protonpump inhibitor. In this prospective, randomized, doubleblind trial, Chan and colleagues hypothesize that clopidogrel monotherapy would “not be inferior” to aspirin plus esomeprazole in a population of patients who had recovered from aspirin-induced hemorrhagic ulcers.
The study population was drawn from patients taking aspirin who were evaluated for an upper gastrointestinal bleed and had ulcer disease documented on endoscopy. Patients with documented Helicobacter pylori infection were treated with a 1-week course of a standard triple-drug regimen. All subjects, regardless of H. pylori status, were treated with an 8-week course of proton-pump inhibitors (PPI). Inclusion criteria included endoscopic confirmation of ulcer healing and successful eradication of H. pylori, if it was present. The location of the ulcers was not specified in the study.
Exclusion criteria included use of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, anticoagulant drugs, corticosteroids, or other anti-platelet agents; history of gastric surgery; presence of erosive esophagitis; gastric outlet obstruction; cancer; need for dialysis; or terminal illness.
Subjects who met the inclusion criteria were randomized to receive either 75 mg of clopidogrel and placebo or 80 mg of aspirin daily plus 20 mg of esomeprazole twice a day for a 12 months. Patients returned for evaluation every 3 months during the 1-year study period. The primary endpoint was recurrence of ulcer bleeding, which was predefined as clinical or laboratory evidence of gastrointestinal hemorrhage with a documented recurrence of ulcers on endoscopy. Lower gastrointestinal bleeding was a secondary endpoint.
Of 492 consecutive patients who were evaluated, 320 met inclusion criteria and were evenly divided into the clopidogrel plus placebo or the aspirin plus esomeprazole arms. Only 3 patients were lost to followup. During the study period, 34 cases of suspected gastrointestinal hemorrhage (defined as hematemesis, melena, or 2 g/dL decrease of hemoglobin) were identified. During endoscopy,14 cases were confirmed to be due to recurrent ulcer bleeding. Of these, 13 ulcers were in the clopidogrel arm (6 gastric ulcers, 5 duodenal, and 2 both) and 1 ulcer (duodenal) in the aspirin plus esomeprazole arm, a statistically significant difference (p=.001).
Fourteen patients were determined to have a lower gastrointestinal hemorrhage. Interestingly, these cases were evenly divided between the clopidogrel group (7 cases) and the aspirin plus esomeprazole (7 cases). This finding suggests the effect of esomeprazole in this study may be specific in preventing recurrent upper gastrointestinal ulcer formation and hemorrhage. The 2 groups had equivalent rates of recurrent ischemic events.
This study addresses an important clinical question, frequently encountered by hospitalists. The recommendation that clopidogrel be used instead of aspirin in patients who require antiplatelet therapy but have a history of upper gastrointestinal hemorrhage is based on studies using high-dose (325 mg) aspirin and excluded patients on acid-suppressing therapy. However, this study failed to prove noninferiority of clopidogrel to aspirin and esomeprazole for this indication. Although this study was not designed to show superiority of aspirin and esomeprazole over clopidogrel, these results indicate that this may be the case, and such a study would be timely. (CG)
Coronary-Artery Revascularization Before Elective Major Vascular Sugery
McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med. 2004;351:2861-3.
Cardiac risk stratification and treatment prior to non-cardiac surgery is a frequent reason for medical consultation, and yet the optimal approach to managing these patients remains controversial. National guidelines, based on expert opinion and inferred from published data, suggest that preoperative cardiac revascularization be reserved for patients with unstable coronary syndromes or for whom coronary artery bypass grad ing has been shown to improve mortality. Despite these recommendations, there remains considerable variability in clinical practice, which is compounded by a paucity of prospective randomized trials to validate one approach over another.
In this multicenter randomized controlled trial, McFalls et al. studied whether coronary artery revascularization prior to elective vascular surgery would reduce mortality among a cohort of patients with angiographically documented stable coronary artery disease. The investigators evaluated 5859 patients from 18 centers scheduled for abdominal aortic aneurysm or lower extremity vascular surgery. Patients felt to be at high risk for perioperative cardiac complications based on cardiology consultation, established clinical criteria, or the presence of ischemia on stress imaging studies were referred for coronary angiography. Of this cohort, 4669 (80%) were excluded due to subsequent determination of insufficient cardiac risk (28%), urgent need for vascular surgery (18%), severe comorbid illness (13%), patient preference (11%), or prior revascularization without new ischemia (11%). Of the 1190 patients who underwent angiography, 680 were excluded due to protocol criteria including: the absence of obstructive coronary artery disease (54%), coronary disease not amenable to revascularization (32%), led main artery stenosis ≥ 50% (8%), led ventricular ejection fraction <20% (2%), or severe aortic stenosis (AVA<1.0 cm2) (1%).
Of the 510 patients who remained, 252 were randomized to proceed with vascular surgery with optimal medical management, of which 9 crossed over due to the need for urgent cardiac revascularization. Two hundred fifty-eight patients were randomized to elective preoperative revascularization; 99 underwent CABG, 141 underwent PCI, and 18 were excluded due to need for urgent vascular surgery, patient preference, or in one case, stroke. Both groups were similar with respect to baseline clinical variables, including the incidence of previous myocardial infarction, congestive heart failure, diabetes mellitus, led ventricular ejection fraction, and 3vessel coronary artery disease. They were also similar in the use of perioperative betablockers (~ 85%), statins, and aspirin.
At 2.7 years after randomization, mortality was 22% in the revascularization group and 22% in the medical management group, the relative risk was 0.98 (95% CI 0.7-1.37; p=.92), which was not statistically significant. The median time from randomization to vascular surgery was 54 days in the revascularization group and 18 days in the medical management group not undergoing revascularization (p<.001). Although not designed to address short-term outcomes, there were no differences in the rates of early postoperative myocardial infarction, death, or hospital length of stay. It is also worth noting that 316 of the 510 patients who were ultimately randomized had undergone nuclear imaging studies, of which 226 (72%) had moderate to large reversible perfusion defects detected. These outcome data suggest that the presence of reversible perfusions defects is not in itself a reason for preoperative revascularization.
This well-designed study demonstrates that in the absence of unstable coronary syndromes, led main disease, severe aortic stenosis, or severely depressed led ventricular ejection fraction, there is no morbidity or mortality benefit to revascularization among patients with stable coronary artery disease prior to vascular surgery. Because vascular surgery is the highest risk category among non-cardiac procedures, it may be reasonable to extend these findings to lower risk surgeries as well, and in this sense this study is particularly relevant to consultative practice. While this study provides clear evidence on how to manage this cohort of patients, it remains unclear what the optimal strategy is to identify and manage those patients who were excluded from the trial. (DF)
Amiodarone or a Implantable Cardioverter-Defibrilator for Congestive Heart Failure
Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005 20;352:225-37.
Ventricular arrhythmias are the leading cause of sudden cardiac death in patients with systolic heart failure. Treatment with antiarrhythmic drug therapy has failed to improve survival in these patients, due to their proarrhythmic effects. Unlike other antiarrhythmics, amiodarone is a drug with low proarrhythmic effects. Some studies have suggested that amiodarone may be beneficial in patients with systolic heart failure. Conversely, several primary and secondary prevention trials have demonstrated that placement of an implantable cardioverter-defibrillator (ICD) confers a survival benefit in patients with ischemic cardiomyopathy. However, the role of ICDs in nonischemic heart failure remained unproven.
Bardy and colleagues developed the Sudden Cardiac Death in Heart Failure Trial (SCDHeFT) to evaluate the hypothesis that treatment with amiodarone or a shock-only, single-lead ICD would decrease death from any cause in a population of patients with mild to moderate heart failure. They randomly assigned 2521 patients with New York Heart Association (NYHA) class II or II heart failure (and a led ventricular ejection fraction (LVEF) of 35% or less to conventional medical therapy plus placebo, conventional therapy plus treatment with amiodarone or conventional therapy plus a conservatively programmed, shock-only, single-lead ICD.
Fifty-two percent of patients had ischemic heart failure and 48% had nonischemic heart failure. Placebo and amiodarone were given in double-blind fashion. The primary endpoint was death from any cause with a median followup of 45.5 months. The results were as follows:
Placebo Group - 244 deaths (29% Death Rate)
Amiodarone Group - 240 deaths (28% Death Rate)
ICD Group - 182 deaths (22% Death Rate)
Patients treated with amiodarone had a similar risk of death as those who received placebo (hazard ratio, 1.06; 97.5% CI: 0.86–1.30; p=0.53). Patients implanted with an ICD had a 23% decreased risk of death when compared with those who received placebo (0.77; 97.5% CI: 0.62–0.96; p=.007). This resulted in an absolute risk reduction of 7.2% at 5 years. The authors concluded that in patients with NYHA class II or III heart failure and a LVEF of 35% or less, implantation of a single-lead, shock-only ICD reduced overall mortality by 23%, while treatment with amiodarone had no effect on survival. The benefit of ICD placement reached or approached significance in both the ischemic (hazard ratio .79, CI: 0.60–1.04, p= .05) and nonischemic (hazard ratio 0.73, CI: 0.50–1.07, p= 0.06) subgroups.
It is important to note that an additional subgroup analysis showed that ICD therapy had a significant survival benefit only in NYHA class II patients but not in NYHA class III patients. Amiodarone therapy had no benefit in class II patients and actually decreased survival in class III patients compared to those receiving placebo. In light of results from previous trials that demonstrated a greater survival benefit from ICD placement with worsening ejection fraction in patients with ischemic heart failure, the authors were unable to explain whether the differences in subclasses were biologically plausible.
This study is important for several reasons. First, it suggested that patients with systolic heart failure due to either ischemic or non ischemic causes would benefit from placement of an ICD. Second, these results support the conclusions of previous trials that demonstrate a survival advantage of ICD placement in patients with ischemic heart failure. Finally, this study also demonstrates that amiodarone therapy offers no survival benefit in this population of patients. (JL)
Clopidogrel versus Aspirin and Esomeprazole to Prevent Recurrent Ulcer Bleeding
Chan F, Ching J, Hung L, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352:238-44.
The optimal choice of antiplatelet therapy for patients with coronary heart disease who have had a recent upper gastrointestinal hemorrhage has not been well studied. Clopidogrel has been shown to cause fewer episodes of gastrointestinal hemorrhage than aspirin, but it is unknown whether clopidogrel monotherapy is in fact superior to aspirin plus a protonpump inhibitor. In this prospective, randomized, doubleblind trial, Chan and colleagues hypothesize that clopidogrel monotherapy would “not be inferior” to aspirin plus esomeprazole in a population of patients who had recovered from aspirin-induced hemorrhagic ulcers.
The study population was drawn from patients taking aspirin who were evaluated for an upper gastrointestinal bleed and had ulcer disease documented on endoscopy. Patients with documented Helicobacter pylori infection were treated with a 1-week course of a standard triple-drug regimen. All subjects, regardless of H. pylori status, were treated with an 8-week course of proton-pump inhibitors (PPI). Inclusion criteria included endoscopic confirmation of ulcer healing and successful eradication of H. pylori, if it was present. The location of the ulcers was not specified in the study.
Exclusion criteria included use of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, anticoagulant drugs, corticosteroids, or other anti-platelet agents; history of gastric surgery; presence of erosive esophagitis; gastric outlet obstruction; cancer; need for dialysis; or terminal illness.
Subjects who met the inclusion criteria were randomized to receive either 75 mg of clopidogrel and placebo or 80 mg of aspirin daily plus 20 mg of esomeprazole twice a day for a 12 months. Patients returned for evaluation every 3 months during the 1-year study period. The primary endpoint was recurrence of ulcer bleeding, which was predefined as clinical or laboratory evidence of gastrointestinal hemorrhage with a documented recurrence of ulcers on endoscopy. Lower gastrointestinal bleeding was a secondary endpoint.
Of 492 consecutive patients who were evaluated, 320 met inclusion criteria and were evenly divided into the clopidogrel plus placebo or the aspirin plus esomeprazole arms. Only 3 patients were lost to followup. During the study period, 34 cases of suspected gastrointestinal hemorrhage (defined as hematemesis, melena, or 2 g/dL decrease of hemoglobin) were identified. During endoscopy,14 cases were confirmed to be due to recurrent ulcer bleeding. Of these, 13 ulcers were in the clopidogrel arm (6 gastric ulcers, 5 duodenal, and 2 both) and 1 ulcer (duodenal) in the aspirin plus esomeprazole arm, a statistically significant difference (p=.001).
Fourteen patients were determined to have a lower gastrointestinal hemorrhage. Interestingly, these cases were evenly divided between the clopidogrel group (7 cases) and the aspirin plus esomeprazole (7 cases). This finding suggests the effect of esomeprazole in this study may be specific in preventing recurrent upper gastrointestinal ulcer formation and hemorrhage. The 2 groups had equivalent rates of recurrent ischemic events.
This study addresses an important clinical question, frequently encountered by hospitalists. The recommendation that clopidogrel be used instead of aspirin in patients who require antiplatelet therapy but have a history of upper gastrointestinal hemorrhage is based on studies using high-dose (325 mg) aspirin and excluded patients on acid-suppressing therapy. However, this study failed to prove noninferiority of clopidogrel to aspirin and esomeprazole for this indication. Although this study was not designed to show superiority of aspirin and esomeprazole over clopidogrel, these results indicate that this may be the case, and such a study would be timely. (CG)
Coronary-Artery Revascularization Before Elective Major Vascular Sugery
McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med. 2004;351:2861-3.
Cardiac risk stratification and treatment prior to non-cardiac surgery is a frequent reason for medical consultation, and yet the optimal approach to managing these patients remains controversial. National guidelines, based on expert opinion and inferred from published data, suggest that preoperative cardiac revascularization be reserved for patients with unstable coronary syndromes or for whom coronary artery bypass grad ing has been shown to improve mortality. Despite these recommendations, there remains considerable variability in clinical practice, which is compounded by a paucity of prospective randomized trials to validate one approach over another.
In this multicenter randomized controlled trial, McFalls et al. studied whether coronary artery revascularization prior to elective vascular surgery would reduce mortality among a cohort of patients with angiographically documented stable coronary artery disease. The investigators evaluated 5859 patients from 18 centers scheduled for abdominal aortic aneurysm or lower extremity vascular surgery. Patients felt to be at high risk for perioperative cardiac complications based on cardiology consultation, established clinical criteria, or the presence of ischemia on stress imaging studies were referred for coronary angiography. Of this cohort, 4669 (80%) were excluded due to subsequent determination of insufficient cardiac risk (28%), urgent need for vascular surgery (18%), severe comorbid illness (13%), patient preference (11%), or prior revascularization without new ischemia (11%). Of the 1190 patients who underwent angiography, 680 were excluded due to protocol criteria including: the absence of obstructive coronary artery disease (54%), coronary disease not amenable to revascularization (32%), led main artery stenosis ≥ 50% (8%), led ventricular ejection fraction <20% (2%), or severe aortic stenosis (AVA<1.0 cm2) (1%).
Of the 510 patients who remained, 252 were randomized to proceed with vascular surgery with optimal medical management, of which 9 crossed over due to the need for urgent cardiac revascularization. Two hundred fifty-eight patients were randomized to elective preoperative revascularization; 99 underwent CABG, 141 underwent PCI, and 18 were excluded due to need for urgent vascular surgery, patient preference, or in one case, stroke. Both groups were similar with respect to baseline clinical variables, including the incidence of previous myocardial infarction, congestive heart failure, diabetes mellitus, led ventricular ejection fraction, and 3vessel coronary artery disease. They were also similar in the use of perioperative betablockers (~ 85%), statins, and aspirin.
At 2.7 years after randomization, mortality was 22% in the revascularization group and 22% in the medical management group, the relative risk was 0.98 (95% CI 0.7-1.37; p=.92), which was not statistically significant. The median time from randomization to vascular surgery was 54 days in the revascularization group and 18 days in the medical management group not undergoing revascularization (p<.001). Although not designed to address short-term outcomes, there were no differences in the rates of early postoperative myocardial infarction, death, or hospital length of stay. It is also worth noting that 316 of the 510 patients who were ultimately randomized had undergone nuclear imaging studies, of which 226 (72%) had moderate to large reversible perfusion defects detected. These outcome data suggest that the presence of reversible perfusions defects is not in itself a reason for preoperative revascularization.
This well-designed study demonstrates that in the absence of unstable coronary syndromes, led main disease, severe aortic stenosis, or severely depressed led ventricular ejection fraction, there is no morbidity or mortality benefit to revascularization among patients with stable coronary artery disease prior to vascular surgery. Because vascular surgery is the highest risk category among non-cardiac procedures, it may be reasonable to extend these findings to lower risk surgeries as well, and in this sense this study is particularly relevant to consultative practice. While this study provides clear evidence on how to manage this cohort of patients, it remains unclear what the optimal strategy is to identify and manage those patients who were excluded from the trial. (DF)
Amiodarone or a Implantable Cardioverter-Defibrilator for Congestive Heart Failure
Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005 20;352:225-37.
Ventricular arrhythmias are the leading cause of sudden cardiac death in patients with systolic heart failure. Treatment with antiarrhythmic drug therapy has failed to improve survival in these patients, due to their proarrhythmic effects. Unlike other antiarrhythmics, amiodarone is a drug with low proarrhythmic effects. Some studies have suggested that amiodarone may be beneficial in patients with systolic heart failure. Conversely, several primary and secondary prevention trials have demonstrated that placement of an implantable cardioverter-defibrillator (ICD) confers a survival benefit in patients with ischemic cardiomyopathy. However, the role of ICDs in nonischemic heart failure remained unproven.
Bardy and colleagues developed the Sudden Cardiac Death in Heart Failure Trial (SCDHeFT) to evaluate the hypothesis that treatment with amiodarone or a shock-only, single-lead ICD would decrease death from any cause in a population of patients with mild to moderate heart failure. They randomly assigned 2521 patients with New York Heart Association (NYHA) class II or II heart failure (and a led ventricular ejection fraction (LVEF) of 35% or less to conventional medical therapy plus placebo, conventional therapy plus treatment with amiodarone or conventional therapy plus a conservatively programmed, shock-only, single-lead ICD.
Fifty-two percent of patients had ischemic heart failure and 48% had nonischemic heart failure. Placebo and amiodarone were given in double-blind fashion. The primary endpoint was death from any cause with a median followup of 45.5 months. The results were as follows:
Placebo Group - 244 deaths (29% Death Rate)
Amiodarone Group - 240 deaths (28% Death Rate)
ICD Group - 182 deaths (22% Death Rate)
Patients treated with amiodarone had a similar risk of death as those who received placebo (hazard ratio, 1.06; 97.5% CI: 0.86–1.30; p=0.53). Patients implanted with an ICD had a 23% decreased risk of death when compared with those who received placebo (0.77; 97.5% CI: 0.62–0.96; p=.007). This resulted in an absolute risk reduction of 7.2% at 5 years. The authors concluded that in patients with NYHA class II or III heart failure and a LVEF of 35% or less, implantation of a single-lead, shock-only ICD reduced overall mortality by 23%, while treatment with amiodarone had no effect on survival. The benefit of ICD placement reached or approached significance in both the ischemic (hazard ratio .79, CI: 0.60–1.04, p= .05) and nonischemic (hazard ratio 0.73, CI: 0.50–1.07, p= 0.06) subgroups.
It is important to note that an additional subgroup analysis showed that ICD therapy had a significant survival benefit only in NYHA class II patients but not in NYHA class III patients. Amiodarone therapy had no benefit in class II patients and actually decreased survival in class III patients compared to those receiving placebo. In light of results from previous trials that demonstrated a greater survival benefit from ICD placement with worsening ejection fraction in patients with ischemic heart failure, the authors were unable to explain whether the differences in subclasses were biologically plausible.
This study is important for several reasons. First, it suggested that patients with systolic heart failure due to either ischemic or non ischemic causes would benefit from placement of an ICD. Second, these results support the conclusions of previous trials that demonstrate a survival advantage of ICD placement in patients with ischemic heart failure. Finally, this study also demonstrates that amiodarone therapy offers no survival benefit in this population of patients. (JL)
Clopidogrel versus Aspirin and Esomeprazole to Prevent Recurrent Ulcer Bleeding
Chan F, Ching J, Hung L, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352:238-44.
The optimal choice of antiplatelet therapy for patients with coronary heart disease who have had a recent upper gastrointestinal hemorrhage has not been well studied. Clopidogrel has been shown to cause fewer episodes of gastrointestinal hemorrhage than aspirin, but it is unknown whether clopidogrel monotherapy is in fact superior to aspirin plus a protonpump inhibitor. In this prospective, randomized, doubleblind trial, Chan and colleagues hypothesize that clopidogrel monotherapy would “not be inferior” to aspirin plus esomeprazole in a population of patients who had recovered from aspirin-induced hemorrhagic ulcers.
The study population was drawn from patients taking aspirin who were evaluated for an upper gastrointestinal bleed and had ulcer disease documented on endoscopy. Patients with documented Helicobacter pylori infection were treated with a 1-week course of a standard triple-drug regimen. All subjects, regardless of H. pylori status, were treated with an 8-week course of proton-pump inhibitors (PPI). Inclusion criteria included endoscopic confirmation of ulcer healing and successful eradication of H. pylori, if it was present. The location of the ulcers was not specified in the study.
Exclusion criteria included use of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, anticoagulant drugs, corticosteroids, or other anti-platelet agents; history of gastric surgery; presence of erosive esophagitis; gastric outlet obstruction; cancer; need for dialysis; or terminal illness.
Subjects who met the inclusion criteria were randomized to receive either 75 mg of clopidogrel and placebo or 80 mg of aspirin daily plus 20 mg of esomeprazole twice a day for a 12 months. Patients returned for evaluation every 3 months during the 1-year study period. The primary endpoint was recurrence of ulcer bleeding, which was predefined as clinical or laboratory evidence of gastrointestinal hemorrhage with a documented recurrence of ulcers on endoscopy. Lower gastrointestinal bleeding was a secondary endpoint.
Of 492 consecutive patients who were evaluated, 320 met inclusion criteria and were evenly divided into the clopidogrel plus placebo or the aspirin plus esomeprazole arms. Only 3 patients were lost to followup. During the study period, 34 cases of suspected gastrointestinal hemorrhage (defined as hematemesis, melena, or 2 g/dL decrease of hemoglobin) were identified. During endoscopy,14 cases were confirmed to be due to recurrent ulcer bleeding. Of these, 13 ulcers were in the clopidogrel arm (6 gastric ulcers, 5 duodenal, and 2 both) and 1 ulcer (duodenal) in the aspirin plus esomeprazole arm, a statistically significant difference (p=.001).
Fourteen patients were determined to have a lower gastrointestinal hemorrhage. Interestingly, these cases were evenly divided between the clopidogrel group (7 cases) and the aspirin plus esomeprazole (7 cases). This finding suggests the effect of esomeprazole in this study may be specific in preventing recurrent upper gastrointestinal ulcer formation and hemorrhage. The 2 groups had equivalent rates of recurrent ischemic events.
This study addresses an important clinical question, frequently encountered by hospitalists. The recommendation that clopidogrel be used instead of aspirin in patients who require antiplatelet therapy but have a history of upper gastrointestinal hemorrhage is based on studies using high-dose (325 mg) aspirin and excluded patients on acid-suppressing therapy. However, this study failed to prove noninferiority of clopidogrel to aspirin and esomeprazole for this indication. Although this study was not designed to show superiority of aspirin and esomeprazole over clopidogrel, these results indicate that this may be the case, and such a study would be timely. (CG)
Other Literature of Interest
1. Carratala J, FernandezSabe N, Ortega L, et al. Outpatient care compared with hospitalization for community-acquired pneumonia: a randomized trial in low-risk patients. Ann Intern Med. 2005;142: 165-72.
The appropriate triage and management of patients with community-acquired pneumonia (CAP) has important implications for patient outcomes and the allocation of health care resources. Despite the availability of validated risk stratification tools significant variability in clinical practice which results in hospitalization rates that are often inconsistent with the severity of illness. In this unblinded, randomized controlled trial, 224 patients with CAP and a low-risk pneumonia severity index (PSI) score between 51 and 90 (class II and III) were randomized to outpatient oral levofloxacin therapy versus inpatient sequential intravenous and oral levofloxacin therapy. Exclusion criteria included quinolone allergy or use within the previous 3 months, PaO2 < 60 mm Hg, complicated pleural effusion, lung abscess, metastatic infection, inability to maintain oral intake, and severe psychosocial problems precluding outpatient therapy. In an intention-to-treat analysis, the primary endpoints, of cure of pneumonia (resolution of signs, symptoms, and radiographic changes at 30 days), absence of adverse drug reactions, medical complications, or need for hospitalization at 30 days were achieved in 83.6% of outpatients and in 80.7% of hospitalized patients. For the secondary endpoint of patient satisfaction, 91.2% of outpatients versus 79.1% of hospitalized patients (p=.03) were satisfied, but there were no differences between groups with respect to the secondary endpoint of health-related quality of life. Mortality was similar between the 2 groups, and although the study was not sufficiently powered to address this outcome, and interestingly there was trend toward increased medical complications in the hospitalized patients.
Limitations of this study include lack of blinding by investigators and questions about whether the results can be generalized given the geographic variation in microbial susceptibility to quinolone antibiotics. As the authors suggest, this study also highlights limitations in the PSI scoring system, given that patients with clinical findings and comorbidities who would never be treated in the outpatient setting may in fact fall into low-risk PSI categories. These concerns notwithstanding, this study adds to our ability to identify an additional subset of patients with CAP who can be safely managed as outpatients.
2. Choudhry NK, Fletcher RH, Soumerai SB. Systematic review: the relationship between clinical experience and quality of health care.Ann Intern Med. 2005;142:260-73.
Early in the hospital medicine movement, when it was clear that hospitalists provided more efficient care than their colleagues, experience was cited as a reason for this difference. If, for example, a hospitalist cares for patients with community-acquired pneumonia daily, he or she is more likely to make the transition to oral antibiotics sooner, resulting in a shorter length of stay. Everyone recognized the hospitalists were younger, but is it plausible their “inexperience” explained the difference in care?
Choudhry and colleagues explored the available data surrounding clinical experience and quality of care delivered by physicians. They found few studies that specifically evaluated the effects of experience on quality of care. They did find articles that looked at quality of care and included experience or age as part of the physician characteristics
that possibly explained the differences. They reviewed 59 articles, available on MEDLINE, published since 1966. Forty-five studies found an inverse relationship between increasing experience and performance. For example, physicians more recently out of training programs were more familiar with evidence-based therapies for myocardial infarction and more familiar with NIH recommendations for treatment of breast cancer. Experienced physicians were less likely to screen for hypertension and more likely to prescribe inappropriate medications for elderly patients. This led them to the unexpected conclusion that experienced physicians may be at risk for providing lower-quality care and may need improvement interventions. An accompanying editorial by Drs. Weinberger, Duffy, and Cassel of the American Board of Internal Medicine stated, “The profession cannot ignore this striking finding and its implications: Practice does not make perfect, but it must be accompanied by ongoing active effort to maintain competence and quality of care.” They urged all physicians to “embrace the concepts behind maintenance of (board) certification.”
The image of Marcus Welby, MD, would lead one to believe that experience promotes higher quality care. But don’t ask a hospitalist: Many aren’t old enough to remember seeing him on television.
3. Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005;352:969-77.
March was DVT (deep vein thrombosis) Awareness Month. Despite the availability of numerous guidelines, providers fail to consistently prescribe prophylactic measures against venous thromboembolism (VTE) for their hospitalized patients who meet criteria for prophylaxis.
Kucher and colleagues tested an innovative approach to remind providers to undertake such measures for their patients. They designed a computer program to identify hospitalized patients at increased risk for VTE who were not presently receiving VTE prophylaxis. The program reviewed the records of inpatients on the medical and surgical services and assigned a VTE risk score for each patient based on their history (i.e., history of cancer, hypercoagulability, etc.) and their present medical treatment (i.e., hormone therapy, prescribed bed rest, etc.). For patients considered “high risk” for VTE, the computer reviewed orders to identify ongoing use of VTE prophylactic measures. High-risk patients not receiving prophylactic therapies were randomized into 2 groups. The responsible physician in the intervention group received an electronic alert about the risk of VTE in their patient. No alerts were sent to the physicians in the control group. Physicians who received the alerts were forced to acknowledge the alert by either actively withholding prophylaxis or ordering prophylaxis (mechanical or pharmacologic measures). Patients were followed for 90 days with a primary endpoint of clinically diagnosed, objectively confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE). The primary endpoint occurred in 8.2% of the control group versus 4.9% in the invention group (p<.001). The alert reduced the risk of DVT or PE at 90 days by 41% (p=.001).
The results of the study are interesting. The authors acknowledged that many physicians had patients in both groups. So receiving 1 alert may have affected their use of prophylaxis in both groups. They also could not eliminate the possibility of diagnostic bias. Prophylaxis was not blinded and VTE testing was not routinely performed. Would physicians be more likely to order an imaging study for symptomatic patients on no prophylaxis than patients on prophylaxis? Nevertheless, for hospitals that have sufficient computer resources, implementation of such alerts can elevate physician awareness about VTE and other clinical conditions.
4. Lau DT, Kasper JD, Pofer DE, et al. Hospitalization and death associated with potentially inappropriate medication prescriptions among elderly nursing home residents. Arch Intern Med. 2005;165: 68-74.
Lau and colleagues studied the impact of potentially inappropriate medications among residents of longtermcare facilities. They used information from a 1996 national survey of home residents. The sample included 3372 residents, 65 years and older, who lived in a nursing home for 3 months or longer. Over half of the residents were older than 85 years old and 75% were female. Only 10% were black. Nearly two thirds had dementia or other mental disorders. The study used the Beers Criteria to define potentially inappropriate medications. The potential errors in medications were categorized as 1 of 3 types:
- inappropriate choice of medication
- excessive medication dosage
- drug–disease interactions
Residents were considered to have a potentially inappropriate medication if their medication administration records revealed any of the above findings.
A univariate analysis showed that the risk of hospitalization was almost 30% higher among residents who received potentially inappropriate medications in the preceding month and 33% higher among residents who received potentially inappropriate medications for 2 consecutive months, compared with residents with no inappropriate medication exposure. The odds of death in any month were 21% higher among residents who had inappropriate medication exposure during the month of death or the preceeding month, compared with those with no inappropriate medication exposure.
These findings can be generalized to the inpatient setting, where hospitalists have the opportunity to influence and modify prescribing practices in the elderly population.
5. Lessnau KD. Is chest radiography necessary after uncomplicated insertion of a triplelumen catheter in the right internal jugular vein, using the anterior approach? Chest. 2005;127:220-3.
The routine use of chest radiography to confirm proper triplelumen catheter (TLC) placement may be an unnecessary and costly intervention. Lessnau conducted a prospective observational study of 100 consecutive patients over a 4-month period who required non-urgent TLC placement. The primary operators of the procedure included 18 medical residents, 3 pulmonary fellows, and a pulmonary attending with supervision provided for more junior clinicians. Operators followed a standardized approach to TLC placement utilizing the anterior approach to the right internal jugular vein. Complicated procedures were predefined as any procedure that required more than 3 needle passes, resulted in hemorrhage or hematoma formation (where there was concern for pneumothorax), or an absence of blood return in any of the TLC’s lumens. All subjects underwent routine post-procedure chest radiography to determine proper placement of the catheter and to exclude pneumothorax. A blinded radiologist reviewed these images.
Ninety-eight of the 100 catheters were in proper position. One malpositioned catheter was 7 cm above the right atrium in a patient who was 215 cm (>7 feet) tall. The second was noted to be in an S-shaped position on chest radiography. This procedure had required 20 needle passes and 5 slides of the catheter; additionally, blood return was inadequate in 2 lumens of the catheter. An operator reported a possible complication in 10 other procedures, but the only clinical finding in these cases was the development of a local hematoma in 1 patient. Eighty-eight patients had uncomplicated insertions and had normal chest radiographs. There were no pneumothoraces.
This study demonstrates that in carefully controlled and supervised situations, as described in the study, routine chest radiography may be omitted if the insertion goes smoothly. It is important to note that these results are specific to the technique described in the study (using the anterior approach to the right internal jugular, using a short finder needle to initially locate the vein) and cannot be extrapolated to other methods of TLC insertion. Important limitations of the study include the sample size of only 100 patients and the use of only a single anatomic approach to TLC insertion. These findings, although an important first step, will need to be reproduced on a larger scale before we can recommend the cessation of routine chest radiography after TLC placement on a more widespread basis.
6. Safdar N, Fine JP, Maki DG. Metaanalysis: methods for diagnosing intravascular devicerelated bloodstream infection. Ann Intern Med. 2005;142:451-66.
Intravascular device (IVD)–related blood stream infections are a frequent cause of morbidity and mortality, and yet there is lack of a clear consensus on the most accurate method to make this diagnosis.
In this metaanalysis, Safdar et al. reviewed 185 studies, including 8 different diagnostic tests, for the detection of IVD-related bloodstream infections, of which 51 studies met the inclusion criteria. Tests were divided into IVD-sparing and those requiring IVD removal. Pooled sensitivity and specificity, summary measures of accuracy, and the mean log odds ratio were determined. The most accurate IVD-sparing test was paired quantitative blood cultures (simultaneous blood cultures from the IVD and a peripheral site, with a positive result defined as an IVD-site microorganism concentration 3–5 times greater than peripheral site) with a sensitivity of 0.87 (95% CI: 0.83–0.91) and specificity of 0.98 (95% CI: 0.97–0.99). This was followed by quantitative IVD-drawn blood cultures alone (positive result defined as growth of ≥100 CFU), with a sensitivity of 0.77 (95% CI: 0.69–0.85) and a specificity of 0.90 (95% CI: 0.88–0.92). IVD-drawn qualitative blood cultures had a sensitivity of 0.87 (95% CI: 0.80–0.94) and a specificity of 0.83 (95% CI: 0.78–0.88), and IVD- and peripheral-drawn qualitative blood cultures with differential time to positivity had a sensitivity of 0.85 (95% CI: 0.78–0.92) and specificity of 0.81 (95% CI: 0.81–0.97).
The most accurate test requiring IVD removal was quantitative catheter segment culture (segment of catheter is flushed or sonicated and plated, positive if ≥1000 CFU), with sensitivity of 0.83 (95% CI: 0.78–0.88) and specificity of 0.87 (95% CI: 0.85–0.89), followed by semi-quantitative catheter segment culture (5cm segment plated, positive if ≥ 15 CFU) with sensitivity of 0.82 (95% CI: 0.81–0.89) and specificity of 0.82 (95% CI: 0.80–0.84). The least accurate was qualitative catheter segment culture (positive if any growth) with a sensitivity of 0.90 (95% CI: 0.83–0.97) and specificity of 0.72 (95% CI: 0.66–0.78).
The limitations of this study include heterogeneity of study design, including limited data on the use of antibiotics before culture data was obtained and the baseline prevalence of bacteremia in the study populations. In addition, all data was obtained prior to the widespread use of antibiotic-coated catheters. While these results support the catheter-tip quantitative culture techniques that are already widely in use, they are less applicable to blood culture testing techniques, because quantitative assays are rarely used. Fortunately, all of these assays have a high negative predictive value, and false-positive results can be minimized by reserving testing for patients in whom there is moderate-to-high pretest probability of IVD related bloodstream infection.
7. Sopena N, Sabria M, Neunos 2000 Study Group. Multicenter study of hospital-acquired pneumonia in non-ICU patients. Chest. 2005;127:213-9.
A growing body of literature exists on hospital-acquired pneumonia (HAP) in the ICU setting. Sopena and colleagues extend the HAP literature to the non-ICU setting in a multicenter cross-sectional study. Cases of HAP were identified if clinical or radiographic evidence of pneumonia developed 72 hours after admission or within 10 days of a previous discharge. Patients who developed pneumonia in the ICU were excluded from analysis.
During an 18-month study period, 165 cases were identified with complete clinical and microbiologic data. The incidence of HAP was 3.1 ± 1.4 per 1000 hospital admissions. Ninety-eight (59.4%) patients diagnosed with HAP had severe underlying diseases that were classified as fatal (<1 year) or ultimately fatal (in 5 years). Extrinsic risk factors observed in patients with HAP included concurrent steroid use (29%), antibiotic therapy (53.3%), use of H2 blockers (37%), and hospitalization greater than 5 days (76%). Microbiologic data were positive in 60 (36.4%) cases. Streptococcus pneumoniae was diagnosed in 16 cases (9.7%), enterobacteriaceae in 8 (4.8%), Legionella pneumophila in 7 (4.2%), Aspergillus sp in 7 (4.2%), Pseudomonas aeruginosa in 7 (4.2%). Four cases of Staphylococcus aureus were diagnosed (3%), only one of which was methicillin resistant.
Complications of HAP occurred in 52.1% of cases and included respiratory failure (34.5%), pleural effusion (20.6%), septic shock (9.6%), renal failure (4.8%), and empyema (2.4%). Forty-three (26%) patients died during the hospitalization; 23 of these cases were directly attributed to HAP.
A limitation of the study is that the incidence of HAP was somewhat lower than reported in the literature and thus might represent an unintended sampling bias. Moreover, the study demonstrated underlying factors seen in patients with HAP, but these are not necessarily causative. Results useful to hospitalists include a higher than expected rate of Legionella and Aspergillus sp causing HAP in this population. A Legionella outbreak was not the explanation, as these cases were diagnosed in 5 different hospitals. The high frequency of adverse outcomes associated with HAP should alert hospitalists to the risk of nosocomial pneumonia in the non-ICU setting.
1. Carratala J, FernandezSabe N, Ortega L, et al. Outpatient care compared with hospitalization for community-acquired pneumonia: a randomized trial in low-risk patients. Ann Intern Med. 2005;142: 165-72.
The appropriate triage and management of patients with community-acquired pneumonia (CAP) has important implications for patient outcomes and the allocation of health care resources. Despite the availability of validated risk stratification tools significant variability in clinical practice which results in hospitalization rates that are often inconsistent with the severity of illness. In this unblinded, randomized controlled trial, 224 patients with CAP and a low-risk pneumonia severity index (PSI) score between 51 and 90 (class II and III) were randomized to outpatient oral levofloxacin therapy versus inpatient sequential intravenous and oral levofloxacin therapy. Exclusion criteria included quinolone allergy or use within the previous 3 months, PaO2 < 60 mm Hg, complicated pleural effusion, lung abscess, metastatic infection, inability to maintain oral intake, and severe psychosocial problems precluding outpatient therapy. In an intention-to-treat analysis, the primary endpoints, of cure of pneumonia (resolution of signs, symptoms, and radiographic changes at 30 days), absence of adverse drug reactions, medical complications, or need for hospitalization at 30 days were achieved in 83.6% of outpatients and in 80.7% of hospitalized patients. For the secondary endpoint of patient satisfaction, 91.2% of outpatients versus 79.1% of hospitalized patients (p=.03) were satisfied, but there were no differences between groups with respect to the secondary endpoint of health-related quality of life. Mortality was similar between the 2 groups, and although the study was not sufficiently powered to address this outcome, and interestingly there was trend toward increased medical complications in the hospitalized patients.
Limitations of this study include lack of blinding by investigators and questions about whether the results can be generalized given the geographic variation in microbial susceptibility to quinolone antibiotics. As the authors suggest, this study also highlights limitations in the PSI scoring system, given that patients with clinical findings and comorbidities who would never be treated in the outpatient setting may in fact fall into low-risk PSI categories. These concerns notwithstanding, this study adds to our ability to identify an additional subset of patients with CAP who can be safely managed as outpatients.
2. Choudhry NK, Fletcher RH, Soumerai SB. Systematic review: the relationship between clinical experience and quality of health care.Ann Intern Med. 2005;142:260-73.
Early in the hospital medicine movement, when it was clear that hospitalists provided more efficient care than their colleagues, experience was cited as a reason for this difference. If, for example, a hospitalist cares for patients with community-acquired pneumonia daily, he or she is more likely to make the transition to oral antibiotics sooner, resulting in a shorter length of stay. Everyone recognized the hospitalists were younger, but is it plausible their “inexperience” explained the difference in care?
Choudhry and colleagues explored the available data surrounding clinical experience and quality of care delivered by physicians. They found few studies that specifically evaluated the effects of experience on quality of care. They did find articles that looked at quality of care and included experience or age as part of the physician characteristics
that possibly explained the differences. They reviewed 59 articles, available on MEDLINE, published since 1966. Forty-five studies found an inverse relationship between increasing experience and performance. For example, physicians more recently out of training programs were more familiar with evidence-based therapies for myocardial infarction and more familiar with NIH recommendations for treatment of breast cancer. Experienced physicians were less likely to screen for hypertension and more likely to prescribe inappropriate medications for elderly patients. This led them to the unexpected conclusion that experienced physicians may be at risk for providing lower-quality care and may need improvement interventions. An accompanying editorial by Drs. Weinberger, Duffy, and Cassel of the American Board of Internal Medicine stated, “The profession cannot ignore this striking finding and its implications: Practice does not make perfect, but it must be accompanied by ongoing active effort to maintain competence and quality of care.” They urged all physicians to “embrace the concepts behind maintenance of (board) certification.”
The image of Marcus Welby, MD, would lead one to believe that experience promotes higher quality care. But don’t ask a hospitalist: Many aren’t old enough to remember seeing him on television.
3. Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005;352:969-77.
March was DVT (deep vein thrombosis) Awareness Month. Despite the availability of numerous guidelines, providers fail to consistently prescribe prophylactic measures against venous thromboembolism (VTE) for their hospitalized patients who meet criteria for prophylaxis.
Kucher and colleagues tested an innovative approach to remind providers to undertake such measures for their patients. They designed a computer program to identify hospitalized patients at increased risk for VTE who were not presently receiving VTE prophylaxis. The program reviewed the records of inpatients on the medical and surgical services and assigned a VTE risk score for each patient based on their history (i.e., history of cancer, hypercoagulability, etc.) and their present medical treatment (i.e., hormone therapy, prescribed bed rest, etc.). For patients considered “high risk” for VTE, the computer reviewed orders to identify ongoing use of VTE prophylactic measures. High-risk patients not receiving prophylactic therapies were randomized into 2 groups. The responsible physician in the intervention group received an electronic alert about the risk of VTE in their patient. No alerts were sent to the physicians in the control group. Physicians who received the alerts were forced to acknowledge the alert by either actively withholding prophylaxis or ordering prophylaxis (mechanical or pharmacologic measures). Patients were followed for 90 days with a primary endpoint of clinically diagnosed, objectively confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE). The primary endpoint occurred in 8.2% of the control group versus 4.9% in the invention group (p<.001). The alert reduced the risk of DVT or PE at 90 days by 41% (p=.001).
The results of the study are interesting. The authors acknowledged that many physicians had patients in both groups. So receiving 1 alert may have affected their use of prophylaxis in both groups. They also could not eliminate the possibility of diagnostic bias. Prophylaxis was not blinded and VTE testing was not routinely performed. Would physicians be more likely to order an imaging study for symptomatic patients on no prophylaxis than patients on prophylaxis? Nevertheless, for hospitals that have sufficient computer resources, implementation of such alerts can elevate physician awareness about VTE and other clinical conditions.
4. Lau DT, Kasper JD, Pofer DE, et al. Hospitalization and death associated with potentially inappropriate medication prescriptions among elderly nursing home residents. Arch Intern Med. 2005;165: 68-74.
Lau and colleagues studied the impact of potentially inappropriate medications among residents of longtermcare facilities. They used information from a 1996 national survey of home residents. The sample included 3372 residents, 65 years and older, who lived in a nursing home for 3 months or longer. Over half of the residents were older than 85 years old and 75% were female. Only 10% were black. Nearly two thirds had dementia or other mental disorders. The study used the Beers Criteria to define potentially inappropriate medications. The potential errors in medications were categorized as 1 of 3 types:
- inappropriate choice of medication
- excessive medication dosage
- drug–disease interactions
Residents were considered to have a potentially inappropriate medication if their medication administration records revealed any of the above findings.
A univariate analysis showed that the risk of hospitalization was almost 30% higher among residents who received potentially inappropriate medications in the preceding month and 33% higher among residents who received potentially inappropriate medications for 2 consecutive months, compared with residents with no inappropriate medication exposure. The odds of death in any month were 21% higher among residents who had inappropriate medication exposure during the month of death or the preceeding month, compared with those with no inappropriate medication exposure.
These findings can be generalized to the inpatient setting, where hospitalists have the opportunity to influence and modify prescribing practices in the elderly population.
5. Lessnau KD. Is chest radiography necessary after uncomplicated insertion of a triplelumen catheter in the right internal jugular vein, using the anterior approach? Chest. 2005;127:220-3.
The routine use of chest radiography to confirm proper triplelumen catheter (TLC) placement may be an unnecessary and costly intervention. Lessnau conducted a prospective observational study of 100 consecutive patients over a 4-month period who required non-urgent TLC placement. The primary operators of the procedure included 18 medical residents, 3 pulmonary fellows, and a pulmonary attending with supervision provided for more junior clinicians. Operators followed a standardized approach to TLC placement utilizing the anterior approach to the right internal jugular vein. Complicated procedures were predefined as any procedure that required more than 3 needle passes, resulted in hemorrhage or hematoma formation (where there was concern for pneumothorax), or an absence of blood return in any of the TLC’s lumens. All subjects underwent routine post-procedure chest radiography to determine proper placement of the catheter and to exclude pneumothorax. A blinded radiologist reviewed these images.
Ninety-eight of the 100 catheters were in proper position. One malpositioned catheter was 7 cm above the right atrium in a patient who was 215 cm (>7 feet) tall. The second was noted to be in an S-shaped position on chest radiography. This procedure had required 20 needle passes and 5 slides of the catheter; additionally, blood return was inadequate in 2 lumens of the catheter. An operator reported a possible complication in 10 other procedures, but the only clinical finding in these cases was the development of a local hematoma in 1 patient. Eighty-eight patients had uncomplicated insertions and had normal chest radiographs. There were no pneumothoraces.
This study demonstrates that in carefully controlled and supervised situations, as described in the study, routine chest radiography may be omitted if the insertion goes smoothly. It is important to note that these results are specific to the technique described in the study (using the anterior approach to the right internal jugular, using a short finder needle to initially locate the vein) and cannot be extrapolated to other methods of TLC insertion. Important limitations of the study include the sample size of only 100 patients and the use of only a single anatomic approach to TLC insertion. These findings, although an important first step, will need to be reproduced on a larger scale before we can recommend the cessation of routine chest radiography after TLC placement on a more widespread basis.
6. Safdar N, Fine JP, Maki DG. Metaanalysis: methods for diagnosing intravascular devicerelated bloodstream infection. Ann Intern Med. 2005;142:451-66.
Intravascular device (IVD)–related blood stream infections are a frequent cause of morbidity and mortality, and yet there is lack of a clear consensus on the most accurate method to make this diagnosis.
In this metaanalysis, Safdar et al. reviewed 185 studies, including 8 different diagnostic tests, for the detection of IVD-related bloodstream infections, of which 51 studies met the inclusion criteria. Tests were divided into IVD-sparing and those requiring IVD removal. Pooled sensitivity and specificity, summary measures of accuracy, and the mean log odds ratio were determined. The most accurate IVD-sparing test was paired quantitative blood cultures (simultaneous blood cultures from the IVD and a peripheral site, with a positive result defined as an IVD-site microorganism concentration 3–5 times greater than peripheral site) with a sensitivity of 0.87 (95% CI: 0.83–0.91) and specificity of 0.98 (95% CI: 0.97–0.99). This was followed by quantitative IVD-drawn blood cultures alone (positive result defined as growth of ≥100 CFU), with a sensitivity of 0.77 (95% CI: 0.69–0.85) and a specificity of 0.90 (95% CI: 0.88–0.92). IVD-drawn qualitative blood cultures had a sensitivity of 0.87 (95% CI: 0.80–0.94) and a specificity of 0.83 (95% CI: 0.78–0.88), and IVD- and peripheral-drawn qualitative blood cultures with differential time to positivity had a sensitivity of 0.85 (95% CI: 0.78–0.92) and specificity of 0.81 (95% CI: 0.81–0.97).
The most accurate test requiring IVD removal was quantitative catheter segment culture (segment of catheter is flushed or sonicated and plated, positive if ≥1000 CFU), with sensitivity of 0.83 (95% CI: 0.78–0.88) and specificity of 0.87 (95% CI: 0.85–0.89), followed by semi-quantitative catheter segment culture (5cm segment plated, positive if ≥ 15 CFU) with sensitivity of 0.82 (95% CI: 0.81–0.89) and specificity of 0.82 (95% CI: 0.80–0.84). The least accurate was qualitative catheter segment culture (positive if any growth) with a sensitivity of 0.90 (95% CI: 0.83–0.97) and specificity of 0.72 (95% CI: 0.66–0.78).
The limitations of this study include heterogeneity of study design, including limited data on the use of antibiotics before culture data was obtained and the baseline prevalence of bacteremia in the study populations. In addition, all data was obtained prior to the widespread use of antibiotic-coated catheters. While these results support the catheter-tip quantitative culture techniques that are already widely in use, they are less applicable to blood culture testing techniques, because quantitative assays are rarely used. Fortunately, all of these assays have a high negative predictive value, and false-positive results can be minimized by reserving testing for patients in whom there is moderate-to-high pretest probability of IVD related bloodstream infection.
7. Sopena N, Sabria M, Neunos 2000 Study Group. Multicenter study of hospital-acquired pneumonia in non-ICU patients. Chest. 2005;127:213-9.
A growing body of literature exists on hospital-acquired pneumonia (HAP) in the ICU setting. Sopena and colleagues extend the HAP literature to the non-ICU setting in a multicenter cross-sectional study. Cases of HAP were identified if clinical or radiographic evidence of pneumonia developed 72 hours after admission or within 10 days of a previous discharge. Patients who developed pneumonia in the ICU were excluded from analysis.
During an 18-month study period, 165 cases were identified with complete clinical and microbiologic data. The incidence of HAP was 3.1 ± 1.4 per 1000 hospital admissions. Ninety-eight (59.4%) patients diagnosed with HAP had severe underlying diseases that were classified as fatal (<1 year) or ultimately fatal (in 5 years). Extrinsic risk factors observed in patients with HAP included concurrent steroid use (29%), antibiotic therapy (53.3%), use of H2 blockers (37%), and hospitalization greater than 5 days (76%). Microbiologic data were positive in 60 (36.4%) cases. Streptococcus pneumoniae was diagnosed in 16 cases (9.7%), enterobacteriaceae in 8 (4.8%), Legionella pneumophila in 7 (4.2%), Aspergillus sp in 7 (4.2%), Pseudomonas aeruginosa in 7 (4.2%). Four cases of Staphylococcus aureus were diagnosed (3%), only one of which was methicillin resistant.
Complications of HAP occurred in 52.1% of cases and included respiratory failure (34.5%), pleural effusion (20.6%), septic shock (9.6%), renal failure (4.8%), and empyema (2.4%). Forty-three (26%) patients died during the hospitalization; 23 of these cases were directly attributed to HAP.
A limitation of the study is that the incidence of HAP was somewhat lower than reported in the literature and thus might represent an unintended sampling bias. Moreover, the study demonstrated underlying factors seen in patients with HAP, but these are not necessarily causative. Results useful to hospitalists include a higher than expected rate of Legionella and Aspergillus sp causing HAP in this population. A Legionella outbreak was not the explanation, as these cases were diagnosed in 5 different hospitals. The high frequency of adverse outcomes associated with HAP should alert hospitalists to the risk of nosocomial pneumonia in the non-ICU setting.
1. Carratala J, FernandezSabe N, Ortega L, et al. Outpatient care compared with hospitalization for community-acquired pneumonia: a randomized trial in low-risk patients. Ann Intern Med. 2005;142: 165-72.
The appropriate triage and management of patients with community-acquired pneumonia (CAP) has important implications for patient outcomes and the allocation of health care resources. Despite the availability of validated risk stratification tools significant variability in clinical practice which results in hospitalization rates that are often inconsistent with the severity of illness. In this unblinded, randomized controlled trial, 224 patients with CAP and a low-risk pneumonia severity index (PSI) score between 51 and 90 (class II and III) were randomized to outpatient oral levofloxacin therapy versus inpatient sequential intravenous and oral levofloxacin therapy. Exclusion criteria included quinolone allergy or use within the previous 3 months, PaO2 < 60 mm Hg, complicated pleural effusion, lung abscess, metastatic infection, inability to maintain oral intake, and severe psychosocial problems precluding outpatient therapy. In an intention-to-treat analysis, the primary endpoints, of cure of pneumonia (resolution of signs, symptoms, and radiographic changes at 30 days), absence of adverse drug reactions, medical complications, or need for hospitalization at 30 days were achieved in 83.6% of outpatients and in 80.7% of hospitalized patients. For the secondary endpoint of patient satisfaction, 91.2% of outpatients versus 79.1% of hospitalized patients (p=.03) were satisfied, but there were no differences between groups with respect to the secondary endpoint of health-related quality of life. Mortality was similar between the 2 groups, and although the study was not sufficiently powered to address this outcome, and interestingly there was trend toward increased medical complications in the hospitalized patients.
Limitations of this study include lack of blinding by investigators and questions about whether the results can be generalized given the geographic variation in microbial susceptibility to quinolone antibiotics. As the authors suggest, this study also highlights limitations in the PSI scoring system, given that patients with clinical findings and comorbidities who would never be treated in the outpatient setting may in fact fall into low-risk PSI categories. These concerns notwithstanding, this study adds to our ability to identify an additional subset of patients with CAP who can be safely managed as outpatients.
2. Choudhry NK, Fletcher RH, Soumerai SB. Systematic review: the relationship between clinical experience and quality of health care.Ann Intern Med. 2005;142:260-73.
Early in the hospital medicine movement, when it was clear that hospitalists provided more efficient care than their colleagues, experience was cited as a reason for this difference. If, for example, a hospitalist cares for patients with community-acquired pneumonia daily, he or she is more likely to make the transition to oral antibiotics sooner, resulting in a shorter length of stay. Everyone recognized the hospitalists were younger, but is it plausible their “inexperience” explained the difference in care?
Choudhry and colleagues explored the available data surrounding clinical experience and quality of care delivered by physicians. They found few studies that specifically evaluated the effects of experience on quality of care. They did find articles that looked at quality of care and included experience or age as part of the physician characteristics
that possibly explained the differences. They reviewed 59 articles, available on MEDLINE, published since 1966. Forty-five studies found an inverse relationship between increasing experience and performance. For example, physicians more recently out of training programs were more familiar with evidence-based therapies for myocardial infarction and more familiar with NIH recommendations for treatment of breast cancer. Experienced physicians were less likely to screen for hypertension and more likely to prescribe inappropriate medications for elderly patients. This led them to the unexpected conclusion that experienced physicians may be at risk for providing lower-quality care and may need improvement interventions. An accompanying editorial by Drs. Weinberger, Duffy, and Cassel of the American Board of Internal Medicine stated, “The profession cannot ignore this striking finding and its implications: Practice does not make perfect, but it must be accompanied by ongoing active effort to maintain competence and quality of care.” They urged all physicians to “embrace the concepts behind maintenance of (board) certification.”
The image of Marcus Welby, MD, would lead one to believe that experience promotes higher quality care. But don’t ask a hospitalist: Many aren’t old enough to remember seeing him on television.
3. Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005;352:969-77.
March was DVT (deep vein thrombosis) Awareness Month. Despite the availability of numerous guidelines, providers fail to consistently prescribe prophylactic measures against venous thromboembolism (VTE) for their hospitalized patients who meet criteria for prophylaxis.
Kucher and colleagues tested an innovative approach to remind providers to undertake such measures for their patients. They designed a computer program to identify hospitalized patients at increased risk for VTE who were not presently receiving VTE prophylaxis. The program reviewed the records of inpatients on the medical and surgical services and assigned a VTE risk score for each patient based on their history (i.e., history of cancer, hypercoagulability, etc.) and their present medical treatment (i.e., hormone therapy, prescribed bed rest, etc.). For patients considered “high risk” for VTE, the computer reviewed orders to identify ongoing use of VTE prophylactic measures. High-risk patients not receiving prophylactic therapies were randomized into 2 groups. The responsible physician in the intervention group received an electronic alert about the risk of VTE in their patient. No alerts were sent to the physicians in the control group. Physicians who received the alerts were forced to acknowledge the alert by either actively withholding prophylaxis or ordering prophylaxis (mechanical or pharmacologic measures). Patients were followed for 90 days with a primary endpoint of clinically diagnosed, objectively confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE). The primary endpoint occurred in 8.2% of the control group versus 4.9% in the invention group (p<.001). The alert reduced the risk of DVT or PE at 90 days by 41% (p=.001).
The results of the study are interesting. The authors acknowledged that many physicians had patients in both groups. So receiving 1 alert may have affected their use of prophylaxis in both groups. They also could not eliminate the possibility of diagnostic bias. Prophylaxis was not blinded and VTE testing was not routinely performed. Would physicians be more likely to order an imaging study for symptomatic patients on no prophylaxis than patients on prophylaxis? Nevertheless, for hospitals that have sufficient computer resources, implementation of such alerts can elevate physician awareness about VTE and other clinical conditions.
4. Lau DT, Kasper JD, Pofer DE, et al. Hospitalization and death associated with potentially inappropriate medication prescriptions among elderly nursing home residents. Arch Intern Med. 2005;165: 68-74.
Lau and colleagues studied the impact of potentially inappropriate medications among residents of longtermcare facilities. They used information from a 1996 national survey of home residents. The sample included 3372 residents, 65 years and older, who lived in a nursing home for 3 months or longer. Over half of the residents were older than 85 years old and 75% were female. Only 10% were black. Nearly two thirds had dementia or other mental disorders. The study used the Beers Criteria to define potentially inappropriate medications. The potential errors in medications were categorized as 1 of 3 types:
- inappropriate choice of medication
- excessive medication dosage
- drug–disease interactions
Residents were considered to have a potentially inappropriate medication if their medication administration records revealed any of the above findings.
A univariate analysis showed that the risk of hospitalization was almost 30% higher among residents who received potentially inappropriate medications in the preceding month and 33% higher among residents who received potentially inappropriate medications for 2 consecutive months, compared with residents with no inappropriate medication exposure. The odds of death in any month were 21% higher among residents who had inappropriate medication exposure during the month of death or the preceeding month, compared with those with no inappropriate medication exposure.
These findings can be generalized to the inpatient setting, where hospitalists have the opportunity to influence and modify prescribing practices in the elderly population.
5. Lessnau KD. Is chest radiography necessary after uncomplicated insertion of a triplelumen catheter in the right internal jugular vein, using the anterior approach? Chest. 2005;127:220-3.
The routine use of chest radiography to confirm proper triplelumen catheter (TLC) placement may be an unnecessary and costly intervention. Lessnau conducted a prospective observational study of 100 consecutive patients over a 4-month period who required non-urgent TLC placement. The primary operators of the procedure included 18 medical residents, 3 pulmonary fellows, and a pulmonary attending with supervision provided for more junior clinicians. Operators followed a standardized approach to TLC placement utilizing the anterior approach to the right internal jugular vein. Complicated procedures were predefined as any procedure that required more than 3 needle passes, resulted in hemorrhage or hematoma formation (where there was concern for pneumothorax), or an absence of blood return in any of the TLC’s lumens. All subjects underwent routine post-procedure chest radiography to determine proper placement of the catheter and to exclude pneumothorax. A blinded radiologist reviewed these images.
Ninety-eight of the 100 catheters were in proper position. One malpositioned catheter was 7 cm above the right atrium in a patient who was 215 cm (>7 feet) tall. The second was noted to be in an S-shaped position on chest radiography. This procedure had required 20 needle passes and 5 slides of the catheter; additionally, blood return was inadequate in 2 lumens of the catheter. An operator reported a possible complication in 10 other procedures, but the only clinical finding in these cases was the development of a local hematoma in 1 patient. Eighty-eight patients had uncomplicated insertions and had normal chest radiographs. There were no pneumothoraces.
This study demonstrates that in carefully controlled and supervised situations, as described in the study, routine chest radiography may be omitted if the insertion goes smoothly. It is important to note that these results are specific to the technique described in the study (using the anterior approach to the right internal jugular, using a short finder needle to initially locate the vein) and cannot be extrapolated to other methods of TLC insertion. Important limitations of the study include the sample size of only 100 patients and the use of only a single anatomic approach to TLC insertion. These findings, although an important first step, will need to be reproduced on a larger scale before we can recommend the cessation of routine chest radiography after TLC placement on a more widespread basis.
6. Safdar N, Fine JP, Maki DG. Metaanalysis: methods for diagnosing intravascular devicerelated bloodstream infection. Ann Intern Med. 2005;142:451-66.
Intravascular device (IVD)–related blood stream infections are a frequent cause of morbidity and mortality, and yet there is lack of a clear consensus on the most accurate method to make this diagnosis.
In this metaanalysis, Safdar et al. reviewed 185 studies, including 8 different diagnostic tests, for the detection of IVD-related bloodstream infections, of which 51 studies met the inclusion criteria. Tests were divided into IVD-sparing and those requiring IVD removal. Pooled sensitivity and specificity, summary measures of accuracy, and the mean log odds ratio were determined. The most accurate IVD-sparing test was paired quantitative blood cultures (simultaneous blood cultures from the IVD and a peripheral site, with a positive result defined as an IVD-site microorganism concentration 3–5 times greater than peripheral site) with a sensitivity of 0.87 (95% CI: 0.83–0.91) and specificity of 0.98 (95% CI: 0.97–0.99). This was followed by quantitative IVD-drawn blood cultures alone (positive result defined as growth of ≥100 CFU), with a sensitivity of 0.77 (95% CI: 0.69–0.85) and a specificity of 0.90 (95% CI: 0.88–0.92). IVD-drawn qualitative blood cultures had a sensitivity of 0.87 (95% CI: 0.80–0.94) and a specificity of 0.83 (95% CI: 0.78–0.88), and IVD- and peripheral-drawn qualitative blood cultures with differential time to positivity had a sensitivity of 0.85 (95% CI: 0.78–0.92) and specificity of 0.81 (95% CI: 0.81–0.97).
The most accurate test requiring IVD removal was quantitative catheter segment culture (segment of catheter is flushed or sonicated and plated, positive if ≥1000 CFU), with sensitivity of 0.83 (95% CI: 0.78–0.88) and specificity of 0.87 (95% CI: 0.85–0.89), followed by semi-quantitative catheter segment culture (5cm segment plated, positive if ≥ 15 CFU) with sensitivity of 0.82 (95% CI: 0.81–0.89) and specificity of 0.82 (95% CI: 0.80–0.84). The least accurate was qualitative catheter segment culture (positive if any growth) with a sensitivity of 0.90 (95% CI: 0.83–0.97) and specificity of 0.72 (95% CI: 0.66–0.78).
The limitations of this study include heterogeneity of study design, including limited data on the use of antibiotics before culture data was obtained and the baseline prevalence of bacteremia in the study populations. In addition, all data was obtained prior to the widespread use of antibiotic-coated catheters. While these results support the catheter-tip quantitative culture techniques that are already widely in use, they are less applicable to blood culture testing techniques, because quantitative assays are rarely used. Fortunately, all of these assays have a high negative predictive value, and false-positive results can be minimized by reserving testing for patients in whom there is moderate-to-high pretest probability of IVD related bloodstream infection.
7. Sopena N, Sabria M, Neunos 2000 Study Group. Multicenter study of hospital-acquired pneumonia in non-ICU patients. Chest. 2005;127:213-9.
A growing body of literature exists on hospital-acquired pneumonia (HAP) in the ICU setting. Sopena and colleagues extend the HAP literature to the non-ICU setting in a multicenter cross-sectional study. Cases of HAP were identified if clinical or radiographic evidence of pneumonia developed 72 hours after admission or within 10 days of a previous discharge. Patients who developed pneumonia in the ICU were excluded from analysis.
During an 18-month study period, 165 cases were identified with complete clinical and microbiologic data. The incidence of HAP was 3.1 ± 1.4 per 1000 hospital admissions. Ninety-eight (59.4%) patients diagnosed with HAP had severe underlying diseases that were classified as fatal (<1 year) or ultimately fatal (in 5 years). Extrinsic risk factors observed in patients with HAP included concurrent steroid use (29%), antibiotic therapy (53.3%), use of H2 blockers (37%), and hospitalization greater than 5 days (76%). Microbiologic data were positive in 60 (36.4%) cases. Streptococcus pneumoniae was diagnosed in 16 cases (9.7%), enterobacteriaceae in 8 (4.8%), Legionella pneumophila in 7 (4.2%), Aspergillus sp in 7 (4.2%), Pseudomonas aeruginosa in 7 (4.2%). Four cases of Staphylococcus aureus were diagnosed (3%), only one of which was methicillin resistant.
Complications of HAP occurred in 52.1% of cases and included respiratory failure (34.5%), pleural effusion (20.6%), septic shock (9.6%), renal failure (4.8%), and empyema (2.4%). Forty-three (26%) patients died during the hospitalization; 23 of these cases were directly attributed to HAP.
A limitation of the study is that the incidence of HAP was somewhat lower than reported in the literature and thus might represent an unintended sampling bias. Moreover, the study demonstrated underlying factors seen in patients with HAP, but these are not necessarily causative. Results useful to hospitalists include a higher than expected rate of Legionella and Aspergillus sp causing HAP in this population. A Legionella outbreak was not the explanation, as these cases were diagnosed in 5 different hospitals. The high frequency of adverse outcomes associated with HAP should alert hospitalists to the risk of nosocomial pneumonia in the non-ICU setting.