More then 2.5 million patients in the United States are on long-term anticoagulation therapy for atrial fibrillation, venous thromboembolic disease, or mechanical heart valves,¹ and the number is expected to rise as the population ages. Each year, about 10% of these patients undergo an invasive procedure or surgery that requires temporary interruption of anticoagulation.²

Most physicians are familiar with the perioperative management of warfarin, a vitamin K antagonist, since for decades it has been the sole oral anticoagulant available. However, many physicians lack experience with the three target-specific oral anticoagulants (TSOACs; also known as “novel” oral anticoagulants) approved so far: the direct thrombin inhibitor dabigatran (Pradaxa) and the direct factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis).

With their rapid onset of action, predictable pharmacokinetics, relatively short half-lives, and fewer drug-drug interactions than warfarin, TSOACs overcome many of the limitations of the older oral anticoagulant warfarin. In many ways, these qualities simplify the perioperative management of anticoagulation. At the same time, these new drugs also bring new challenges: caution is needed in patients with renal impairment; the level of anticoagulation is difficult to assess; and there is no specific antidote or standardized procedure to reverse their anticoagulant effect. While various periprocedural protocols for TSOAC therapy have been proposed, evidence-based guidelines are still to come.

This article first discusses the pharmacology of dabigatran, rivaroxaban, and apixaban that is pertinent to the perioperative period. It then briefly reviews the general principles of perioperative management of anticoagulation. The final section provides specific recommendations for the perioperative management of TSOACs.

PHARMACOLOGY OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

Dabigatran, a factor IIa inhibitor

Information from references 3, 4, 14, and 23.

Dabigatran is an oral direct thrombin (factor IIa) inhibitor. It exerts its anticoagulant effect by blocking the generation of fibrin, inhibiting platelet aggregation, and dampening the activity of factors V, VIII, and XI (Figure 1).^3,4 From its introduction in October 2010 through August 2012, nearly 3.7 million prescriptions were dispensed to 725,000 patients in the United States.⁵

Indications for dabigatran. Dabigatran is approved in the United States and Canada for preventing stroke in nonvalvular atrial fibrillation (Table 1).⁶ More recently, it received US approval for treating deep vein thrombosis or pulmonary embolism after 5 to 10 days of a parenteral anticoagulant.^7,8 It is also approved in Europe and Canada for preventing venous thromboembolism (VTE) after total hip replacement and knee arthroplasty.^9,10

Dabigatran is contraindicated in patients with a mechanical heart valve, based on a phase 2 study in which it conferred a higher risk of thromboembolism and bleeding than warfarin.^3,11

Pharmacokinetics of dabigatran. Dabigatran is formulated as a prodrug, dabigatran etexilate, in a capsule containing multiple small pellets.¹² The capsules should not be crushed, as this significantly increases oral bioavailability. The prodrug is absorbed across the gastric mucosa and is then rapidly converted to the active form (Table 2).

Plasma concentrations peak within 2 hours of ingestion, which means that therapeutic anticoagulation is achieved shortly after taking the drug.

Only 35% of dabigatran is protein-bound, which allows it to be removed by hemodialysis. Nearly 85% of the drug is eliminated in the urine. It has a half-life of 13 to 15 hours in patients with normal renal function.³ However, its half-life increases to about 27 hours in patients whose creatinine clearance is less than 30 mL/min. As a result, the dose must be reduced in patients with renal impairment (Table 1).

Dabigatran is not metabolized by the cytochrome P450 enzymes, but it is a substrate for P-glycoprotein, so it still has the potential for drug-drug interactions.³ Practitioners should be familiar with these potential interactions (Table 3), as they can result in higher- or lower-than-expected plasma concentrations of dabigatran in the perioperative period.¹³

Rivaroxaban, a factor Xa inhibitor

Rivaroxaban is an oral direct factor Xa inhibitor. It has been approved by the US Food and Drug Administration (FDA) for the prevention of stroke in nonvalvular atrial fibrillation, for VTE treatment, and for VTE prophylaxis after hip replacement or knee replacement (Table 1).^14–20 It has not yet been studied in patients with hip fracture.

Pharmacokinetics of rivaroxaban. Rivaroxaban is manufactured as a tablet that is best absorbed in the stomach (Table 2).¹⁴ In contrast to dabigatran, it can be crushed and, for example, mixed with applesauce for patients who have trouble swallowing. It can also be mixed with water and given via nasogastric tube; however, postpyloric administration should be avoided.

Plasma concentrations peak within a few hours after ingestion. Rivaroxaban is highly protein-bound, so it cannot be eliminated by hemodialysis.

The drug relies on renal elimination to a smaller degree than dabigatran, with one-third of the dose eliminated unchanged in the urine, one-third eliminated in the urine as inactive metabolite, and the remaining one-third eliminated in the feces. However, enough parent compound is cleared through the kidneys that the half-life of rivaroxaban increases from 8.3 hours in healthy individuals to 9.5 hours in patients whose creatinine clearance is less than 30 mL/min.²¹ As with dabigatran, the dose must be adjusted for renal impairment (Table 1).

Rivaroxaban has significant liver metabolism, specifically through the cytochrome P450 3A4 enzyme, and it is also a substrate of P-glycoprotein. Therefore, potential drug-drug interactions must be taken into account, as they may lead to important alterations in plasma concentrations (Table 3).

Apixaban, a factor Xa inhibitor

Apixaban is also an oral direct factor Xa inhibitor. It is the newest of the oral anticoagulants to be approved in the United States, specifically for preventing stroke in nonvalvular atrial fibrillation (Table 1).²²

Pharmacokinetics of apixaban. Apixaban is produced as a tablet that is absorbed slowly through the gastrointestinal tract, mainly the distal small bowel and ascending colon (Table  2).²³

Peak plasma concentrations are reached a few hours after ingestion. Like rivaroxaban, apixaban is highly protein-bound, so it cannot be removed by hemodialysis.

Apixaban is similar to rivaroxaban in that 27% of the parent compound is cleared through the kidneys, it undergoes significant hepatic metabolism through cytochrome P450 3A4, and it is a substrate for P-glycoprotein.

Drug-drug interactions must be considered as a potential source of altered drug exposure and clearance (Table 3).

Unlike dabigatran and rivaroxaban, dose reduction is not based on the calculated creatinine clearance. Instead, a reduced dose is required if the patient meets two of the following three criteria:

• Serum creatinine level ≥ 1.5 mg/dL
• Age ≥ 80
• Weight ≤ 60 kg (Table 1).

The American Heart Association/American Stroke Association guidelines further recommend against using apixaban in patients with a creatinine clearance less than 25 mL/min.²⁴

Edoxaban, a factor Xa inhibitor in development

Edoxaban (Savaysa), another factor Xa inhibitor, is available in Japan and has been submitted for approval in the United States for treating VTE and for preventing stroke in patients with

PERIOPERATIVE CONSIDERATIONS IN ANTICOAGULATION

Before addressing the perioperative management of TSOACs, let us review the evidence guiding the perioperative management of any chronic anticoagulant.

In fact, no large prospective randomized trial has clearly defined the risks and benefits of using or withholding a bridging anticoagulation strategy around surgery and other procedures, though the PERIOP 2 and BRIDGE trials are currently ongoing.^25,26 There are some data regarding continuing anticoagulation without interruption, but they have mainly been derived from specific groups (eg, patients on warfarin undergoing cardiac pacemaker or defibrillator placement) and in procedures that pose a very low risk of bleeding complications (eg, minor dental extractions, cataract surgery, dermatologic procedures).^2,27 Recommendations are, therefore, necessarily based on small perioperative trials and data gleaned from cohort review and from studies that did not involve surgical patients.

Ultimately, the decisions whether to discontinue oral anticoagulants and whether to employ bridging anticoagulation are based on assumptions about the risks of bleeding and the risk of thrombotic events, with similar assumptions regarding the effects of anticoagulants on both outcomes. In addition, the relative acceptance of bleeding vs thrombotic risks implicitly guides these complex decisions.

Perioperative bleeding risk

Many risk factors specific to the patient and to the type of surgery affect the rates and severity of perioperative bleeding.²⁸

As for patient-specific risk factors, a small retrospective cohort analysis revealed that a HAS-BLED score of 3 or higher was highly discriminating in predicting perioperative bleeding in atrial fibrillation patients receiving anticoagulation.²⁹ (The HAS-BLED score is based on hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio [INR], elderly [age > 65] and drug therapy.³⁰) However, there are no widely validated tools that incorporate patient-specific factors to accurately predict bleeding risk in an individual patient.

Therefore, the American College of Chest Physicians (ACCP) guidelines suggest coarsely categorizing bleeding risk as either low or high solely on the basis of the type of procedure.² Procedures considered “high-risk” have a risk greater than 1.5% to 2% and include urologic surgery involving the prostate or kidney, colonic polyp resections, surgeries involving highly vascular organs such as the liver or spleen, joint replacements, cancer surgeries, and cardiac or neurosurgical procedures.

Perioperative thrombotic risk

The ACCP guidelines² place patients with atrial fibrillation, VTE, or mechanical heart valves in three risk groups for perioperative thromboembolism without anticoagulation, based on their annual risk of a thrombotic event:

• High risk—annual risk of a thrombotic event > 10%
• Moderate risk—5% to 10%
• Low risk—< 5%.

Comparing the risks calculated by these methods with the real-world risk of perioperative thrombosis highlights the problem of applying nonperioperative risk calculations: the perioperative period exposes patients to a higher risk than these models would predict.³¹ Nonetheless, these risk categorizations likely have some validity in stratifying patients into risk groups, even if the absolute risks are inaccurate.

Perioperative bridging for patients taking warfarin

Many patients with atrial fibrillation, VTE, or a mechanical heart valve need to interrupt their warfarin therapy because of the bleeding risk of an upcoming procedure.

The perioperative management of warfarin and other vitamin K antagonists is challenging because of the pharmacokinetics and pharmacodynamics of these drugs. Because it has a long half-life, warfarin usually must be stopped 4 to 5 days before a procedure in order to allow not only adequate clearance of the drug itself, but also restoration of functional clotting factors to normal or near-normal levels.¹² Warfarin can generally be resumed 12 to 24 hours after surgery, assuming adequate hemostasis has been achieved, and it will again take several days for the INR to reach the therapeutic range.

The ACCP guidelines recommend using the perioperative risk of thromboembolism to make decisions about the need for bridging anticoagulation during warfarin interruption.² They suggest that patients at high risk of thrombosis receive bridging with an alternative anticoagulant such as low-molecular-weight heparin or unfractionated heparin, because of the prolonged duration of subtherapeutic anticoagulation.

There has been clinical interest in using a TSOAC instead of low-molecular-weight or unfractionated heparin for bridging in the perioperative setting. Although this approach may be attractive from a cost and convenience perspective, it cannot be endorsed as yet because of the lack of information on the pros and cons of such an approach.

Patients at low thrombotic risk do not require bridging. In patients at moderate risk, the decision to bridge or not to bridge is based on careful consideration of patient-specific and surgery-specific factors.

PERIOPERATIVE MANAGEMENT OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

As summarized above, the perioperative management strategy for chronic anticoagulation is based on limited evidence, even for drugs as well established as warfarin.

The most recent ACCP guidelines on the perioperative management of antithrombotic therapy do not mention TSOACs.² For now, the management strategy must be based on the pharmacokinetics of the drugs, package inserts from the manufacturers, and expert recommendations.^{3,14,23,32–34} Fortunately, because TSOACs have a more favorable pharmacokinetic profile than that of warfarin, their perioperative uses should be more streamlined. As always, the goal is to minimize the risk of both periprocedural bleeding and thromboembolism.

Timing of cessation of anticoagulation

The timing of cessation of TSOACs before an elective procedure depends primarily on two factors: the bleeding risk of the procedure and the patient’s renal function. Complete clearance of the medication is not necessary in all circumstances.

TSOACs should be stopped four to five half-lives before a procedure with a high bleeding risk, so that there is no or only minimal residual anticoagulant effect. The drug can be stopped two to three half-lives before a procedure with a low bleeding risk. Remember: the half-life increases as creatinine clearance decreases.

Specific recommendations may vary across institutions, but a suggested strategy is shown in Table 4.^{3,4,21,23,32–35} For the small subset of patients on P-glycoprotein or cytochrome P450 inhibitors or inducers, further adjustment in the time of discontinuation may be required.

Therapy does not need to be interrupted for procedures with a very low bleeding risk, as defined above.^33,34 There is also preliminary evidence that TSOACs, similar to warfarin, may be continued during cardiac pacemaker or defibrillator placement.³⁶

Evidence from clinical trials of perioperative TSOAC management

While the above recommendations are logical, studies are needed to prospectively evaluate perioperative management strategies.

The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), which compared the effects of dabigatran and warfarin in preventing stroke in patients with atrial fibrillation, is one of the few clinical trials that also looked at periprocedural bleeding.³⁷ About a quarter of the RE-LY participants required interruption of anticoagulation for a procedure.

Warfarin was managed according to local practices. For most of the study, the protocol required that dabigatran be discontinued 24 hours before a procedure, regardless of renal function or procedure type. The protocol was later amended and closely mirrored the management plan outlined in Table 4.

With either protocol, there was no statistically significant difference between dabigatran and warfarin in the rates of bleeding and thrombotic complications in the 7 days before or 30 days after the procedure.

A major limitation of the study was that most patients underwent a procedure with a low bleeding risk, so the analysis was likely underpowered to evaluate rates of bleeding in higher-risk procedures.

The ROCKET-AF trial (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) also shed light on periprocedural bleeding.¹⁵ About 15% of the participants required temporary interruption of anticoagulation for a surgical or invasive procedure.³⁸

The study protocol called for discontinuing rivaroxaban 2 days before any procedure. Warfarin was to be held for 4 days to achieve a goal INR of 1.5 or less.¹⁵

Rates of major and nonmajor clinically significant bleeding at 30 days were similar with rivaroxaban and with warfarin.³⁸ As with the RE-LY trial, the retrospective analysis was probably underpowered for assessing rates of bleeding in procedures with higher risk.

Perioperative bridging

While stopping a TSOAC in the perioperative period decreases the risk of bleeding, it naturally increases the risk of thromboembolism. However, patients on TSOACs should not routinely require perioperative bridging with an alternative anticoagulant, regardless of thrombotic risk.

Of note, dabigatran, rivaroxaban, and apixaban carry black-box warnings that discontinuation places patients at higher risk of thrombotic events.^3,14,23 These warnings further state that coverage with an alternative anticoagulant should be strongly considered during interruption of therapy for reasons other than pathologic bleeding.

However, it does not necessarily follow that perioperative bridging is required. For example, the warning for rivaroxaban is based on the finding in the ROCKET-AF trial that patients in the rivaroxaban group had higher rates of stroke than those in the warfarin group after the study drugs were stopped at the end of the trial.³⁹ While there was initial concern that this could represent a prothrombotic rebound effect, the authors subsequently showed that patients in the rivaroxaban group were more likely to have had a subtherapeutic INR when transitioning to open-label vitamin-K-antagonist therapy.^39,40 There was no difference in the rate of stroke or systemic embolism between the rivaroxaban and warfarin groups when anticoagulation was temporarily interrupted for a procedure.³⁸

The risks and benefits of perioperative bridging with TSOACs are difficult to evaluate, given the dearth of trial data. In the RE-LY trial, only 17% of patients on dabigatran and 28% of patients on warfarin underwent periprocedural bridging.³⁷ The selection criteria and protocol for bridging were not reported. In the ROCKET-AF trial, only 9% of patients received bridging therapy despite a mean CHADS₂ score of 3.4.³⁸ (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age ≥ 75, and diabetes; 2 points for stroke or transient ischemic attack.) The decision to bridge or not was left to the individual investigator. As a result, the literature offers diverse opinions about the appropriateness of transitioning to an alternative anticoagulant.^41–43

Bridging does not make sense in most instances, since anticoagulants such as low-molecular-weight heparin have pharmacokinetics similar to those of the available TSOACs and also depend on renal clearance.⁴¹ However, there may be situations in which patients must be switched to a parenteral anticoagulant such as unfractionated or low-molecular-weight heparin. For example, if a TSOAC has to be held, the patient has acute renal failure, and a needed procedure is still several days away, it would be reasonable to start a heparin drip for an inpatient at increased thrombotic risk.

In patients with normal renal function, these alternative anticoagulants should be started at the time the next TSOAC dose would have been due.^3,14,23 In patients with reduced renal function, initiation of an alternative anticoagulant may need to be delayed 12 to 48 hours depending on which TSOAC is being used, as well as on the degree of renal dysfunction. This delay would help ensure that the onset of anticoagulation with the alternative anticoagulant is timed with the offset of therapeutic anticoagulation with the TSOAC.

Although limited, information from available coagulation assays may assist with the timing of initiation of an alternative anticoagulant (see the following section on laboratory monitoring). Serial testing with appropriate coagulation assays may help identify when most of a TSOAC has been cleared from a patient.

Laboratory monitoring

Inevitably, some patients on TSOACs require urgent or emergency surgery. In certain situations, such as before an orthopedic spine procedure, in which the complications of bleeding could be devastating, it may be necessary to know if any residual anticoagulant effect is present.

Monitoring dabigatran. As one might expect, direct thrombin inhibitors such as dabigatran can prolong the prothrombin time and activated partial thromboplastin time (aPTT).^44–47 However, the prothrombin time is not recommended for assessing the level of anticoagulation from dabigatran. Many institutions may be using a normal aPTT to rule out therapeutic concentrations of dabigatran, based on results from early in vitro and ex vivo studies.⁴⁶ While appealing from a practical standpoint, practitioners should exercise caution when relying on the aPTT to assess the risk of perioperative bleeding. A more recent investigation in patients treated with dabigatran found that up to 35% of patients with a normal aPTT still had a plasma concentration in the therapeutic range.⁴⁸

The thrombin time and ecarin clotting time are more sensitive tests for dabigatran. A normal thrombin time or ecarin clotting time indicates that no or only minimal dabigatran is present.⁴⁸ Unfortunately, these two tests often are either unavailable or are associated with long turnaround times, which limits their usefulness in the perioperative setting.

Monitoring rivaroxaban and apixaban. Factor Xa inhibitors such as rivaroxaban and apixaban can also influence the prothrombin time and aPTT (Figure 1).^{44–47,49,50} The aPTT is relatively insensitive to these drugs at low concentrations. It has been suggested that a normal prothrombin time can reasonably exclude therapeutic concentrations of rivaroxaban.^45,46 However, the effects on the prothrombin time are highly variable, changing with the reagent used.^49,50 In addition, apixaban appears to have less impact on the prothrombin time overall. The INR is not recommended for monitoring the effect of factor Xa inhibitors.

Anti-factor Xa assays likely represent the best option to provide true quantitative information on the level of anticoagulation with either rivaroxaban or apixaban. However, the assays must be specifically calibrated for each drug for results to be useful. (Anti-factor Xa assays cannot be used for heparin or low-molecular-weight heparin.) Further, most institutions do not yet have this capability. When appropriately calibrated, normal anti-factor Xa levels would exclude any effect of rivaroxaban or apixaban.

Reversal of anticoagulation

If patients on TSOACs require emergency surgery or present with significant bleeding in the setting of persistent anticoagulation, it may be necessary to try to reverse the anticoagulation.

Unlike warfarin or heparin, TSOACS do not have specific reversal agents, though specific antidotes are being developed. For example, researchers are evaluating antibodies capable of neutralizing dabigatran, as well as recombinant thrombin and factor Xa molecules that could antagonize dabigatran and rivaroxaban, respectively.^51–53

Reversal can be attempted by neutralizing or removing the offending drug. Activated charcoal may be able to reduce absorption of TSOACs that were recently ingested,⁴⁴ and dabigatran can be removed by hemodialysis.

However, certain practical considerations may limit the use of dialysis in the perioperative period. Insertion of a temporary dialysis line in an anticoagulated patient poses additional bleeding risks. A standard 4-hour hemodialysis session may remove only about 70% of dabigatran from the plasma, which may not be enough to prevent perioperative bleeding.⁵⁴ Dabigatran also tends to redistribute from adipose tissue back into plasma after each dialysis session.⁵⁵ Serial sessions of high-flux intermittent hemodialysis or continuous renal replacement therapy may therefore be needed to counteract rebound elevations in the dabigatran concentration.

Reversal can also be attempted through activation of the coagulation cascade via other mechanisms. Fresh-frozen plasma is unlikely to be a practical solution for reversal.⁴⁴ Although it can readily replace the clotting factors depleted by vitamin K antagonists, large volumes of fresh-frozen plasma would be needed to overwhelm thrombin or factor Xa inhibition by TSOACs.

There are limited data on the use of prothrombin complex concentrates or recombinant activated factor VIIa in patients on TSOACs, though their use can be considered.⁵⁶ In a trial in 12 healthy participants, a nonactivated four-factor prothrombin complex concentrate containing factors II, VII, IX, and X immediately and completely reversed the anticoagulant effect of rivaroxaban but had no effect on dabigatran.⁵⁷ Before 2013, there were no nonactivated four-factor prothrombin complex concentrates available in the United States. The FDA has since approved Kcentra for the urgent reversal of vitamin K antagonists, meaning that the reversal of TSOACs in major bleeding events would still be off-label.⁵⁸ Giving any of the clotting factors carries a risk of thromboembolism.

Resumption of anticoagulation

TSOACs have a rapid onset of action, and therapeutic levels are reached within a few hours of administration.

Extrapolating from the ACCP guidelines, TSOACs can generally be restarted at therapeutic doses 24 hours after low-bleeding-risk procedures.² Therapeutic dosing should be delayed 48 to 72 hours after a procedure with a high bleeding risk, assuming adequate hemostasis has been achieved. Prophylactic unfractionated heparin or low-molecular-weight heparin therapy can be given in the interim if deemed safe. Alternatively, for orthopedic patients ultimately transitioning back to therapeutic rivaroxaban after hip or knee arthroplasty, prophylactic rivaroxaban doses can be started 6 to 10 hours after surgery.¹⁴

There are numerous reasons why the resumption of TSOACs may have to be delayed after surgery, including nothing-by-mouth status, postoperative nausea and vomiting, ileus, gastric or bowel resection, and the anticipated need for future procedures. Since dabigatran capsules cannot be crushed, they cannot be given via nasogastric tube in patients with postoperative dysphagia. Parenteral anticoagulants should be used until these issues resolve.

Unfractionated heparin is still the preferred anticoagulant in unstable or potentially unstable patients, given its ease of monitoring, quick offset of action, and reversibility. When patients have stabilized, TSOACs can be resumed when the next dose of low-molecular-weight heparin would have been due or when the unfractionated heparin drip is discontinued.^3,14,23

UNTIL EVIDENCE-BASED GUIDELINES ARE DEVELOPED

The development of TSOACs has ushered in an exciting new era for anticoagulant therapy. Providers involved in perioperative medicine will increasingly encounter patients on dabigatran, rivaroxaban, and apixaban. However, until evidence-based guidelines are developed for these new anticoagulants, clinicians will have to apply their knowledge of pharmacology and critically evaluate expert recommendations in order to manage patients safely throughout the perioperative period.

More then 2.5 million patients in the United States are on long-term anticoagulation therapy for atrial fibrillation, venous thromboembolic disease, or mechanical heart valves,¹ and the number is expected to rise as the population ages. Each year, about 10% of these patients undergo an invasive procedure or surgery that requires temporary interruption of anticoagulation.²

Most physicians are familiar with the perioperative management of warfarin, a vitamin K antagonist, since for decades it has been the sole oral anticoagulant available. However, many physicians lack experience with the three target-specific oral anticoagulants (TSOACs; also known as “novel” oral anticoagulants) approved so far: the direct thrombin inhibitor dabigatran (Pradaxa) and the direct factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis).

With their rapid onset of action, predictable pharmacokinetics, relatively short half-lives, and fewer drug-drug interactions than warfarin, TSOACs overcome many of the limitations of the older oral anticoagulant warfarin. In many ways, these qualities simplify the perioperative management of anticoagulation. At the same time, these new drugs also bring new challenges: caution is needed in patients with renal impairment; the level of anticoagulation is difficult to assess; and there is no specific antidote or standardized procedure to reverse their anticoagulant effect. While various periprocedural protocols for TSOAC therapy have been proposed, evidence-based guidelines are still to come.

This article first discusses the pharmacology of dabigatran, rivaroxaban, and apixaban that is pertinent to the perioperative period. It then briefly reviews the general principles of perioperative management of anticoagulation. The final section provides specific recommendations for the perioperative management of TSOACs.

PHARMACOLOGY OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

Dabigatran, a factor IIa inhibitor

Information from references 3, 4, 14, and 23.

Dabigatran is an oral direct thrombin (factor IIa) inhibitor. It exerts its anticoagulant effect by blocking the generation of fibrin, inhibiting platelet aggregation, and dampening the activity of factors V, VIII, and XI (Figure 1).^3,4 From its introduction in October 2010 through August 2012, nearly 3.7 million prescriptions were dispensed to 725,000 patients in the United States.⁵

Indications for dabigatran. Dabigatran is approved in the United States and Canada for preventing stroke in nonvalvular atrial fibrillation (Table 1).⁶ More recently, it received US approval for treating deep vein thrombosis or pulmonary embolism after 5 to 10 days of a parenteral anticoagulant.^7,8 It is also approved in Europe and Canada for preventing venous thromboembolism (VTE) after total hip replacement and knee arthroplasty.^9,10

Dabigatran is contraindicated in patients with a mechanical heart valve, based on a phase 2 study in which it conferred a higher risk of thromboembolism and bleeding than warfarin.^3,11

Pharmacokinetics of dabigatran. Dabigatran is formulated as a prodrug, dabigatran etexilate, in a capsule containing multiple small pellets.¹² The capsules should not be crushed, as this significantly increases oral bioavailability. The prodrug is absorbed across the gastric mucosa and is then rapidly converted to the active form (Table 2).

Plasma concentrations peak within 2 hours of ingestion, which means that therapeutic anticoagulation is achieved shortly after taking the drug.

Only 35% of dabigatran is protein-bound, which allows it to be removed by hemodialysis. Nearly 85% of the drug is eliminated in the urine. It has a half-life of 13 to 15 hours in patients with normal renal function.³ However, its half-life increases to about 27 hours in patients whose creatinine clearance is less than 30 mL/min. As a result, the dose must be reduced in patients with renal impairment (Table 1).

Dabigatran is not metabolized by the cytochrome P450 enzymes, but it is a substrate for P-glycoprotein, so it still has the potential for drug-drug interactions.³ Practitioners should be familiar with these potential interactions (Table 3), as they can result in higher- or lower-than-expected plasma concentrations of dabigatran in the perioperative period.¹³

Rivaroxaban, a factor Xa inhibitor

Rivaroxaban is an oral direct factor Xa inhibitor. It has been approved by the US Food and Drug Administration (FDA) for the prevention of stroke in nonvalvular atrial fibrillation, for VTE treatment, and for VTE prophylaxis after hip replacement or knee replacement (Table 1).^14–20 It has not yet been studied in patients with hip fracture.

Pharmacokinetics of rivaroxaban. Rivaroxaban is manufactured as a tablet that is best absorbed in the stomach (Table 2).¹⁴ In contrast to dabigatran, it can be crushed and, for example, mixed with applesauce for patients who have trouble swallowing. It can also be mixed with water and given via nasogastric tube; however, postpyloric administration should be avoided.

Plasma concentrations peak within a few hours after ingestion. Rivaroxaban is highly protein-bound, so it cannot be eliminated by hemodialysis.

The drug relies on renal elimination to a smaller degree than dabigatran, with one-third of the dose eliminated unchanged in the urine, one-third eliminated in the urine as inactive metabolite, and the remaining one-third eliminated in the feces. However, enough parent compound is cleared through the kidneys that the half-life of rivaroxaban increases from 8.3 hours in healthy individuals to 9.5 hours in patients whose creatinine clearance is less than 30 mL/min.²¹ As with dabigatran, the dose must be adjusted for renal impairment (Table 1).

Rivaroxaban has significant liver metabolism, specifically through the cytochrome P450 3A4 enzyme, and it is also a substrate of P-glycoprotein. Therefore, potential drug-drug interactions must be taken into account, as they may lead to important alterations in plasma concentrations (Table 3).

Apixaban, a factor Xa inhibitor

Apixaban is also an oral direct factor Xa inhibitor. It is the newest of the oral anticoagulants to be approved in the United States, specifically for preventing stroke in nonvalvular atrial fibrillation (Table 1).²²

Pharmacokinetics of apixaban. Apixaban is produced as a tablet that is absorbed slowly through the gastrointestinal tract, mainly the distal small bowel and ascending colon (Table  2).²³

Peak plasma concentrations are reached a few hours after ingestion. Like rivaroxaban, apixaban is highly protein-bound, so it cannot be removed by hemodialysis.

Apixaban is similar to rivaroxaban in that 27% of the parent compound is cleared through the kidneys, it undergoes significant hepatic metabolism through cytochrome P450 3A4, and it is a substrate for P-glycoprotein.

Drug-drug interactions must be considered as a potential source of altered drug exposure and clearance (Table 3).

Unlike dabigatran and rivaroxaban, dose reduction is not based on the calculated creatinine clearance. Instead, a reduced dose is required if the patient meets two of the following three criteria:

• Serum creatinine level ≥ 1.5 mg/dL
• Age ≥ 80
• Weight ≤ 60 kg (Table 1).

The American Heart Association/American Stroke Association guidelines further recommend against using apixaban in patients with a creatinine clearance less than 25 mL/min.²⁴

Edoxaban, a factor Xa inhibitor in development

Edoxaban (Savaysa), another factor Xa inhibitor, is available in Japan and has been submitted for approval in the United States for treating VTE and for preventing stroke in patients with

PERIOPERATIVE CONSIDERATIONS IN ANTICOAGULATION

Before addressing the perioperative management of TSOACs, let us review the evidence guiding the perioperative management of any chronic anticoagulant.

In fact, no large prospective randomized trial has clearly defined the risks and benefits of using or withholding a bridging anticoagulation strategy around surgery and other procedures, though the PERIOP 2 and BRIDGE trials are currently ongoing.^25,26 There are some data regarding continuing anticoagulation without interruption, but they have mainly been derived from specific groups (eg, patients on warfarin undergoing cardiac pacemaker or defibrillator placement) and in procedures that pose a very low risk of bleeding complications (eg, minor dental extractions, cataract surgery, dermatologic procedures).^2,27 Recommendations are, therefore, necessarily based on small perioperative trials and data gleaned from cohort review and from studies that did not involve surgical patients.

Ultimately, the decisions whether to discontinue oral anticoagulants and whether to employ bridging anticoagulation are based on assumptions about the risks of bleeding and the risk of thrombotic events, with similar assumptions regarding the effects of anticoagulants on both outcomes. In addition, the relative acceptance of bleeding vs thrombotic risks implicitly guides these complex decisions.

Perioperative bleeding risk

Many risk factors specific to the patient and to the type of surgery affect the rates and severity of perioperative bleeding.²⁸

As for patient-specific risk factors, a small retrospective cohort analysis revealed that a HAS-BLED score of 3 or higher was highly discriminating in predicting perioperative bleeding in atrial fibrillation patients receiving anticoagulation.²⁹ (The HAS-BLED score is based on hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio [INR], elderly [age > 65] and drug therapy.³⁰) However, there are no widely validated tools that incorporate patient-specific factors to accurately predict bleeding risk in an individual patient.

Therefore, the American College of Chest Physicians (ACCP) guidelines suggest coarsely categorizing bleeding risk as either low or high solely on the basis of the type of procedure.² Procedures considered “high-risk” have a risk greater than 1.5% to 2% and include urologic surgery involving the prostate or kidney, colonic polyp resections, surgeries involving highly vascular organs such as the liver or spleen, joint replacements, cancer surgeries, and cardiac or neurosurgical procedures.

Perioperative thrombotic risk

The ACCP guidelines² place patients with atrial fibrillation, VTE, or mechanical heart valves in three risk groups for perioperative thromboembolism without anticoagulation, based on their annual risk of a thrombotic event:

• High risk—annual risk of a thrombotic event > 10%
• Moderate risk—5% to 10%
• Low risk—< 5%.

Comparing the risks calculated by these methods with the real-world risk of perioperative thrombosis highlights the problem of applying nonperioperative risk calculations: the perioperative period exposes patients to a higher risk than these models would predict.³¹ Nonetheless, these risk categorizations likely have some validity in stratifying patients into risk groups, even if the absolute risks are inaccurate.

Perioperative bridging for patients taking warfarin

Many patients with atrial fibrillation, VTE, or a mechanical heart valve need to interrupt their warfarin therapy because of the bleeding risk of an upcoming procedure.

The perioperative management of warfarin and other vitamin K antagonists is challenging because of the pharmacokinetics and pharmacodynamics of these drugs. Because it has a long half-life, warfarin usually must be stopped 4 to 5 days before a procedure in order to allow not only adequate clearance of the drug itself, but also restoration of functional clotting factors to normal or near-normal levels.¹² Warfarin can generally be resumed 12 to 24 hours after surgery, assuming adequate hemostasis has been achieved, and it will again take several days for the INR to reach the therapeutic range.

The ACCP guidelines recommend using the perioperative risk of thromboembolism to make decisions about the need for bridging anticoagulation during warfarin interruption.² They suggest that patients at high risk of thrombosis receive bridging with an alternative anticoagulant such as low-molecular-weight heparin or unfractionated heparin, because of the prolonged duration of subtherapeutic anticoagulation.

There has been clinical interest in using a TSOAC instead of low-molecular-weight or unfractionated heparin for bridging in the perioperative setting. Although this approach may be attractive from a cost and convenience perspective, it cannot be endorsed as yet because of the lack of information on the pros and cons of such an approach.

Patients at low thrombotic risk do not require bridging. In patients at moderate risk, the decision to bridge or not to bridge is based on careful consideration of patient-specific and surgery-specific factors.

PERIOPERATIVE MANAGEMENT OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

As summarized above, the perioperative management strategy for chronic anticoagulation is based on limited evidence, even for drugs as well established as warfarin.

The most recent ACCP guidelines on the perioperative management of antithrombotic therapy do not mention TSOACs.² For now, the management strategy must be based on the pharmacokinetics of the drugs, package inserts from the manufacturers, and expert recommendations.^{3,14,23,32–34} Fortunately, because TSOACs have a more favorable pharmacokinetic profile than that of warfarin, their perioperative uses should be more streamlined. As always, the goal is to minimize the risk of both periprocedural bleeding and thromboembolism.

Timing of cessation of anticoagulation

The timing of cessation of TSOACs before an elective procedure depends primarily on two factors: the bleeding risk of the procedure and the patient’s renal function. Complete clearance of the medication is not necessary in all circumstances.

TSOACs should be stopped four to five half-lives before a procedure with a high bleeding risk, so that there is no or only minimal residual anticoagulant effect. The drug can be stopped two to three half-lives before a procedure with a low bleeding risk. Remember: the half-life increases as creatinine clearance decreases.

Specific recommendations may vary across institutions, but a suggested strategy is shown in Table 4.^{3,4,21,23,32–35} For the small subset of patients on P-glycoprotein or cytochrome P450 inhibitors or inducers, further adjustment in the time of discontinuation may be required.

Therapy does not need to be interrupted for procedures with a very low bleeding risk, as defined above.^33,34 There is also preliminary evidence that TSOACs, similar to warfarin, may be continued during cardiac pacemaker or defibrillator placement.³⁶

Evidence from clinical trials of perioperative TSOAC management

While the above recommendations are logical, studies are needed to prospectively evaluate perioperative management strategies.

The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), which compared the effects of dabigatran and warfarin in preventing stroke in patients with atrial fibrillation, is one of the few clinical trials that also looked at periprocedural bleeding.³⁷ About a quarter of the RE-LY participants required interruption of anticoagulation for a procedure.

Warfarin was managed according to local practices. For most of the study, the protocol required that dabigatran be discontinued 24 hours before a procedure, regardless of renal function or procedure type. The protocol was later amended and closely mirrored the management plan outlined in Table 4.

With either protocol, there was no statistically significant difference between dabigatran and warfarin in the rates of bleeding and thrombotic complications in the 7 days before or 30 days after the procedure.

A major limitation of the study was that most patients underwent a procedure with a low bleeding risk, so the analysis was likely underpowered to evaluate rates of bleeding in higher-risk procedures.

The ROCKET-AF trial (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) also shed light on periprocedural bleeding.¹⁵ About 15% of the participants required temporary interruption of anticoagulation for a surgical or invasive procedure.³⁸

The study protocol called for discontinuing rivaroxaban 2 days before any procedure. Warfarin was to be held for 4 days to achieve a goal INR of 1.5 or less.¹⁵

Rates of major and nonmajor clinically significant bleeding at 30 days were similar with rivaroxaban and with warfarin.³⁸ As with the RE-LY trial, the retrospective analysis was probably underpowered for assessing rates of bleeding in procedures with higher risk.

Perioperative bridging

While stopping a TSOAC in the perioperative period decreases the risk of bleeding, it naturally increases the risk of thromboembolism. However, patients on TSOACs should not routinely require perioperative bridging with an alternative anticoagulant, regardless of thrombotic risk.

Of note, dabigatran, rivaroxaban, and apixaban carry black-box warnings that discontinuation places patients at higher risk of thrombotic events.^3,14,23 These warnings further state that coverage with an alternative anticoagulant should be strongly considered during interruption of therapy for reasons other than pathologic bleeding.

However, it does not necessarily follow that perioperative bridging is required. For example, the warning for rivaroxaban is based on the finding in the ROCKET-AF trial that patients in the rivaroxaban group had higher rates of stroke than those in the warfarin group after the study drugs were stopped at the end of the trial.³⁹ While there was initial concern that this could represent a prothrombotic rebound effect, the authors subsequently showed that patients in the rivaroxaban group were more likely to have had a subtherapeutic INR when transitioning to open-label vitamin-K-antagonist therapy.^39,40 There was no difference in the rate of stroke or systemic embolism between the rivaroxaban and warfarin groups when anticoagulation was temporarily interrupted for a procedure.³⁸

The risks and benefits of perioperative bridging with TSOACs are difficult to evaluate, given the dearth of trial data. In the RE-LY trial, only 17% of patients on dabigatran and 28% of patients on warfarin underwent periprocedural bridging.³⁷ The selection criteria and protocol for bridging were not reported. In the ROCKET-AF trial, only 9% of patients received bridging therapy despite a mean CHADS₂ score of 3.4.³⁸ (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age ≥ 75, and diabetes; 2 points for stroke or transient ischemic attack.) The decision to bridge or not was left to the individual investigator. As a result, the literature offers diverse opinions about the appropriateness of transitioning to an alternative anticoagulant.^41–43

Bridging does not make sense in most instances, since anticoagulants such as low-molecular-weight heparin have pharmacokinetics similar to those of the available TSOACs and also depend on renal clearance.⁴¹ However, there may be situations in which patients must be switched to a parenteral anticoagulant such as unfractionated or low-molecular-weight heparin. For example, if a TSOAC has to be held, the patient has acute renal failure, and a needed procedure is still several days away, it would be reasonable to start a heparin drip for an inpatient at increased thrombotic risk.

In patients with normal renal function, these alternative anticoagulants should be started at the time the next TSOAC dose would have been due.^3,14,23 In patients with reduced renal function, initiation of an alternative anticoagulant may need to be delayed 12 to 48 hours depending on which TSOAC is being used, as well as on the degree of renal dysfunction. This delay would help ensure that the onset of anticoagulation with the alternative anticoagulant is timed with the offset of therapeutic anticoagulation with the TSOAC.

Although limited, information from available coagulation assays may assist with the timing of initiation of an alternative anticoagulant (see the following section on laboratory monitoring). Serial testing with appropriate coagulation assays may help identify when most of a TSOAC has been cleared from a patient.

Laboratory monitoring

Inevitably, some patients on TSOACs require urgent or emergency surgery. In certain situations, such as before an orthopedic spine procedure, in which the complications of bleeding could be devastating, it may be necessary to know if any residual anticoagulant effect is present.

Monitoring dabigatran. As one might expect, direct thrombin inhibitors such as dabigatran can prolong the prothrombin time and activated partial thromboplastin time (aPTT).^44–47 However, the prothrombin time is not recommended for assessing the level of anticoagulation from dabigatran. Many institutions may be using a normal aPTT to rule out therapeutic concentrations of dabigatran, based on results from early in vitro and ex vivo studies.⁴⁶ While appealing from a practical standpoint, practitioners should exercise caution when relying on the aPTT to assess the risk of perioperative bleeding. A more recent investigation in patients treated with dabigatran found that up to 35% of patients with a normal aPTT still had a plasma concentration in the therapeutic range.⁴⁸

The thrombin time and ecarin clotting time are more sensitive tests for dabigatran. A normal thrombin time or ecarin clotting time indicates that no or only minimal dabigatran is present.⁴⁸ Unfortunately, these two tests often are either unavailable or are associated with long turnaround times, which limits their usefulness in the perioperative setting.

Monitoring rivaroxaban and apixaban. Factor Xa inhibitors such as rivaroxaban and apixaban can also influence the prothrombin time and aPTT (Figure 1).^{44–47,49,50} The aPTT is relatively insensitive to these drugs at low concentrations. It has been suggested that a normal prothrombin time can reasonably exclude therapeutic concentrations of rivaroxaban.^45,46 However, the effects on the prothrombin time are highly variable, changing with the reagent used.^49,50 In addition, apixaban appears to have less impact on the prothrombin time overall. The INR is not recommended for monitoring the effect of factor Xa inhibitors.

Anti-factor Xa assays likely represent the best option to provide true quantitative information on the level of anticoagulation with either rivaroxaban or apixaban. However, the assays must be specifically calibrated for each drug for results to be useful. (Anti-factor Xa assays cannot be used for heparin or low-molecular-weight heparin.) Further, most institutions do not yet have this capability. When appropriately calibrated, normal anti-factor Xa levels would exclude any effect of rivaroxaban or apixaban.

Reversal of anticoagulation

If patients on TSOACs require emergency surgery or present with significant bleeding in the setting of persistent anticoagulation, it may be necessary to try to reverse the anticoagulation.

Unlike warfarin or heparin, TSOACS do not have specific reversal agents, though specific antidotes are being developed. For example, researchers are evaluating antibodies capable of neutralizing dabigatran, as well as recombinant thrombin and factor Xa molecules that could antagonize dabigatran and rivaroxaban, respectively.^51–53

Reversal can be attempted by neutralizing or removing the offending drug. Activated charcoal may be able to reduce absorption of TSOACs that were recently ingested,⁴⁴ and dabigatran can be removed by hemodialysis.

However, certain practical considerations may limit the use of dialysis in the perioperative period. Insertion of a temporary dialysis line in an anticoagulated patient poses additional bleeding risks. A standard 4-hour hemodialysis session may remove only about 70% of dabigatran from the plasma, which may not be enough to prevent perioperative bleeding.⁵⁴ Dabigatran also tends to redistribute from adipose tissue back into plasma after each dialysis session.⁵⁵ Serial sessions of high-flux intermittent hemodialysis or continuous renal replacement therapy may therefore be needed to counteract rebound elevations in the dabigatran concentration.

Reversal can also be attempted through activation of the coagulation cascade via other mechanisms. Fresh-frozen plasma is unlikely to be a practical solution for reversal.⁴⁴ Although it can readily replace the clotting factors depleted by vitamin K antagonists, large volumes of fresh-frozen plasma would be needed to overwhelm thrombin or factor Xa inhibition by TSOACs.

There are limited data on the use of prothrombin complex concentrates or recombinant activated factor VIIa in patients on TSOACs, though their use can be considered.⁵⁶ In a trial in 12 healthy participants, a nonactivated four-factor prothrombin complex concentrate containing factors II, VII, IX, and X immediately and completely reversed the anticoagulant effect of rivaroxaban but had no effect on dabigatran.⁵⁷ Before 2013, there were no nonactivated four-factor prothrombin complex concentrates available in the United States. The FDA has since approved Kcentra for the urgent reversal of vitamin K antagonists, meaning that the reversal of TSOACs in major bleeding events would still be off-label.⁵⁸ Giving any of the clotting factors carries a risk of thromboembolism.

Resumption of anticoagulation

TSOACs have a rapid onset of action, and therapeutic levels are reached within a few hours of administration.

Extrapolating from the ACCP guidelines, TSOACs can generally be restarted at therapeutic doses 24 hours after low-bleeding-risk procedures.² Therapeutic dosing should be delayed 48 to 72 hours after a procedure with a high bleeding risk, assuming adequate hemostasis has been achieved. Prophylactic unfractionated heparin or low-molecular-weight heparin therapy can be given in the interim if deemed safe. Alternatively, for orthopedic patients ultimately transitioning back to therapeutic rivaroxaban after hip or knee arthroplasty, prophylactic rivaroxaban doses can be started 6 to 10 hours after surgery.¹⁴

There are numerous reasons why the resumption of TSOACs may have to be delayed after surgery, including nothing-by-mouth status, postoperative nausea and vomiting, ileus, gastric or bowel resection, and the anticipated need for future procedures. Since dabigatran capsules cannot be crushed, they cannot be given via nasogastric tube in patients with postoperative dysphagia. Parenteral anticoagulants should be used until these issues resolve.

Unfractionated heparin is still the preferred anticoagulant in unstable or potentially unstable patients, given its ease of monitoring, quick offset of action, and reversibility. When patients have stabilized, TSOACs can be resumed when the next dose of low-molecular-weight heparin would have been due or when the unfractionated heparin drip is discontinued.^3,14,23

UNTIL EVIDENCE-BASED GUIDELINES ARE DEVELOPED

The development of TSOACs has ushered in an exciting new era for anticoagulant therapy. Providers involved in perioperative medicine will increasingly encounter patients on dabigatran, rivaroxaban, and apixaban. However, until evidence-based guidelines are developed for these new anticoagulants, clinicians will have to apply their knowledge of pharmacology and critically evaluate expert recommendations in order to manage patients safely throughout the perioperative period.

More then 2.5 million patients in the United States are on long-term anticoagulation therapy for atrial fibrillation, venous thromboembolic disease, or mechanical heart valves,¹ and the number is expected to rise as the population ages. Each year, about 10% of these patients undergo an invasive procedure or surgery that requires temporary interruption of anticoagulation.²

Most physicians are familiar with the perioperative management of warfarin, a vitamin K antagonist, since for decades it has been the sole oral anticoagulant available. However, many physicians lack experience with the three target-specific oral anticoagulants (TSOACs; also known as “novel” oral anticoagulants) approved so far: the direct thrombin inhibitor dabigatran (Pradaxa) and the direct factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis).

With their rapid onset of action, predictable pharmacokinetics, relatively short half-lives, and fewer drug-drug interactions than warfarin, TSOACs overcome many of the limitations of the older oral anticoagulant warfarin. In many ways, these qualities simplify the perioperative management of anticoagulation. At the same time, these new drugs also bring new challenges: caution is needed in patients with renal impairment; the level of anticoagulation is difficult to assess; and there is no specific antidote or standardized procedure to reverse their anticoagulant effect. While various periprocedural protocols for TSOAC therapy have been proposed, evidence-based guidelines are still to come.

This article first discusses the pharmacology of dabigatran, rivaroxaban, and apixaban that is pertinent to the perioperative period. It then briefly reviews the general principles of perioperative management of anticoagulation. The final section provides specific recommendations for the perioperative management of TSOACs.

PHARMACOLOGY OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

Dabigatran, a factor IIa inhibitor

Information from references 3, 4, 14, and 23.

Dabigatran is an oral direct thrombin (factor IIa) inhibitor. It exerts its anticoagulant effect by blocking the generation of fibrin, inhibiting platelet aggregation, and dampening the activity of factors V, VIII, and XI (Figure 1).^3,4 From its introduction in October 2010 through August 2012, nearly 3.7 million prescriptions were dispensed to 725,000 patients in the United States.⁵

Indications for dabigatran. Dabigatran is approved in the United States and Canada for preventing stroke in nonvalvular atrial fibrillation (Table 1).⁶ More recently, it received US approval for treating deep vein thrombosis or pulmonary embolism after 5 to 10 days of a parenteral anticoagulant.^7,8 It is also approved in Europe and Canada for preventing venous thromboembolism (VTE) after total hip replacement and knee arthroplasty.^9,10

Dabigatran is contraindicated in patients with a mechanical heart valve, based on a phase 2 study in which it conferred a higher risk of thromboembolism and bleeding than warfarin.^3,11

Pharmacokinetics of dabigatran. Dabigatran is formulated as a prodrug, dabigatran etexilate, in a capsule containing multiple small pellets.¹² The capsules should not be crushed, as this significantly increases oral bioavailability. The prodrug is absorbed across the gastric mucosa and is then rapidly converted to the active form (Table 2).

Plasma concentrations peak within 2 hours of ingestion, which means that therapeutic anticoagulation is achieved shortly after taking the drug.

Only 35% of dabigatran is protein-bound, which allows it to be removed by hemodialysis. Nearly 85% of the drug is eliminated in the urine. It has a half-life of 13 to 15 hours in patients with normal renal function.³ However, its half-life increases to about 27 hours in patients whose creatinine clearance is less than 30 mL/min. As a result, the dose must be reduced in patients with renal impairment (Table 1).

Dabigatran is not metabolized by the cytochrome P450 enzymes, but it is a substrate for P-glycoprotein, so it still has the potential for drug-drug interactions.³ Practitioners should be familiar with these potential interactions (Table 3), as they can result in higher- or lower-than-expected plasma concentrations of dabigatran in the perioperative period.¹³

Rivaroxaban, a factor Xa inhibitor

Rivaroxaban is an oral direct factor Xa inhibitor. It has been approved by the US Food and Drug Administration (FDA) for the prevention of stroke in nonvalvular atrial fibrillation, for VTE treatment, and for VTE prophylaxis after hip replacement or knee replacement (Table 1).^14–20 It has not yet been studied in patients with hip fracture.

Pharmacokinetics of rivaroxaban. Rivaroxaban is manufactured as a tablet that is best absorbed in the stomach (Table 2).¹⁴ In contrast to dabigatran, it can be crushed and, for example, mixed with applesauce for patients who have trouble swallowing. It can also be mixed with water and given via nasogastric tube; however, postpyloric administration should be avoided.

Plasma concentrations peak within a few hours after ingestion. Rivaroxaban is highly protein-bound, so it cannot be eliminated by hemodialysis.

The drug relies on renal elimination to a smaller degree than dabigatran, with one-third of the dose eliminated unchanged in the urine, one-third eliminated in the urine as inactive metabolite, and the remaining one-third eliminated in the feces. However, enough parent compound is cleared through the kidneys that the half-life of rivaroxaban increases from 8.3 hours in healthy individuals to 9.5 hours in patients whose creatinine clearance is less than 30 mL/min.²¹ As with dabigatran, the dose must be adjusted for renal impairment (Table 1).

Rivaroxaban has significant liver metabolism, specifically through the cytochrome P450 3A4 enzyme, and it is also a substrate of P-glycoprotein. Therefore, potential drug-drug interactions must be taken into account, as they may lead to important alterations in plasma concentrations (Table 3).

Apixaban, a factor Xa inhibitor

Apixaban is also an oral direct factor Xa inhibitor. It is the newest of the oral anticoagulants to be approved in the United States, specifically for preventing stroke in nonvalvular atrial fibrillation (Table 1).²²

Pharmacokinetics of apixaban. Apixaban is produced as a tablet that is absorbed slowly through the gastrointestinal tract, mainly the distal small bowel and ascending colon (Table  2).²³

Peak plasma concentrations are reached a few hours after ingestion. Like rivaroxaban, apixaban is highly protein-bound, so it cannot be removed by hemodialysis.

Apixaban is similar to rivaroxaban in that 27% of the parent compound is cleared through the kidneys, it undergoes significant hepatic metabolism through cytochrome P450 3A4, and it is a substrate for P-glycoprotein.

Drug-drug interactions must be considered as a potential source of altered drug exposure and clearance (Table 3).

Unlike dabigatran and rivaroxaban, dose reduction is not based on the calculated creatinine clearance. Instead, a reduced dose is required if the patient meets two of the following three criteria:

• Serum creatinine level ≥ 1.5 mg/dL
• Age ≥ 80
• Weight ≤ 60 kg (Table 1).

The American Heart Association/American Stroke Association guidelines further recommend against using apixaban in patients with a creatinine clearance less than 25 mL/min.²⁴

Edoxaban, a factor Xa inhibitor in development

Edoxaban (Savaysa), another factor Xa inhibitor, is available in Japan and has been submitted for approval in the United States for treating VTE and for preventing stroke in patients with

PERIOPERATIVE CONSIDERATIONS IN ANTICOAGULATION

Before addressing the perioperative management of TSOACs, let us review the evidence guiding the perioperative management of any chronic anticoagulant.

In fact, no large prospective randomized trial has clearly defined the risks and benefits of using or withholding a bridging anticoagulation strategy around surgery and other procedures, though the PERIOP 2 and BRIDGE trials are currently ongoing.^25,26 There are some data regarding continuing anticoagulation without interruption, but they have mainly been derived from specific groups (eg, patients on warfarin undergoing cardiac pacemaker or defibrillator placement) and in procedures that pose a very low risk of bleeding complications (eg, minor dental extractions, cataract surgery, dermatologic procedures).^2,27 Recommendations are, therefore, necessarily based on small perioperative trials and data gleaned from cohort review and from studies that did not involve surgical patients.

Ultimately, the decisions whether to discontinue oral anticoagulants and whether to employ bridging anticoagulation are based on assumptions about the risks of bleeding and the risk of thrombotic events, with similar assumptions regarding the effects of anticoagulants on both outcomes. In addition, the relative acceptance of bleeding vs thrombotic risks implicitly guides these complex decisions.

Perioperative bleeding risk

Many risk factors specific to the patient and to the type of surgery affect the rates and severity of perioperative bleeding.²⁸

As for patient-specific risk factors, a small retrospective cohort analysis revealed that a HAS-BLED score of 3 or higher was highly discriminating in predicting perioperative bleeding in atrial fibrillation patients receiving anticoagulation.²⁹ (The HAS-BLED score is based on hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio [INR], elderly [age > 65] and drug therapy.³⁰) However, there are no widely validated tools that incorporate patient-specific factors to accurately predict bleeding risk in an individual patient.

Therefore, the American College of Chest Physicians (ACCP) guidelines suggest coarsely categorizing bleeding risk as either low or high solely on the basis of the type of procedure.² Procedures considered “high-risk” have a risk greater than 1.5% to 2% and include urologic surgery involving the prostate or kidney, colonic polyp resections, surgeries involving highly vascular organs such as the liver or spleen, joint replacements, cancer surgeries, and cardiac or neurosurgical procedures.

Perioperative thrombotic risk

The ACCP guidelines² place patients with atrial fibrillation, VTE, or mechanical heart valves in three risk groups for perioperative thromboembolism without anticoagulation, based on their annual risk of a thrombotic event:

• High risk—annual risk of a thrombotic event > 10%
• Moderate risk—5% to 10%
• Low risk—< 5%.

Comparing the risks calculated by these methods with the real-world risk of perioperative thrombosis highlights the problem of applying nonperioperative risk calculations: the perioperative period exposes patients to a higher risk than these models would predict.³¹ Nonetheless, these risk categorizations likely have some validity in stratifying patients into risk groups, even if the absolute risks are inaccurate.

Perioperative bridging for patients taking warfarin

Many patients with atrial fibrillation, VTE, or a mechanical heart valve need to interrupt their warfarin therapy because of the bleeding risk of an upcoming procedure.

The perioperative management of warfarin and other vitamin K antagonists is challenging because of the pharmacokinetics and pharmacodynamics of these drugs. Because it has a long half-life, warfarin usually must be stopped 4 to 5 days before a procedure in order to allow not only adequate clearance of the drug itself, but also restoration of functional clotting factors to normal or near-normal levels.¹² Warfarin can generally be resumed 12 to 24 hours after surgery, assuming adequate hemostasis has been achieved, and it will again take several days for the INR to reach the therapeutic range.

The ACCP guidelines recommend using the perioperative risk of thromboembolism to make decisions about the need for bridging anticoagulation during warfarin interruption.² They suggest that patients at high risk of thrombosis receive bridging with an alternative anticoagulant such as low-molecular-weight heparin or unfractionated heparin, because of the prolonged duration of subtherapeutic anticoagulation.

There has been clinical interest in using a TSOAC instead of low-molecular-weight or unfractionated heparin for bridging in the perioperative setting. Although this approach may be attractive from a cost and convenience perspective, it cannot be endorsed as yet because of the lack of information on the pros and cons of such an approach.

Patients at low thrombotic risk do not require bridging. In patients at moderate risk, the decision to bridge or not to bridge is based on careful consideration of patient-specific and surgery-specific factors.

PERIOPERATIVE MANAGEMENT OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

As summarized above, the perioperative management strategy for chronic anticoagulation is based on limited evidence, even for drugs as well established as warfarin.

The most recent ACCP guidelines on the perioperative management of antithrombotic therapy do not mention TSOACs.² For now, the management strategy must be based on the pharmacokinetics of the drugs, package inserts from the manufacturers, and expert recommendations.^{3,14,23,32–34} Fortunately, because TSOACs have a more favorable pharmacokinetic profile than that of warfarin, their perioperative uses should be more streamlined. As always, the goal is to minimize the risk of both periprocedural bleeding and thromboembolism.

Timing of cessation of anticoagulation

The timing of cessation of TSOACs before an elective procedure depends primarily on two factors: the bleeding risk of the procedure and the patient’s renal function. Complete clearance of the medication is not necessary in all circumstances.

TSOACs should be stopped four to five half-lives before a procedure with a high bleeding risk, so that there is no or only minimal residual anticoagulant effect. The drug can be stopped two to three half-lives before a procedure with a low bleeding risk. Remember: the half-life increases as creatinine clearance decreases.

Specific recommendations may vary across institutions, but a suggested strategy is shown in Table 4.^{3,4,21,23,32–35} For the small subset of patients on P-glycoprotein or cytochrome P450 inhibitors or inducers, further adjustment in the time of discontinuation may be required.

Therapy does not need to be interrupted for procedures with a very low bleeding risk, as defined above.^33,34 There is also preliminary evidence that TSOACs, similar to warfarin, may be continued during cardiac pacemaker or defibrillator placement.³⁶

Evidence from clinical trials of perioperative TSOAC management

While the above recommendations are logical, studies are needed to prospectively evaluate perioperative management strategies.

The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), which compared the effects of dabigatran and warfarin in preventing stroke in patients with atrial fibrillation, is one of the few clinical trials that also looked at periprocedural bleeding.³⁷ About a quarter of the RE-LY participants required interruption of anticoagulation for a procedure.

Warfarin was managed according to local practices. For most of the study, the protocol required that dabigatran be discontinued 24 hours before a procedure, regardless of renal function or procedure type. The protocol was later amended and closely mirrored the management plan outlined in Table 4.

With either protocol, there was no statistically significant difference between dabigatran and warfarin in the rates of bleeding and thrombotic complications in the 7 days before or 30 days after the procedure.

A major limitation of the study was that most patients underwent a procedure with a low bleeding risk, so the analysis was likely underpowered to evaluate rates of bleeding in higher-risk procedures.

The ROCKET-AF trial (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) also shed light on periprocedural bleeding.¹⁵ About 15% of the participants required temporary interruption of anticoagulation for a surgical or invasive procedure.³⁸

The study protocol called for discontinuing rivaroxaban 2 days before any procedure. Warfarin was to be held for 4 days to achieve a goal INR of 1.5 or less.¹⁵

Rates of major and nonmajor clinically significant bleeding at 30 days were similar with rivaroxaban and with warfarin.³⁸ As with the RE-LY trial, the retrospective analysis was probably underpowered for assessing rates of bleeding in procedures with higher risk.

Perioperative bridging

While stopping a TSOAC in the perioperative period decreases the risk of bleeding, it naturally increases the risk of thromboembolism. However, patients on TSOACs should not routinely require perioperative bridging with an alternative anticoagulant, regardless of thrombotic risk.

Of note, dabigatran, rivaroxaban, and apixaban carry black-box warnings that discontinuation places patients at higher risk of thrombotic events.^3,14,23 These warnings further state that coverage with an alternative anticoagulant should be strongly considered during interruption of therapy for reasons other than pathologic bleeding.

However, it does not necessarily follow that perioperative bridging is required. For example, the warning for rivaroxaban is based on the finding in the ROCKET-AF trial that patients in the rivaroxaban group had higher rates of stroke than those in the warfarin group after the study drugs were stopped at the end of the trial.³⁹ While there was initial concern that this could represent a prothrombotic rebound effect, the authors subsequently showed that patients in the rivaroxaban group were more likely to have had a subtherapeutic INR when transitioning to open-label vitamin-K-antagonist therapy.^39,40 There was no difference in the rate of stroke or systemic embolism between the rivaroxaban and warfarin groups when anticoagulation was temporarily interrupted for a procedure.³⁸

The risks and benefits of perioperative bridging with TSOACs are difficult to evaluate, given the dearth of trial data. In the RE-LY trial, only 17% of patients on dabigatran and 28% of patients on warfarin underwent periprocedural bridging.³⁷ The selection criteria and protocol for bridging were not reported. In the ROCKET-AF trial, only 9% of patients received bridging therapy despite a mean CHADS₂ score of 3.4.³⁸ (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age ≥ 75, and diabetes; 2 points for stroke or transient ischemic attack.) The decision to bridge or not was left to the individual investigator. As a result, the literature offers diverse opinions about the appropriateness of transitioning to an alternative anticoagulant.^41–43

Bridging does not make sense in most instances, since anticoagulants such as low-molecular-weight heparin have pharmacokinetics similar to those of the available TSOACs and also depend on renal clearance.⁴¹ However, there may be situations in which patients must be switched to a parenteral anticoagulant such as unfractionated or low-molecular-weight heparin. For example, if a TSOAC has to be held, the patient has acute renal failure, and a needed procedure is still several days away, it would be reasonable to start a heparin drip for an inpatient at increased thrombotic risk.

In patients with normal renal function, these alternative anticoagulants should be started at the time the next TSOAC dose would have been due.^3,14,23 In patients with reduced renal function, initiation of an alternative anticoagulant may need to be delayed 12 to 48 hours depending on which TSOAC is being used, as well as on the degree of renal dysfunction. This delay would help ensure that the onset of anticoagulation with the alternative anticoagulant is timed with the offset of therapeutic anticoagulation with the TSOAC.

Although limited, information from available coagulation assays may assist with the timing of initiation of an alternative anticoagulant (see the following section on laboratory monitoring). Serial testing with appropriate coagulation assays may help identify when most of a TSOAC has been cleared from a patient.

Laboratory monitoring

Inevitably, some patients on TSOACs require urgent or emergency surgery. In certain situations, such as before an orthopedic spine procedure, in which the complications of bleeding could be devastating, it may be necessary to know if any residual anticoagulant effect is present.

Monitoring dabigatran. As one might expect, direct thrombin inhibitors such as dabigatran can prolong the prothrombin time and activated partial thromboplastin time (aPTT).^44–47 However, the prothrombin time is not recommended for assessing the level of anticoagulation from dabigatran. Many institutions may be using a normal aPTT to rule out therapeutic concentrations of dabigatran, based on results from early in vitro and ex vivo studies.⁴⁶ While appealing from a practical standpoint, practitioners should exercise caution when relying on the aPTT to assess the risk of perioperative bleeding. A more recent investigation in patients treated with dabigatran found that up to 35% of patients with a normal aPTT still had a plasma concentration in the therapeutic range.⁴⁸

The thrombin time and ecarin clotting time are more sensitive tests for dabigatran. A normal thrombin time or ecarin clotting time indicates that no or only minimal dabigatran is present.⁴⁸ Unfortunately, these two tests often are either unavailable or are associated with long turnaround times, which limits their usefulness in the perioperative setting.

Monitoring rivaroxaban and apixaban. Factor Xa inhibitors such as rivaroxaban and apixaban can also influence the prothrombin time and aPTT (Figure 1).^{44–47,49,50} The aPTT is relatively insensitive to these drugs at low concentrations. It has been suggested that a normal prothrombin time can reasonably exclude therapeutic concentrations of rivaroxaban.^45,46 However, the effects on the prothrombin time are highly variable, changing with the reagent used.^49,50 In addition, apixaban appears to have less impact on the prothrombin time overall. The INR is not recommended for monitoring the effect of factor Xa inhibitors.

Anti-factor Xa assays likely represent the best option to provide true quantitative information on the level of anticoagulation with either rivaroxaban or apixaban. However, the assays must be specifically calibrated for each drug for results to be useful. (Anti-factor Xa assays cannot be used for heparin or low-molecular-weight heparin.) Further, most institutions do not yet have this capability. When appropriately calibrated, normal anti-factor Xa levels would exclude any effect of rivaroxaban or apixaban.

Reversal of anticoagulation

If patients on TSOACs require emergency surgery or present with significant bleeding in the setting of persistent anticoagulation, it may be necessary to try to reverse the anticoagulation.

Unlike warfarin or heparin, TSOACS do not have specific reversal agents, though specific antidotes are being developed. For example, researchers are evaluating antibodies capable of neutralizing dabigatran, as well as recombinant thrombin and factor Xa molecules that could antagonize dabigatran and rivaroxaban, respectively.^51–53

Reversal can be attempted by neutralizing or removing the offending drug. Activated charcoal may be able to reduce absorption of TSOACs that were recently ingested,⁴⁴ and dabigatran can be removed by hemodialysis.

However, certain practical considerations may limit the use of dialysis in the perioperative period. Insertion of a temporary dialysis line in an anticoagulated patient poses additional bleeding risks. A standard 4-hour hemodialysis session may remove only about 70% of dabigatran from the plasma, which may not be enough to prevent perioperative bleeding.⁵⁴ Dabigatran also tends to redistribute from adipose tissue back into plasma after each dialysis session.⁵⁵ Serial sessions of high-flux intermittent hemodialysis or continuous renal replacement therapy may therefore be needed to counteract rebound elevations in the dabigatran concentration.

Reversal can also be attempted through activation of the coagulation cascade via other mechanisms. Fresh-frozen plasma is unlikely to be a practical solution for reversal.⁴⁴ Although it can readily replace the clotting factors depleted by vitamin K antagonists, large volumes of fresh-frozen plasma would be needed to overwhelm thrombin or factor Xa inhibition by TSOACs.

There are limited data on the use of prothrombin complex concentrates or recombinant activated factor VIIa in patients on TSOACs, though their use can be considered.⁵⁶ In a trial in 12 healthy participants, a nonactivated four-factor prothrombin complex concentrate containing factors II, VII, IX, and X immediately and completely reversed the anticoagulant effect of rivaroxaban but had no effect on dabigatran.⁵⁷ Before 2013, there were no nonactivated four-factor prothrombin complex concentrates available in the United States. The FDA has since approved Kcentra for the urgent reversal of vitamin K antagonists, meaning that the reversal of TSOACs in major bleeding events would still be off-label.⁵⁸ Giving any of the clotting factors carries a risk of thromboembolism.

Resumption of anticoagulation

TSOACs have a rapid onset of action, and therapeutic levels are reached within a few hours of administration.

Extrapolating from the ACCP guidelines, TSOACs can generally be restarted at therapeutic doses 24 hours after low-bleeding-risk procedures.² Therapeutic dosing should be delayed 48 to 72 hours after a procedure with a high bleeding risk, assuming adequate hemostasis has been achieved. Prophylactic unfractionated heparin or low-molecular-weight heparin therapy can be given in the interim if deemed safe. Alternatively, for orthopedic patients ultimately transitioning back to therapeutic rivaroxaban after hip or knee arthroplasty, prophylactic rivaroxaban doses can be started 6 to 10 hours after surgery.¹⁴

There are numerous reasons why the resumption of TSOACs may have to be delayed after surgery, including nothing-by-mouth status, postoperative nausea and vomiting, ileus, gastric or bowel resection, and the anticipated need for future procedures. Since dabigatran capsules cannot be crushed, they cannot be given via nasogastric tube in patients with postoperative dysphagia. Parenteral anticoagulants should be used until these issues resolve.

Unfractionated heparin is still the preferred anticoagulant in unstable or potentially unstable patients, given its ease of monitoring, quick offset of action, and reversibility. When patients have stabilized, TSOACs can be resumed when the next dose of low-molecular-weight heparin would have been due or when the unfractionated heparin drip is discontinued.^3,14,23

UNTIL EVIDENCE-BASED GUIDELINES ARE DEVELOPED

The development of TSOACs has ushered in an exciting new era for anticoagulant therapy. Providers involved in perioperative medicine will increasingly encounter patients on dabigatran, rivaroxaban, and apixaban. However, until evidence-based guidelines are developed for these new anticoagulants, clinicians will have to apply their knowledge of pharmacology and critically evaluate expert recommendations in order to manage patients safely throughout the perioperative period.

Obstetricians are often blamed for causing neonatal brachial plexus palsy (NBPP). For that reason, understanding the true pathophysiology and causation of this birth-related entity is of extreme importance.

In Part 1 of this two-part series, I summarized findings from the new report on NBPP from the American College of Obstetricians and Gynecologists (ACOG), focusing on whether the phenomenon of shoulder dystocia and NBPP can be predicted or prevented.¹ Here, in Part 2, I focus on ACOG’s conclusions concerning pathophysiology and causation of NBPP, as well as the College’s recommendations for applying that knowledge to practice.

Some infants are more susceptible than others to the forces of labor and delivery
Babies emerge from the uterus and maternal pelvis by a combination of uterine ­contractions and maternal pushing (endogenous forces) aided by the traction forces applied by the birth attendant (exogenous forces). Research over the past 2 decades has shown that endogenous forces play a significant—if not dominant—role in the causation of NBPP.

Stretching and potential injury to the brachial plexus occur when the long axis of the fetus is pushed down the birth canal while either the maternal symphysis pubis or sacral promontory catches and holds either the anterior or posterior shoulder of the fetus, respectively. This conjunction of events generates a stretching force on the tissues that connect the fetal trunk and head—the neck—under which lies the brachial plexus. The same anatomic relationships and labor forces also vigorously compress the fetal neck against the maternal symphysis pubis or sacral promontory and may cause compression injury. Any traction applied by the clinician accentuates these stretching and pressure forces acting on the nerves of the brachial plexus.

How the neonate responds to these forces depends on the tensile strength of its tissues, the metabolic condition of the fetus after a potentially long labor (as measured by acid-base status), the degree of protective muscle tone around the fetal shoulder and neck, and other fluctuating conditions. In other words, because of the many variables involved, some fetuses are more or less susceptible to injury than others.

Maternal forces alone can cause NBPP
The ACOG report¹ makes an important statement:

Some plaintiff attorneys and their expert witnesses have tried to make the case that, although endogenous forces can cause temporary brachial plexus injuries, they cannot cause permanent brachial plexus injuries. However, as the ACOG report goes on to state:

The report acknowledges that the clinician can increase brachial plexus stretch by applying downward lateral traction to the neonate’s head during delivery efforts. However, contrary to claims often made by the plaintiff bar, in the presence of shoulder dystocia, even properly applied axial traction will necessarily increase the stretching of the brachial plexus. The report also notes that traction applied in the plane of the fetal cervicothoracic spine typically is along a vector estimated to be 25° to 45° below the horizontal plane of a woman in lithotomy position, not in an exact straight line with the maternal trunk. This degree of delivery force below the horizon is defined as normal “axial traction.”

Exogenous forces have yet to be definitively measured
Multiple attempts have been made to quantify the amount of force applied by clinicians in various delivery scenarios. However, in the published studies in which this force has been “measured,” the accuracy of the findings has not been validated. The three studies in which delivery force was directly measured in a clinical setting “provide a limited assessment of exogenous forces” and “do not address the angle at which forces were applied.”^3–5 All other studies used artificial models.

As a result, few conclusions from such studies are directly applicable to the clinical arena. Moreover, in other studies using simulated birth scenarios, there was no feedback to participating clinicians as to whether the force they applied would have been sufficient to deliver the “fetus.” It was therefore difficult for participants in such studies to “determine how the situation corresponds with the force they would apply clinically.”¹

Cadaver studies have been inadequate to assess the in situ response of the brachial plexus
Many plaintiff claims regarding the cause of brachial plexus injury use cadaver studies as evidence. However, most such studies were conducted between 98 and 140 years ago. In these older studies, quantitative evaluation was rare. And in the few more recent studies, there are several reasons why the data obtained are problematic:

• the nerves being studied were dissected free from supporting tissues
• nerve tissue deteriorates quickly post­mortem
• some studies used adult tissues; there may be significant differences between adult and newborn nerve tissue that obscure comparison.

The ACOG report concludes the section on cadaver studies by stating:

Physical models also fall short
The problem with the use of physical models in evaluating NBPP centers on the need to find materials that have the same or similar properties as the tissues of interest. These sorts of bioengineering limitations generally do not allow for findings that have direct clinical applicability.

Of interest, however, is the finding of at least two groups of investigators that less traction is required when simulating delivery of a model infant when rotational maneuvers (Rubin’s) are employed rather than after McRoberts repositioning. 

Computer models have yielded data on the relative effects of endogenous and exogenous forces
Sophisticated computer analysis has been used to investigate both endogenous and ­exogenous delivery forces. Results of such studies have shown that maternal endo­genous forces exert twice as much pressure on the base of the fetal neck against the maternal symphysis pubis as do deliverer-­induced ­exogenous forces.

Is there a threshold of force?
Data that include measurement of the force applied to the brachial plexus nerves of a live infant during a real delivery are almost nonexistent. One group—on the basis of a single case of transient NBPP and potentially flawed pressure measurements—has suggested that the threshold for NBPP in the human is 100 Newtons.³ However, other studies have shown that physician-applied forces in routine deliveries commonly exceed this hypothesized cutoff—yet the rate of NBPP remains low. In measuring delivery forces it must be remembered that significant variation exists between individual neonates, both in terms of mechanical properties and anatomy. Because of this ­variation—and the nonlinear behavior of nerve tissues—the specific force needed to cause a nerve injury or rupture in a given neonate has not been established.

Chapter 3 of the ACOG report closes with a statement:

NBPP and shoulder dystocia
Shoulder dystocia is defined as a delivery that requires additional obstetric maneuvers after gentle downward traction on the fetal head fails to deliver the fetal shoulders. The ACOG report makes the important point that shoulder dystocia is not formally diagnosed until a trial of downward axial traction has been unsuccessful in delivering the anterior shoulder. This point is a refutation of the frequent plaintiff claim that, once a shoulder dystocia is thought to be present, no traction whatsoever should be applied by the clinician at any time during the remainder of the delivery.

Shoulder dystocia incidence is rising
The reported incidence of shoulder dystocia has increased over the past several decades. It is unclear whether this increase is related to maternal obesity, fetal macrosomia, or more widespread reporting. However, paradoxes exist in the relationship among risk factors, shoulder dystocia, and brachial plexus injury:

• although there is an increased incidence of shoulder dystocia with increased birth weight, the mean birth weight of neonates with recognized shoulder dystocia is not significantly higher than the mean birth weight of all term infants
• strategies to reduce NBPP by ­preventing shoulder dystocia—including early induction of labor and prophylactic use of McRoberts maneuver and suprapubic pressure—have not been effective in reducing the incidence of NBPP.

The ACOG report makes the statement: “Maternal and fetal factors associated with shoulder dystocia do not allow for reliable prediction of persistent NBPP.”¹

What is optimal management of shoulder dystocia?
The last obstetric part of the ACOG report takes as its focus the management of shoulder dystocia. It discusses the importance of communication among members of the delivery team and with the mother whose neonate is experiencing a shoulder dystocia. The report states:

This statement contrasts with claims frequently made by plaintiff medical expert witnesses that the woman experiencing a shoulder dystocia should absolutely cease from pushing.

In a section on team training, the report describes the delivery team’s priorities:

Studies evaluating process standardization, the use of checklists, teamwork training, crew resource management, and evidence-based medicine have shown that these tools improve neonatal and maternal outcomes.

Simulation training also has been shown to help reduce transient NBPP (see the box below for more on simulation programs for shoulder dystocia). Whether it also can lower the rate of permanent NBPP is unclear.¹

In the new ACOG report on neonatal brachial plexus injury, simulation training is discussed as one solution to the dilemma of how clinicians can gain experience in managing obstetric events that occur infrequently.¹ Simulation training also has the potential to improve teamwork, communication, and the situational awareness of the health-care team as a whole. Several studies over the past few years have shown that, in some units, the implementation of simulation training actually has decreased the number of cases of neonatal brachial plexus palsy (NBPP), compared with no simulation training.

For example, Draycott and colleagues explored the rate of neonatal injury associated with shoulder dystocia before and after implementation of a mandatory 1-day simulation training program at Southmead Hospital in Bristol, United Kingdom.² The program consisted of practice on a shoulder dystocia training mannequin and covered risk factors, recognition of shoulder dystocia, maneuvers, and documentation. The training used a stepwise approach, beginning with a call for help and continuing through McRoberts’ positioning, suprapubic pressure, and internal maneuvers such as delivery of the posterior arm (Figure).

There were 15,908 births in the pretraining period and 13,117 in the posttraining period, with shoulder dystocia rates comparable between the two periods. Not only did clinical management of shoulder dystocia improve after training, but there was a significant reduction in neonatal injury at birth after shoulder dystocia (30 injuries of 324 shoulder dystocia cases [9.3%] before training vs six injuries of 262 shoulder dystocia cases [2.3%] afterward).²

In another study of obstetric brachial plexus injury before and after implementation of simulation training for shoulder dystocia, Inglis and colleagues found a decline in the rate of such injury from 30% to 10.67% (P<.01).³ Shoulder dystocia training remained associated with reduced obstetric brachial plexus injury after logistic-regression analysis.³

Shoulder dystocia training is now recommended by the Joint Commission on Accreditation of Healthcare Organizations in the United States. However, in its report, ACOG concludes—despite studies from Draycott and colleagues and others—that, owing to “limited data,” “there remains no evidence that introduction of simulation can reduce the frequency of persistent NBPP.”¹

References

1. American College of Obstetricians and Gynecologists. Executive summary: neonatal brachial plexus palsy. Report of the American College of Obstetricians and Gynecologists’ Task Force on neonatal brachial plexus palsy. Obstet Gynecol. 2014;123(4):902–904.
2. Draycott TJ, Crofts FJ, Ash JP, et al. Improving neonatal outcome through practical shoulder dystocia training. Obstet Gynecol. 2008;112(1):14–20.
3. Inglis SR, Feier N, Chetiyaar JB, et al. Effects of shoulder dystocia training on the incidence of brachial plexus palsy. Am J Obstet Gynecol. 2011;204(4):322.e1–e6.

Delivery of the posterior arm
The report reaffirms the previous statement from the ACOG practice bulletin on shoulder dystocia, which asserts that no specific sequence of maneuvers for resolving shoulder dystocia has been shown to be superior to any other.⁶ It does note, however, that recent studies seem to demonstrate a benefit when delivery of the posterior arm is prioritized over the usual first-line maneuvers of McRoberts positioning and the application of suprapubic pressure. If confirmed, such findings may alter the standard of care for shoulder dystocia resolution and result in a change in ACOG recommendations.

Documentation may be enhanced by use of a checklist
The ACOG report stresses the importance of accurate, contemporaneous documentation of the management of shoulder dystocia, observing that checklists and documentation reminders help ensure the completeness and relevance of notes after shoulder dystocia deliveries and NBPP. ACOG has produced such a checklist, which can be found in the appendix of the report itself.1

How long before central neurologic injury occurs?
Another issue covered in the report is how long a clinician has to resolve a shoulder dystocia before central neurologic damage occurs. Studies have shown that permanent neurologic injury can occur as soon as 2 minutes after shoulder impaction, although the risk of acidosis or severe hypoxic-ischemic encephalopathy remains low until impaction has lasted at least 5 minutes.

Other issues covered in the report
The last chapters of the ACOG report focus on orthopedic aspects of brachial plexus injury, including diagnosis, treatment, and prognosis.

The report concludes with a glossary and three appendices:

• Royal College of Obstetricians and Gynecologists Green Top Guidebook #42 on shoulder dystocia
• ACOG Practice Bulletin #40 on shoulder dystocia
• ACOG Patient Safety Checklist #6 on the documentation of shoulder dystocia.

Why the ACOG report is foundational
The ACOG report on NBPP is an important and much-needed document. It includes a comprehensive review of the literature on brachial plexus injury and shoulder dystocia, written by nationally recognized experts in the field. Most important, it makes definitive statements that counteract false and dubious claims often made by the plaintiff bar in brachial plexus injury cases and provides evidence to back those statements.

The report:

• disproves the claim that “excessive” physician traction is the only etiology of brachial plexus injuries
• demonstrates that no differentiation can be made between the etiology of permanent versus temporary brachial plexus injuries
• describes how brachial plexus injuries can occur in the absence of physician traction or even of shoulder dystocia
• provides a summary of scientific information about brachial plexus injuries that will benefit obstetric clinicians
• provides a wealth of literature documentation that will enable physician defendants to counteract many of the claims plaintiffs and their expert witnesses make in brachial plexus injury cases.

The report is—and will remain—a foundational document in obstetrics for many years to come.

Share your thoughts on this article! Send your Letter to the Editor to [email protected].

Obstetricians are often blamed for causing neonatal brachial plexus palsy (NBPP). For that reason, understanding the true pathophysiology and causation of this birth-related entity is of extreme importance.

In Part 1 of this two-part series, I summarized findings from the new report on NBPP from the American College of Obstetricians and Gynecologists (ACOG), focusing on whether the phenomenon of shoulder dystocia and NBPP can be predicted or prevented.¹ Here, in Part 2, I focus on ACOG’s conclusions concerning pathophysiology and causation of NBPP, as well as the College’s recommendations for applying that knowledge to practice.

Some infants are more susceptible than others to the forces of labor and delivery
Babies emerge from the uterus and maternal pelvis by a combination of uterine ­contractions and maternal pushing (endogenous forces) aided by the traction forces applied by the birth attendant (exogenous forces). Research over the past 2 decades has shown that endogenous forces play a significant—if not dominant—role in the causation of NBPP.

Stretching and potential injury to the brachial plexus occur when the long axis of the fetus is pushed down the birth canal while either the maternal symphysis pubis or sacral promontory catches and holds either the anterior or posterior shoulder of the fetus, respectively. This conjunction of events generates a stretching force on the tissues that connect the fetal trunk and head—the neck—under which lies the brachial plexus. The same anatomic relationships and labor forces also vigorously compress the fetal neck against the maternal symphysis pubis or sacral promontory and may cause compression injury. Any traction applied by the clinician accentuates these stretching and pressure forces acting on the nerves of the brachial plexus.

How the neonate responds to these forces depends on the tensile strength of its tissues, the metabolic condition of the fetus after a potentially long labor (as measured by acid-base status), the degree of protective muscle tone around the fetal shoulder and neck, and other fluctuating conditions. In other words, because of the many variables involved, some fetuses are more or less susceptible to injury than others.

Maternal forces alone can cause NBPP
The ACOG report¹ makes an important statement:

Some plaintiff attorneys and their expert witnesses have tried to make the case that, although endogenous forces can cause temporary brachial plexus injuries, they cannot cause permanent brachial plexus injuries. However, as the ACOG report goes on to state:

The report acknowledges that the clinician can increase brachial plexus stretch by applying downward lateral traction to the neonate’s head during delivery efforts. However, contrary to claims often made by the plaintiff bar, in the presence of shoulder dystocia, even properly applied axial traction will necessarily increase the stretching of the brachial plexus. The report also notes that traction applied in the plane of the fetal cervicothoracic spine typically is along a vector estimated to be 25° to 45° below the horizontal plane of a woman in lithotomy position, not in an exact straight line with the maternal trunk. This degree of delivery force below the horizon is defined as normal “axial traction.”

Exogenous forces have yet to be definitively measured
Multiple attempts have been made to quantify the amount of force applied by clinicians in various delivery scenarios. However, in the published studies in which this force has been “measured,” the accuracy of the findings has not been validated. The three studies in which delivery force was directly measured in a clinical setting “provide a limited assessment of exogenous forces” and “do not address the angle at which forces were applied.”^3–5 All other studies used artificial models.

As a result, few conclusions from such studies are directly applicable to the clinical arena. Moreover, in other studies using simulated birth scenarios, there was no feedback to participating clinicians as to whether the force they applied would have been sufficient to deliver the “fetus.” It was therefore difficult for participants in such studies to “determine how the situation corresponds with the force they would apply clinically.”¹

Cadaver studies have been inadequate to assess the in situ response of the brachial plexus
Many plaintiff claims regarding the cause of brachial plexus injury use cadaver studies as evidence. However, most such studies were conducted between 98 and 140 years ago. In these older studies, quantitative evaluation was rare. And in the few more recent studies, there are several reasons why the data obtained are problematic:

• the nerves being studied were dissected free from supporting tissues
• nerve tissue deteriorates quickly post­mortem
• some studies used adult tissues; there may be significant differences between adult and newborn nerve tissue that obscure comparison.

The ACOG report concludes the section on cadaver studies by stating:

Physical models also fall short
The problem with the use of physical models in evaluating NBPP centers on the need to find materials that have the same or similar properties as the tissues of interest. These sorts of bioengineering limitations generally do not allow for findings that have direct clinical applicability.

Of interest, however, is the finding of at least two groups of investigators that less traction is required when simulating delivery of a model infant when rotational maneuvers (Rubin’s) are employed rather than after McRoberts repositioning. 

Computer models have yielded data on the relative effects of endogenous and exogenous forces
Sophisticated computer analysis has been used to investigate both endogenous and ­exogenous delivery forces. Results of such studies have shown that maternal endo­genous forces exert twice as much pressure on the base of the fetal neck against the maternal symphysis pubis as do deliverer-­induced ­exogenous forces.

Is there a threshold of force?
Data that include measurement of the force applied to the brachial plexus nerves of a live infant during a real delivery are almost nonexistent. One group—on the basis of a single case of transient NBPP and potentially flawed pressure measurements—has suggested that the threshold for NBPP in the human is 100 Newtons.³ However, other studies have shown that physician-applied forces in routine deliveries commonly exceed this hypothesized cutoff—yet the rate of NBPP remains low. In measuring delivery forces it must be remembered that significant variation exists between individual neonates, both in terms of mechanical properties and anatomy. Because of this ­variation—and the nonlinear behavior of nerve tissues—the specific force needed to cause a nerve injury or rupture in a given neonate has not been established.

Chapter 3 of the ACOG report closes with a statement:

NBPP and shoulder dystocia
Shoulder dystocia is defined as a delivery that requires additional obstetric maneuvers after gentle downward traction on the fetal head fails to deliver the fetal shoulders. The ACOG report makes the important point that shoulder dystocia is not formally diagnosed until a trial of downward axial traction has been unsuccessful in delivering the anterior shoulder. This point is a refutation of the frequent plaintiff claim that, once a shoulder dystocia is thought to be present, no traction whatsoever should be applied by the clinician at any time during the remainder of the delivery.

Shoulder dystocia incidence is rising
The reported incidence of shoulder dystocia has increased over the past several decades. It is unclear whether this increase is related to maternal obesity, fetal macrosomia, or more widespread reporting. However, paradoxes exist in the relationship among risk factors, shoulder dystocia, and brachial plexus injury:

• although there is an increased incidence of shoulder dystocia with increased birth weight, the mean birth weight of neonates with recognized shoulder dystocia is not significantly higher than the mean birth weight of all term infants
• strategies to reduce NBPP by ­preventing shoulder dystocia—including early induction of labor and prophylactic use of McRoberts maneuver and suprapubic pressure—have not been effective in reducing the incidence of NBPP.

The ACOG report makes the statement: “Maternal and fetal factors associated with shoulder dystocia do not allow for reliable prediction of persistent NBPP.”¹

What is optimal management of shoulder dystocia?
The last obstetric part of the ACOG report takes as its focus the management of shoulder dystocia. It discusses the importance of communication among members of the delivery team and with the mother whose neonate is experiencing a shoulder dystocia. The report states:

This statement contrasts with claims frequently made by plaintiff medical expert witnesses that the woman experiencing a shoulder dystocia should absolutely cease from pushing.

In a section on team training, the report describes the delivery team’s priorities:

Studies evaluating process standardization, the use of checklists, teamwork training, crew resource management, and evidence-based medicine have shown that these tools improve neonatal and maternal outcomes.

Simulation training also has been shown to help reduce transient NBPP (see the box below for more on simulation programs for shoulder dystocia). Whether it also can lower the rate of permanent NBPP is unclear.¹

In the new ACOG report on neonatal brachial plexus injury, simulation training is discussed as one solution to the dilemma of how clinicians can gain experience in managing obstetric events that occur infrequently.¹ Simulation training also has the potential to improve teamwork, communication, and the situational awareness of the health-care team as a whole. Several studies over the past few years have shown that, in some units, the implementation of simulation training actually has decreased the number of cases of neonatal brachial plexus palsy (NBPP), compared with no simulation training.

For example, Draycott and colleagues explored the rate of neonatal injury associated with shoulder dystocia before and after implementation of a mandatory 1-day simulation training program at Southmead Hospital in Bristol, United Kingdom.² The program consisted of practice on a shoulder dystocia training mannequin and covered risk factors, recognition of shoulder dystocia, maneuvers, and documentation. The training used a stepwise approach, beginning with a call for help and continuing through McRoberts’ positioning, suprapubic pressure, and internal maneuvers such as delivery of the posterior arm (Figure).

There were 15,908 births in the pretraining period and 13,117 in the posttraining period, with shoulder dystocia rates comparable between the two periods. Not only did clinical management of shoulder dystocia improve after training, but there was a significant reduction in neonatal injury at birth after shoulder dystocia (30 injuries of 324 shoulder dystocia cases [9.3%] before training vs six injuries of 262 shoulder dystocia cases [2.3%] afterward).²

In another study of obstetric brachial plexus injury before and after implementation of simulation training for shoulder dystocia, Inglis and colleagues found a decline in the rate of such injury from 30% to 10.67% (P<.01).³ Shoulder dystocia training remained associated with reduced obstetric brachial plexus injury after logistic-regression analysis.³

Shoulder dystocia training is now recommended by the Joint Commission on Accreditation of Healthcare Organizations in the United States. However, in its report, ACOG concludes—despite studies from Draycott and colleagues and others—that, owing to “limited data,” “there remains no evidence that introduction of simulation can reduce the frequency of persistent NBPP.”¹

References

1. American College of Obstetricians and Gynecologists. Executive summary: neonatal brachial plexus palsy. Report of the American College of Obstetricians and Gynecologists’ Task Force on neonatal brachial plexus palsy. Obstet Gynecol. 2014;123(4):902–904.
2. Draycott TJ, Crofts FJ, Ash JP, et al. Improving neonatal outcome through practical shoulder dystocia training. Obstet Gynecol. 2008;112(1):14–20.
3. Inglis SR, Feier N, Chetiyaar JB, et al. Effects of shoulder dystocia training on the incidence of brachial plexus palsy. Am J Obstet Gynecol. 2011;204(4):322.e1–e6.

Delivery of the posterior arm
The report reaffirms the previous statement from the ACOG practice bulletin on shoulder dystocia, which asserts that no specific sequence of maneuvers for resolving shoulder dystocia has been shown to be superior to any other.⁶ It does note, however, that recent studies seem to demonstrate a benefit when delivery of the posterior arm is prioritized over the usual first-line maneuvers of McRoberts positioning and the application of suprapubic pressure. If confirmed, such findings may alter the standard of care for shoulder dystocia resolution and result in a change in ACOG recommendations.

Documentation may be enhanced by use of a checklist
The ACOG report stresses the importance of accurate, contemporaneous documentation of the management of shoulder dystocia, observing that checklists and documentation reminders help ensure the completeness and relevance of notes after shoulder dystocia deliveries and NBPP. ACOG has produced such a checklist, which can be found in the appendix of the report itself.1

How long before central neurologic injury occurs?
Another issue covered in the report is how long a clinician has to resolve a shoulder dystocia before central neurologic damage occurs. Studies have shown that permanent neurologic injury can occur as soon as 2 minutes after shoulder impaction, although the risk of acidosis or severe hypoxic-ischemic encephalopathy remains low until impaction has lasted at least 5 minutes.

Other issues covered in the report
The last chapters of the ACOG report focus on orthopedic aspects of brachial plexus injury, including diagnosis, treatment, and prognosis.

The report concludes with a glossary and three appendices:

• Royal College of Obstetricians and Gynecologists Green Top Guidebook #42 on shoulder dystocia
• ACOG Practice Bulletin #40 on shoulder dystocia
• ACOG Patient Safety Checklist #6 on the documentation of shoulder dystocia.

Why the ACOG report is foundational
The ACOG report on NBPP is an important and much-needed document. It includes a comprehensive review of the literature on brachial plexus injury and shoulder dystocia, written by nationally recognized experts in the field. Most important, it makes definitive statements that counteract false and dubious claims often made by the plaintiff bar in brachial plexus injury cases and provides evidence to back those statements.

The report:

• disproves the claim that “excessive” physician traction is the only etiology of brachial plexus injuries
• demonstrates that no differentiation can be made between the etiology of permanent versus temporary brachial plexus injuries
• describes how brachial plexus injuries can occur in the absence of physician traction or even of shoulder dystocia
• provides a summary of scientific information about brachial plexus injuries that will benefit obstetric clinicians
• provides a wealth of literature documentation that will enable physician defendants to counteract many of the claims plaintiffs and their expert witnesses make in brachial plexus injury cases.

The report is—and will remain—a foundational document in obstetrics for many years to come.

Share your thoughts on this article! Send your Letter to the Editor to [email protected].

Obstetricians are often blamed for causing neonatal brachial plexus palsy (NBPP). For that reason, understanding the true pathophysiology and causation of this birth-related entity is of extreme importance.

In Part 1 of this two-part series, I summarized findings from the new report on NBPP from the American College of Obstetricians and Gynecologists (ACOG), focusing on whether the phenomenon of shoulder dystocia and NBPP can be predicted or prevented.¹ Here, in Part 2, I focus on ACOG’s conclusions concerning pathophysiology and causation of NBPP, as well as the College’s recommendations for applying that knowledge to practice.

Some infants are more susceptible than others to the forces of labor and delivery
Babies emerge from the uterus and maternal pelvis by a combination of uterine ­contractions and maternal pushing (endogenous forces) aided by the traction forces applied by the birth attendant (exogenous forces). Research over the past 2 decades has shown that endogenous forces play a significant—if not dominant—role in the causation of NBPP.

Stretching and potential injury to the brachial plexus occur when the long axis of the fetus is pushed down the birth canal while either the maternal symphysis pubis or sacral promontory catches and holds either the anterior or posterior shoulder of the fetus, respectively. This conjunction of events generates a stretching force on the tissues that connect the fetal trunk and head—the neck—under which lies the brachial plexus. The same anatomic relationships and labor forces also vigorously compress the fetal neck against the maternal symphysis pubis or sacral promontory and may cause compression injury. Any traction applied by the clinician accentuates these stretching and pressure forces acting on the nerves of the brachial plexus.

How the neonate responds to these forces depends on the tensile strength of its tissues, the metabolic condition of the fetus after a potentially long labor (as measured by acid-base status), the degree of protective muscle tone around the fetal shoulder and neck, and other fluctuating conditions. In other words, because of the many variables involved, some fetuses are more or less susceptible to injury than others.

Maternal forces alone can cause NBPP
The ACOG report¹ makes an important statement:

Some plaintiff attorneys and their expert witnesses have tried to make the case that, although endogenous forces can cause temporary brachial plexus injuries, they cannot cause permanent brachial plexus injuries. However, as the ACOG report goes on to state:

The report acknowledges that the clinician can increase brachial plexus stretch by applying downward lateral traction to the neonate’s head during delivery efforts. However, contrary to claims often made by the plaintiff bar, in the presence of shoulder dystocia, even properly applied axial traction will necessarily increase the stretching of the brachial plexus. The report also notes that traction applied in the plane of the fetal cervicothoracic spine typically is along a vector estimated to be 25° to 45° below the horizontal plane of a woman in lithotomy position, not in an exact straight line with the maternal trunk. This degree of delivery force below the horizon is defined as normal “axial traction.”

Exogenous forces have yet to be definitively measured
Multiple attempts have been made to quantify the amount of force applied by clinicians in various delivery scenarios. However, in the published studies in which this force has been “measured,” the accuracy of the findings has not been validated. The three studies in which delivery force was directly measured in a clinical setting “provide a limited assessment of exogenous forces” and “do not address the angle at which forces were applied.”^3–5 All other studies used artificial models.

As a result, few conclusions from such studies are directly applicable to the clinical arena. Moreover, in other studies using simulated birth scenarios, there was no feedback to participating clinicians as to whether the force they applied would have been sufficient to deliver the “fetus.” It was therefore difficult for participants in such studies to “determine how the situation corresponds with the force they would apply clinically.”¹

Cadaver studies have been inadequate to assess the in situ response of the brachial plexus
Many plaintiff claims regarding the cause of brachial plexus injury use cadaver studies as evidence. However, most such studies were conducted between 98 and 140 years ago. In these older studies, quantitative evaluation was rare. And in the few more recent studies, there are several reasons why the data obtained are problematic:

• the nerves being studied were dissected free from supporting tissues
• nerve tissue deteriorates quickly post­mortem
• some studies used adult tissues; there may be significant differences between adult and newborn nerve tissue that obscure comparison.

The ACOG report concludes the section on cadaver studies by stating:

Physical models also fall short
The problem with the use of physical models in evaluating NBPP centers on the need to find materials that have the same or similar properties as the tissues of interest. These sorts of bioengineering limitations generally do not allow for findings that have direct clinical applicability.

Of interest, however, is the finding of at least two groups of investigators that less traction is required when simulating delivery of a model infant when rotational maneuvers (Rubin’s) are employed rather than after McRoberts repositioning. 

Computer models have yielded data on the relative effects of endogenous and exogenous forces
Sophisticated computer analysis has been used to investigate both endogenous and ­exogenous delivery forces. Results of such studies have shown that maternal endo­genous forces exert twice as much pressure on the base of the fetal neck against the maternal symphysis pubis as do deliverer-­induced ­exogenous forces.

Is there a threshold of force?
Data that include measurement of the force applied to the brachial plexus nerves of a live infant during a real delivery are almost nonexistent. One group—on the basis of a single case of transient NBPP and potentially flawed pressure measurements—has suggested that the threshold for NBPP in the human is 100 Newtons.³ However, other studies have shown that physician-applied forces in routine deliveries commonly exceed this hypothesized cutoff—yet the rate of NBPP remains low. In measuring delivery forces it must be remembered that significant variation exists between individual neonates, both in terms of mechanical properties and anatomy. Because of this ­variation—and the nonlinear behavior of nerve tissues—the specific force needed to cause a nerve injury or rupture in a given neonate has not been established.

Chapter 3 of the ACOG report closes with a statement:

NBPP and shoulder dystocia
Shoulder dystocia is defined as a delivery that requires additional obstetric maneuvers after gentle downward traction on the fetal head fails to deliver the fetal shoulders. The ACOG report makes the important point that shoulder dystocia is not formally diagnosed until a trial of downward axial traction has been unsuccessful in delivering the anterior shoulder. This point is a refutation of the frequent plaintiff claim that, once a shoulder dystocia is thought to be present, no traction whatsoever should be applied by the clinician at any time during the remainder of the delivery.

Shoulder dystocia incidence is rising
The reported incidence of shoulder dystocia has increased over the past several decades. It is unclear whether this increase is related to maternal obesity, fetal macrosomia, or more widespread reporting. However, paradoxes exist in the relationship among risk factors, shoulder dystocia, and brachial plexus injury:

• although there is an increased incidence of shoulder dystocia with increased birth weight, the mean birth weight of neonates with recognized shoulder dystocia is not significantly higher than the mean birth weight of all term infants
• strategies to reduce NBPP by ­preventing shoulder dystocia—including early induction of labor and prophylactic use of McRoberts maneuver and suprapubic pressure—have not been effective in reducing the incidence of NBPP.

The ACOG report makes the statement: “Maternal and fetal factors associated with shoulder dystocia do not allow for reliable prediction of persistent NBPP.”¹

What is optimal management of shoulder dystocia?
The last obstetric part of the ACOG report takes as its focus the management of shoulder dystocia. It discusses the importance of communication among members of the delivery team and with the mother whose neonate is experiencing a shoulder dystocia. The report states:

This statement contrasts with claims frequently made by plaintiff medical expert witnesses that the woman experiencing a shoulder dystocia should absolutely cease from pushing.

In a section on team training, the report describes the delivery team’s priorities:

Studies evaluating process standardization, the use of checklists, teamwork training, crew resource management, and evidence-based medicine have shown that these tools improve neonatal and maternal outcomes.

Simulation training also has been shown to help reduce transient NBPP (see the box below for more on simulation programs for shoulder dystocia). Whether it also can lower the rate of permanent NBPP is unclear.¹

In the new ACOG report on neonatal brachial plexus injury, simulation training is discussed as one solution to the dilemma of how clinicians can gain experience in managing obstetric events that occur infrequently.¹ Simulation training also has the potential to improve teamwork, communication, and the situational awareness of the health-care team as a whole. Several studies over the past few years have shown that, in some units, the implementation of simulation training actually has decreased the number of cases of neonatal brachial plexus palsy (NBPP), compared with no simulation training.

For example, Draycott and colleagues explored the rate of neonatal injury associated with shoulder dystocia before and after implementation of a mandatory 1-day simulation training program at Southmead Hospital in Bristol, United Kingdom.² The program consisted of practice on a shoulder dystocia training mannequin and covered risk factors, recognition of shoulder dystocia, maneuvers, and documentation. The training used a stepwise approach, beginning with a call for help and continuing through McRoberts’ positioning, suprapubic pressure, and internal maneuvers such as delivery of the posterior arm (Figure).

There were 15,908 births in the pretraining period and 13,117 in the posttraining period, with shoulder dystocia rates comparable between the two periods. Not only did clinical management of shoulder dystocia improve after training, but there was a significant reduction in neonatal injury at birth after shoulder dystocia (30 injuries of 324 shoulder dystocia cases [9.3%] before training vs six injuries of 262 shoulder dystocia cases [2.3%] afterward).²

In another study of obstetric brachial plexus injury before and after implementation of simulation training for shoulder dystocia, Inglis and colleagues found a decline in the rate of such injury from 30% to 10.67% (P<.01).³ Shoulder dystocia training remained associated with reduced obstetric brachial plexus injury after logistic-regression analysis.³

Shoulder dystocia training is now recommended by the Joint Commission on Accreditation of Healthcare Organizations in the United States. However, in its report, ACOG concludes—despite studies from Draycott and colleagues and others—that, owing to “limited data,” “there remains no evidence that introduction of simulation can reduce the frequency of persistent NBPP.”¹

References

1. American College of Obstetricians and Gynecologists. Executive summary: neonatal brachial plexus palsy. Report of the American College of Obstetricians and Gynecologists’ Task Force on neonatal brachial plexus palsy. Obstet Gynecol. 2014;123(4):902–904.
2. Draycott TJ, Crofts FJ, Ash JP, et al. Improving neonatal outcome through practical shoulder dystocia training. Obstet Gynecol. 2008;112(1):14–20.
3. Inglis SR, Feier N, Chetiyaar JB, et al. Effects of shoulder dystocia training on the incidence of brachial plexus palsy. Am J Obstet Gynecol. 2011;204(4):322.e1–e6.

Delivery of the posterior arm
The report reaffirms the previous statement from the ACOG practice bulletin on shoulder dystocia, which asserts that no specific sequence of maneuvers for resolving shoulder dystocia has been shown to be superior to any other.⁶ It does note, however, that recent studies seem to demonstrate a benefit when delivery of the posterior arm is prioritized over the usual first-line maneuvers of McRoberts positioning and the application of suprapubic pressure. If confirmed, such findings may alter the standard of care for shoulder dystocia resolution and result in a change in ACOG recommendations.

Documentation may be enhanced by use of a checklist
The ACOG report stresses the importance of accurate, contemporaneous documentation of the management of shoulder dystocia, observing that checklists and documentation reminders help ensure the completeness and relevance of notes after shoulder dystocia deliveries and NBPP. ACOG has produced such a checklist, which can be found in the appendix of the report itself.1

How long before central neurologic injury occurs?
Another issue covered in the report is how long a clinician has to resolve a shoulder dystocia before central neurologic damage occurs. Studies have shown that permanent neurologic injury can occur as soon as 2 minutes after shoulder impaction, although the risk of acidosis or severe hypoxic-ischemic encephalopathy remains low until impaction has lasted at least 5 minutes.

Other issues covered in the report
The last chapters of the ACOG report focus on orthopedic aspects of brachial plexus injury, including diagnosis, treatment, and prognosis.

The report concludes with a glossary and three appendices:

• Royal College of Obstetricians and Gynecologists Green Top Guidebook #42 on shoulder dystocia
• ACOG Practice Bulletin #40 on shoulder dystocia
• ACOG Patient Safety Checklist #6 on the documentation of shoulder dystocia.

Why the ACOG report is foundational
The ACOG report on NBPP is an important and much-needed document. It includes a comprehensive review of the literature on brachial plexus injury and shoulder dystocia, written by nationally recognized experts in the field. Most important, it makes definitive statements that counteract false and dubious claims often made by the plaintiff bar in brachial plexus injury cases and provides evidence to back those statements.

The report:

• disproves the claim that “excessive” physician traction is the only etiology of brachial plexus injuries
• demonstrates that no differentiation can be made between the etiology of permanent versus temporary brachial plexus injuries
• describes how brachial plexus injuries can occur in the absence of physician traction or even of shoulder dystocia
• provides a summary of scientific information about brachial plexus injuries that will benefit obstetric clinicians
• provides a wealth of literature documentation that will enable physician defendants to counteract many of the claims plaintiffs and their expert witnesses make in brachial plexus injury cases.

The report is—and will remain—a foundational document in obstetrics for many years to come.

Share your thoughts on this article! Send your Letter to the Editor to [email protected].

In a casual conversation I was having with a marriage counselor, he mentioned that a growing number of young couples are struggling with impotence. The main cause is watching too much pornography.

Now, it is no surprise that adolescents would watch pornography. Since the dawn of time young men have been seeking arousal from pornographic images. With the advent of the Internet, the availability and variety of images is endless. Teens are able to access pornography on their phones, tablets, computers, and cable. It’s next to impossible for parents to block all access because every adolescent has one form of technology or another; if he doesn’t have access at home, it surely can be seen at a friend’s house.

The physiologic effect of pornography is an excessive release of dopamine that binds to dopamine receptors and causes a maximal state of arousal. These receptors over time become less and less sensitive, so when these young men engage in intercourse, the stimulation is much less, and they are unable to have an erection. Many men do not make the connection between the pornography and their erectile dysfunction, so they may go years without seeking help.

There is a growing trend among younger men to use Viagra and Cialis, according to statistics (Int. J. Impot. Res. 2004;16:313-8). Most are using them for sexual enhancement, but others are seeking them for performance anxiety which may be related to their dysfunction associated with pornography. The problem is, pornography-induced erectile dysfunction is not an issue of blood flow, so these drugs are not helpful in most cases. Since the issue is the sensitivity of the dopamine receptors, the only treatment is to reduce or stop watching pornography, thus allowing the dopamine receptors to become more sensitive.

Now, as a physician, this clearly is an awkward topic to bring up during a routine health physical. But if left unsaid, this behavior could clearly lead to years of dysfunction. What I have found to be a simple solution to the “not so popular topics” is to present a handout with a topic simply stated and easy to read. This allows you to give patients the information without the embarrassment. The purpose is just to identify what is normal and what is not so normal so a patient knows to seek help if the problem occurs. Quick fixes also should be listed if known, especially if the quick fix is just to stop the behavior.

Other topics – such as bacterial vaginosis, the morning after pill, acne, and gynecomastia – can be addressed similarly because teens don’t know what they don’t know, so they may not even consider asking. Many women don’t realize that bacterial vaginosis requires a prescription medication and so may remain symptomatic for long periods of time.

Education is key. As pediatricians, arming our patients with knowledge allows them to at least ask the appropriate questions, which hopefully will get them the right answer.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected].

In a casual conversation I was having with a marriage counselor, he mentioned that a growing number of young couples are struggling with impotence. The main cause is watching too much pornography.

Now, it is no surprise that adolescents would watch pornography. Since the dawn of time young men have been seeking arousal from pornographic images. With the advent of the Internet, the availability and variety of images is endless. Teens are able to access pornography on their phones, tablets, computers, and cable. It’s next to impossible for parents to block all access because every adolescent has one form of technology or another; if he doesn’t have access at home, it surely can be seen at a friend’s house.

The physiologic effect of pornography is an excessive release of dopamine that binds to dopamine receptors and causes a maximal state of arousal. These receptors over time become less and less sensitive, so when these young men engage in intercourse, the stimulation is much less, and they are unable to have an erection. Many men do not make the connection between the pornography and their erectile dysfunction, so they may go years without seeking help.

There is a growing trend among younger men to use Viagra and Cialis, according to statistics (Int. J. Impot. Res. 2004;16:313-8). Most are using them for sexual enhancement, but others are seeking them for performance anxiety which may be related to their dysfunction associated with pornography. The problem is, pornography-induced erectile dysfunction is not an issue of blood flow, so these drugs are not helpful in most cases. Since the issue is the sensitivity of the dopamine receptors, the only treatment is to reduce or stop watching pornography, thus allowing the dopamine receptors to become more sensitive.

Now, as a physician, this clearly is an awkward topic to bring up during a routine health physical. But if left unsaid, this behavior could clearly lead to years of dysfunction. What I have found to be a simple solution to the “not so popular topics” is to present a handout with a topic simply stated and easy to read. This allows you to give patients the information without the embarrassment. The purpose is just to identify what is normal and what is not so normal so a patient knows to seek help if the problem occurs. Quick fixes also should be listed if known, especially if the quick fix is just to stop the behavior.

Other topics – such as bacterial vaginosis, the morning after pill, acne, and gynecomastia – can be addressed similarly because teens don’t know what they don’t know, so they may not even consider asking. Many women don’t realize that bacterial vaginosis requires a prescription medication and so may remain symptomatic for long periods of time.

Education is key. As pediatricians, arming our patients with knowledge allows them to at least ask the appropriate questions, which hopefully will get them the right answer.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected].

In a casual conversation I was having with a marriage counselor, he mentioned that a growing number of young couples are struggling with impotence. The main cause is watching too much pornography.

Now, it is no surprise that adolescents would watch pornography. Since the dawn of time young men have been seeking arousal from pornographic images. With the advent of the Internet, the availability and variety of images is endless. Teens are able to access pornography on their phones, tablets, computers, and cable. It’s next to impossible for parents to block all access because every adolescent has one form of technology or another; if he doesn’t have access at home, it surely can be seen at a friend’s house.

The physiologic effect of pornography is an excessive release of dopamine that binds to dopamine receptors and causes a maximal state of arousal. These receptors over time become less and less sensitive, so when these young men engage in intercourse, the stimulation is much less, and they are unable to have an erection. Many men do not make the connection between the pornography and their erectile dysfunction, so they may go years without seeking help.

There is a growing trend among younger men to use Viagra and Cialis, according to statistics (Int. J. Impot. Res. 2004;16:313-8). Most are using them for sexual enhancement, but others are seeking them for performance anxiety which may be related to their dysfunction associated with pornography. The problem is, pornography-induced erectile dysfunction is not an issue of blood flow, so these drugs are not helpful in most cases. Since the issue is the sensitivity of the dopamine receptors, the only treatment is to reduce or stop watching pornography, thus allowing the dopamine receptors to become more sensitive.

Now, as a physician, this clearly is an awkward topic to bring up during a routine health physical. But if left unsaid, this behavior could clearly lead to years of dysfunction. What I have found to be a simple solution to the “not so popular topics” is to present a handout with a topic simply stated and easy to read. This allows you to give patients the information without the embarrassment. The purpose is just to identify what is normal and what is not so normal so a patient knows to seek help if the problem occurs. Quick fixes also should be listed if known, especially if the quick fix is just to stop the behavior.

Other topics – such as bacterial vaginosis, the morning after pill, acne, and gynecomastia – can be addressed similarly because teens don’t know what they don’t know, so they may not even consider asking. Many women don’t realize that bacterial vaginosis requires a prescription medication and so may remain symptomatic for long periods of time.

Education is key. As pediatricians, arming our patients with knowledge allows them to at least ask the appropriate questions, which hopefully will get them the right answer.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected].

Among the items featured in Dr David Henry’s monthly podcast for The Journal of Community and Supportive Oncology, is a report on bacteremia in adult cancer patients with apparently stable febrile neutropenia and another on practice gaps and barriers optimal care in patients with CML, ALL, or B-cell lymphomas. Also featured is a report on treatment patterns and clinical effectiveness in patients who are treated in the community setting for metastatic castrate-resistant prostate cancer after first-line docetaxel, as well as a Case Report on a patient with metastatic melanoma presenting as disseminated sporotrichosis.

Among the items featured in Dr David Henry’s monthly podcast for The Journal of Community and Supportive Oncology, is a report on bacteremia in adult cancer patients with apparently stable febrile neutropenia and another on practice gaps and barriers optimal care in patients with CML, ALL, or B-cell lymphomas. Also featured is a report on treatment patterns and clinical effectiveness in patients who are treated in the community setting for metastatic castrate-resistant prostate cancer after first-line docetaxel, as well as a Case Report on a patient with metastatic melanoma presenting as disseminated sporotrichosis.

Among the items featured in Dr David Henry’s monthly podcast for The Journal of Community and Supportive Oncology, is a report on bacteremia in adult cancer patients with apparently stable febrile neutropenia and another on practice gaps and barriers optimal care in patients with CML, ALL, or B-cell lymphomas. Also featured is a report on treatment patterns and clinical effectiveness in patients who are treated in the community setting for metastatic castrate-resistant prostate cancer after first-line docetaxel, as well as a Case Report on a patient with metastatic melanoma presenting as disseminated sporotrichosis.

MADRID – The final overall survival analysis of the CLEOPATRA trial showed an unprecedented 15.7-month increase in overall survival for women with HER2-positive metastatic breast cancer.

The results were achieved by adding pertuzumab to first-line trastuzumab and docetaxel chemotherapy (56.5 months vs. 40.8 months; hazard ratio, 0.68; P = .0002).

Importantly, the survival improvement came without excessive toxicity, including cardiac events, lead author Dr. Sandra Swain reported during a presidential symposium at the European Society for Medical Oncology Congress.

The results, now with a median follow-up of 50 months, build on those previously reported from CLEOPATRA, showing a survival trend favoring the combination of two targeted agents with chemotherapy in the first interim analysis and a statistically significant overall survival advantage at 30 months in a second interim analysis.

In a video interview at the meeting, Dr. Swain, medical director of the Washington Cancer Institute, Medstar Washington Hospital Center, discusses the results and their implications for care.

[email protected]

MADRID – The final overall survival analysis of the CLEOPATRA trial showed an unprecedented 15.7-month increase in overall survival for women with HER2-positive metastatic breast cancer.

The results were achieved by adding pertuzumab to first-line trastuzumab and docetaxel chemotherapy (56.5 months vs. 40.8 months; hazard ratio, 0.68; P = .0002).

Importantly, the survival improvement came without excessive toxicity, including cardiac events, lead author Dr. Sandra Swain reported during a presidential symposium at the European Society for Medical Oncology Congress.

The results, now with a median follow-up of 50 months, build on those previously reported from CLEOPATRA, showing a survival trend favoring the combination of two targeted agents with chemotherapy in the first interim analysis and a statistically significant overall survival advantage at 30 months in a second interim analysis.

In a video interview at the meeting, Dr. Swain, medical director of the Washington Cancer Institute, Medstar Washington Hospital Center, discusses the results and their implications for care.

[email protected]

MADRID – The final overall survival analysis of the CLEOPATRA trial showed an unprecedented 15.7-month increase in overall survival for women with HER2-positive metastatic breast cancer.

The results were achieved by adding pertuzumab to first-line trastuzumab and docetaxel chemotherapy (56.5 months vs. 40.8 months; hazard ratio, 0.68; P = .0002).

Importantly, the survival improvement came without excessive toxicity, including cardiac events, lead author Dr. Sandra Swain reported during a presidential symposium at the European Society for Medical Oncology Congress.

The results, now with a median follow-up of 50 months, build on those previously reported from CLEOPATRA, showing a survival trend favoring the combination of two targeted agents with chemotherapy in the first interim analysis and a statistically significant overall survival advantage at 30 months in a second interim analysis.

In a video interview at the meeting, Dr. Swain, medical director of the Washington Cancer Institute, Medstar Washington Hospital Center, discusses the results and their implications for care.

[email protected]

Doctor and patient

Credit: NIH

MADRID—Follow-up data from a phase 1 trial suggest brentuximab vedotin plus chemotherapy may be a feasible frontline option for patients with peripheral T-cell lymphoma (PTCL).

At the ESMO 2014 Congress, investigators presented a 2-year durability analysis from a trial of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (BV+CHP) in patients newly diagnosed with PTCL.

The estimated 2-year overall survival rate was 80% in these patients. And the median progression-free survival was not reached.

Michelle Fanale, MD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these results as abstract 944O.

The research was sponsored by Seattle Genetics Inc. and Takeda Pharmaceuticals International, the companies co-developing brentuximab vedotin (Adcetris).

In this trial, patients received 1 of 2 treatment regimens. The first was sequential treatment (once every 3 weeks) with brentuximab vedotin at 1.8 mg/kg for 2 cycles, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for 6 cycles.

The second was combination BV+CHP every 3 weeks for 6 cycles. Patients who achieved at least a partial response after 6 cycles of treatment were eligible to receive continued single-agent brentuximab vedotin for up to 10 additional 3-week cycles.

Earlier results with both treatment regimens were published in the Journal of Clinical Oncology. At ESMO, Dr Fanale presented 2-year results among the 26 patients who received BV+CHP.

The median patient age was 56 years. Nineteen patients had systemic anaplastic large-cell lymphoma (sALCL), including 16 patients (62%) with ALK-negative disease.

Two patients had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma. The majority of patients had advanced-stage disease and/or were considered high risk.

All 26 patients had an objective response to BV+CHP, including 23 patients (88%) with a complete response. All 23 patients who achieved a complete remission demonstrated normalized glucose uptake by PET.

The median observation time was 27.1 months from the first dose of therapy. The estimated 2-year progression-free survival rate was 54%, with no patients receiving a consolidative stem cell transplant. And the estimated 2-year overall survival rate was 80%.

The most common treatment-emergent adverse events of any grade occurring in more than 40% of patients were peripheral sensory neuropathy, nausea, fatigue, hair loss, diarrhea, and shortness of breath.

Based on the results of this study, Seattle Genetics and Takeda initiated a global phase 3 study called ECHELON-2. This randomized, double-blind, placebo-controlled, multicenter trial was designed to investigate BV+CHP vs CHOP as frontline therapy in patients with CD30-positive PTCL.

The study is currently enrolling patients. It is expected to enroll 300 patients, who will be randomized to receive either treatment every 3 weeks for 6 to 8 cycles.

Doctor and patient

Credit: NIH

MADRID—Follow-up data from a phase 1 trial suggest brentuximab vedotin plus chemotherapy may be a feasible frontline option for patients with peripheral T-cell lymphoma (PTCL).

At the ESMO 2014 Congress, investigators presented a 2-year durability analysis from a trial of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (BV+CHP) in patients newly diagnosed with PTCL.

The estimated 2-year overall survival rate was 80% in these patients. And the median progression-free survival was not reached.

Michelle Fanale, MD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these results as abstract 944O.

The research was sponsored by Seattle Genetics Inc. and Takeda Pharmaceuticals International, the companies co-developing brentuximab vedotin (Adcetris).

In this trial, patients received 1 of 2 treatment regimens. The first was sequential treatment (once every 3 weeks) with brentuximab vedotin at 1.8 mg/kg for 2 cycles, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for 6 cycles.

The second was combination BV+CHP every 3 weeks for 6 cycles. Patients who achieved at least a partial response after 6 cycles of treatment were eligible to receive continued single-agent brentuximab vedotin for up to 10 additional 3-week cycles.

Earlier results with both treatment regimens were published in the Journal of Clinical Oncology. At ESMO, Dr Fanale presented 2-year results among the 26 patients who received BV+CHP.

The median patient age was 56 years. Nineteen patients had systemic anaplastic large-cell lymphoma (sALCL), including 16 patients (62%) with ALK-negative disease.

Two patients had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma. The majority of patients had advanced-stage disease and/or were considered high risk.

All 26 patients had an objective response to BV+CHP, including 23 patients (88%) with a complete response. All 23 patients who achieved a complete remission demonstrated normalized glucose uptake by PET.

The median observation time was 27.1 months from the first dose of therapy. The estimated 2-year progression-free survival rate was 54%, with no patients receiving a consolidative stem cell transplant. And the estimated 2-year overall survival rate was 80%.

The most common treatment-emergent adverse events of any grade occurring in more than 40% of patients were peripheral sensory neuropathy, nausea, fatigue, hair loss, diarrhea, and shortness of breath.

Based on the results of this study, Seattle Genetics and Takeda initiated a global phase 3 study called ECHELON-2. This randomized, double-blind, placebo-controlled, multicenter trial was designed to investigate BV+CHP vs CHOP as frontline therapy in patients with CD30-positive PTCL.

The study is currently enrolling patients. It is expected to enroll 300 patients, who will be randomized to receive either treatment every 3 weeks for 6 to 8 cycles.

Doctor and patient

Credit: NIH

MADRID—Follow-up data from a phase 1 trial suggest brentuximab vedotin plus chemotherapy may be a feasible frontline option for patients with peripheral T-cell lymphoma (PTCL).

At the ESMO 2014 Congress, investigators presented a 2-year durability analysis from a trial of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (BV+CHP) in patients newly diagnosed with PTCL.

The estimated 2-year overall survival rate was 80% in these patients. And the median progression-free survival was not reached.

Michelle Fanale, MD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these results as abstract 944O.

The research was sponsored by Seattle Genetics Inc. and Takeda Pharmaceuticals International, the companies co-developing brentuximab vedotin (Adcetris).

In this trial, patients received 1 of 2 treatment regimens. The first was sequential treatment (once every 3 weeks) with brentuximab vedotin at 1.8 mg/kg for 2 cycles, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for 6 cycles.

The second was combination BV+CHP every 3 weeks for 6 cycles. Patients who achieved at least a partial response after 6 cycles of treatment were eligible to receive continued single-agent brentuximab vedotin for up to 10 additional 3-week cycles.

Earlier results with both treatment regimens were published in the Journal of Clinical Oncology. At ESMO, Dr Fanale presented 2-year results among the 26 patients who received BV+CHP.

The median patient age was 56 years. Nineteen patients had systemic anaplastic large-cell lymphoma (sALCL), including 16 patients (62%) with ALK-negative disease.

Two patients had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma. The majority of patients had advanced-stage disease and/or were considered high risk.

All 26 patients had an objective response to BV+CHP, including 23 patients (88%) with a complete response. All 23 patients who achieved a complete remission demonstrated normalized glucose uptake by PET.

The median observation time was 27.1 months from the first dose of therapy. The estimated 2-year progression-free survival rate was 54%, with no patients receiving a consolidative stem cell transplant. And the estimated 2-year overall survival rate was 80%.

The most common treatment-emergent adverse events of any grade occurring in more than 40% of patients were peripheral sensory neuropathy, nausea, fatigue, hair loss, diarrhea, and shortness of breath.

Based on the results of this study, Seattle Genetics and Takeda initiated a global phase 3 study called ECHELON-2. This randomized, double-blind, placebo-controlled, multicenter trial was designed to investigate BV+CHP vs CHOP as frontline therapy in patients with CD30-positive PTCL.

The study is currently enrolling patients. It is expected to enroll 300 patients, who will be randomized to receive either treatment every 3 weeks for 6 to 8 cycles.

Patient receives chemotherapy

Credit: Rhoda Baer

MADRID—A small molecule called rolapitant can prevent nausea and vomiting in patients receiving cisplatin-based chemotherapy, results of a phase 3 trial suggest.

When given prior to chemotherapy, rolapitant induced a complete response in about 70% of patients.

These patients had no emesis after chemotherapy and did not require any rescue medication.

“This agent makes a significant difference in the way people tolerate their chemotherapy,” said Martin Chasen, MD, of Ottawa Hospital Cancer Centre in Canada.

“Patients experienced no loss in quality of life, and, in fact, many saw meaningful improvements. One of the patients in the rolapitant cohort reported that he had just finished 18 holes of golf one week after receiving chemotherapy. This is in sharp contrast to many patients on current standard anti-emetics that are too ill to get out of bed within a week after each cycle of cisplatin.”

Dr Chasen and his colleagues reported these results at the ESMO 2014 Congress (abstract LBA47_PR).

The team had set out to evaluate rolapitant, a novel antagonist of the NK-1 receptor, for the prevention of severe nausea and vomiting often experienced by patients receiving cisplatin-based chemotherapy, which may cause dose reductions and treatment discontinuation.

The trial included 532 patients who were randomized 1:1 to receive rolapitant plus granisetron/dexamethasone or placebo plus granisetron/dexamethasone prior to chemotherapy.

The primary endpoint was complete response (defined as the patient having no emesis and not requiring any rescue medication) in the delayed phase (>24-120 hours) post-chemotherapy. Key secondary endpoints included complete response during the acute phase (0-24 hours) and overall (0-120 hours).

The trial met its primary endpoint, with 72.7% of patients receiving rolapitant achieving a complete response in the delayed phase, compared to 58.4% of those receiving placebo (P<0.001).

Rolapitant also improved the complete response rate compared to placebo in the acute phase—83.7% and 73.7%, respectively (P=0.005).

Overall, the complete response rates were 70.1% and 56.5%, respectively (P=0.001).

Patients receiving rolapitant tended to report that chemotherapy had less of an impact on their daily quality of life, although the difference between the treatment arms was not significant—72.8% vs 67.8% (P=0.231).

“Rolapitant demonstrated a significant effect in both the acute and delayed phases,” Dr Chasen noted. “Our primary endpoint was achieved in the delayed phase—an incredible result.”

“We know that the NK-1 receptor in the brain must be blocked to control nausea and vomiting. Rolapitant is an exceptionally long-term receptor blocker that binds to the receptor and remains in place for up to 120 hours, therefore not allowing the chemotherapy to induce nausea and vomiting.”

Dr Chasen added that rolapitant may prove effective in patients receiving less emetogenic cancer treatments as well.

Patient receives chemotherapy

Credit: Rhoda Baer

MADRID—A small molecule called rolapitant can prevent nausea and vomiting in patients receiving cisplatin-based chemotherapy, results of a phase 3 trial suggest.

When given prior to chemotherapy, rolapitant induced a complete response in about 70% of patients.

These patients had no emesis after chemotherapy and did not require any rescue medication.

“This agent makes a significant difference in the way people tolerate their chemotherapy,” said Martin Chasen, MD, of Ottawa Hospital Cancer Centre in Canada.

“Patients experienced no loss in quality of life, and, in fact, many saw meaningful improvements. One of the patients in the rolapitant cohort reported that he had just finished 18 holes of golf one week after receiving chemotherapy. This is in sharp contrast to many patients on current standard anti-emetics that are too ill to get out of bed within a week after each cycle of cisplatin.”

Dr Chasen and his colleagues reported these results at the ESMO 2014 Congress (abstract LBA47_PR).

The team had set out to evaluate rolapitant, a novel antagonist of the NK-1 receptor, for the prevention of severe nausea and vomiting often experienced by patients receiving cisplatin-based chemotherapy, which may cause dose reductions and treatment discontinuation.

The trial included 532 patients who were randomized 1:1 to receive rolapitant plus granisetron/dexamethasone or placebo plus granisetron/dexamethasone prior to chemotherapy.

The primary endpoint was complete response (defined as the patient having no emesis and not requiring any rescue medication) in the delayed phase (>24-120 hours) post-chemotherapy. Key secondary endpoints included complete response during the acute phase (0-24 hours) and overall (0-120 hours).

The trial met its primary endpoint, with 72.7% of patients receiving rolapitant achieving a complete response in the delayed phase, compared to 58.4% of those receiving placebo (P<0.001).

Rolapitant also improved the complete response rate compared to placebo in the acute phase—83.7% and 73.7%, respectively (P=0.005).

Overall, the complete response rates were 70.1% and 56.5%, respectively (P=0.001).

Patients receiving rolapitant tended to report that chemotherapy had less of an impact on their daily quality of life, although the difference between the treatment arms was not significant—72.8% vs 67.8% (P=0.231).

“Rolapitant demonstrated a significant effect in both the acute and delayed phases,” Dr Chasen noted. “Our primary endpoint was achieved in the delayed phase—an incredible result.”

“We know that the NK-1 receptor in the brain must be blocked to control nausea and vomiting. Rolapitant is an exceptionally long-term receptor blocker that binds to the receptor and remains in place for up to 120 hours, therefore not allowing the chemotherapy to induce nausea and vomiting.”

Dr Chasen added that rolapitant may prove effective in patients receiving less emetogenic cancer treatments as well.

Patient receives chemotherapy

Credit: Rhoda Baer

MADRID—A small molecule called rolapitant can prevent nausea and vomiting in patients receiving cisplatin-based chemotherapy, results of a phase 3 trial suggest.

When given prior to chemotherapy, rolapitant induced a complete response in about 70% of patients.

These patients had no emesis after chemotherapy and did not require any rescue medication.

“This agent makes a significant difference in the way people tolerate their chemotherapy,” said Martin Chasen, MD, of Ottawa Hospital Cancer Centre in Canada.

“Patients experienced no loss in quality of life, and, in fact, many saw meaningful improvements. One of the patients in the rolapitant cohort reported that he had just finished 18 holes of golf one week after receiving chemotherapy. This is in sharp contrast to many patients on current standard anti-emetics that are too ill to get out of bed within a week after each cycle of cisplatin.”

Dr Chasen and his colleagues reported these results at the ESMO 2014 Congress (abstract LBA47_PR).

The team had set out to evaluate rolapitant, a novel antagonist of the NK-1 receptor, for the prevention of severe nausea and vomiting often experienced by patients receiving cisplatin-based chemotherapy, which may cause dose reductions and treatment discontinuation.

The trial included 532 patients who were randomized 1:1 to receive rolapitant plus granisetron/dexamethasone or placebo plus granisetron/dexamethasone prior to chemotherapy.

The primary endpoint was complete response (defined as the patient having no emesis and not requiring any rescue medication) in the delayed phase (>24-120 hours) post-chemotherapy. Key secondary endpoints included complete response during the acute phase (0-24 hours) and overall (0-120 hours).

The trial met its primary endpoint, with 72.7% of patients receiving rolapitant achieving a complete response in the delayed phase, compared to 58.4% of those receiving placebo (P<0.001).

Rolapitant also improved the complete response rate compared to placebo in the acute phase—83.7% and 73.7%, respectively (P=0.005).

Overall, the complete response rates were 70.1% and 56.5%, respectively (P=0.001).

Patients receiving rolapitant tended to report that chemotherapy had less of an impact on their daily quality of life, although the difference between the treatment arms was not significant—72.8% vs 67.8% (P=0.231).

“Rolapitant demonstrated a significant effect in both the acute and delayed phases,” Dr Chasen noted. “Our primary endpoint was achieved in the delayed phase—an incredible result.”

“We know that the NK-1 receptor in the brain must be blocked to control nausea and vomiting. Rolapitant is an exceptionally long-term receptor blocker that binds to the receptor and remains in place for up to 120 hours, therefore not allowing the chemotherapy to induce nausea and vomiting.”

Dr Chasen added that rolapitant may prove effective in patients receiving less emetogenic cancer treatments as well.

Megakaryocytes

in the bone marrow

Scientists say they’ve shed new light on the mechanism of platelet formation, paving the way to accelerating and enhancing platelet production using stem cells.

The group uncovered their findings by studying the effects of shear stress on megakaryocyte maturation and the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.

“Until recently, these microparticles were viewed as inconsequential cell debris,” said Terry Papoutsakis, PhD, of the University of Delaware in Newark.

“We now know that they play a significant biological role in platelet formation. The enhanced generation of preplatelets and platelet-like particles under shear stress correlates with physiological observations—in healthy adults, both acute and prolonged exercise leads to elevated platelet counts.”

“Now, these findings can be used to develop better bioreactor technologies for producing platelets, preplatelets, platelet-like particles, and megakaryocyte microparticles for transfusion medicine, using stem cells as starting material.”

Dr Papoutsakis and his colleagues described these findings in Blood.

The researchers discovered that shear stress accelerated DNA synthesis of immature megakaryocytes, and this was dependent upon exposure time and the shear stress level.

Physiological shear stress increased the formation of preplatelets and platelet-like particles up to 10.8-fold. And it increased megakaryocyte microparticle production up to 47-fold. Platelet-like particles generated under shear flow showed improved function.

Experiments also revealed that phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. But inhibiting caspase-3 reduced the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.

Finally, the researchers found that coculturing megakaryocyte microparticles with hematopoietic stem and progenitor cells promoted differentiation to mature megakaryocytes that synthesized α- and dense-granules, and formed preplatelets without exogenous thrombopoietin.

The team noted that, unlike platelets themselves, these microparticles can be frozen, which will enable them to be stored and used for platelet production on an as-needed basis.

“Knowing that these microparticles have a biological function opens the door to other applications, including genetic therapies,” Dr Papoutsakis said. “We’re hopeful that our discovery can break the vicious cycle of [immune thrombocytopenia] as well as other conditions that cause reduced platelet count and cause life-threatening bleeding.”

Megakaryocytes

in the bone marrow

Scientists say they’ve shed new light on the mechanism of platelet formation, paving the way to accelerating and enhancing platelet production using stem cells.

The group uncovered their findings by studying the effects of shear stress on megakaryocyte maturation and the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.

“Until recently, these microparticles were viewed as inconsequential cell debris,” said Terry Papoutsakis, PhD, of the University of Delaware in Newark.

“We now know that they play a significant biological role in platelet formation. The enhanced generation of preplatelets and platelet-like particles under shear stress correlates with physiological observations—in healthy adults, both acute and prolonged exercise leads to elevated platelet counts.”

“Now, these findings can be used to develop better bioreactor technologies for producing platelets, preplatelets, platelet-like particles, and megakaryocyte microparticles for transfusion medicine, using stem cells as starting material.”

Dr Papoutsakis and his colleagues described these findings in Blood.

The researchers discovered that shear stress accelerated DNA synthesis of immature megakaryocytes, and this was dependent upon exposure time and the shear stress level.

Physiological shear stress increased the formation of preplatelets and platelet-like particles up to 10.8-fold. And it increased megakaryocyte microparticle production up to 47-fold. Platelet-like particles generated under shear flow showed improved function.

Experiments also revealed that phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. But inhibiting caspase-3 reduced the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.

Finally, the researchers found that coculturing megakaryocyte microparticles with hematopoietic stem and progenitor cells promoted differentiation to mature megakaryocytes that synthesized α- and dense-granules, and formed preplatelets without exogenous thrombopoietin.

The team noted that, unlike platelets themselves, these microparticles can be frozen, which will enable them to be stored and used for platelet production on an as-needed basis.

“Knowing that these microparticles have a biological function opens the door to other applications, including genetic therapies,” Dr Papoutsakis said. “We’re hopeful that our discovery can break the vicious cycle of [immune thrombocytopenia] as well as other conditions that cause reduced platelet count and cause life-threatening bleeding.”

Megakaryocytes

in the bone marrow

Scientists say they’ve shed new light on the mechanism of platelet formation, paving the way to accelerating and enhancing platelet production using stem cells.

The group uncovered their findings by studying the effects of shear stress on megakaryocyte maturation and the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.

“Until recently, these microparticles were viewed as inconsequential cell debris,” said Terry Papoutsakis, PhD, of the University of Delaware in Newark.

“We now know that they play a significant biological role in platelet formation. The enhanced generation of preplatelets and platelet-like particles under shear stress correlates with physiological observations—in healthy adults, both acute and prolonged exercise leads to elevated platelet counts.”

“Now, these findings can be used to develop better bioreactor technologies for producing platelets, preplatelets, platelet-like particles, and megakaryocyte microparticles for transfusion medicine, using stem cells as starting material.”

Dr Papoutsakis and his colleagues described these findings in Blood.

The researchers discovered that shear stress accelerated DNA synthesis of immature megakaryocytes, and this was dependent upon exposure time and the shear stress level.

Physiological shear stress increased the formation of preplatelets and platelet-like particles up to 10.8-fold. And it increased megakaryocyte microparticle production up to 47-fold. Platelet-like particles generated under shear flow showed improved function.

Experiments also revealed that phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. But inhibiting caspase-3 reduced the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.

Finally, the researchers found that coculturing megakaryocyte microparticles with hematopoietic stem and progenitor cells promoted differentiation to mature megakaryocytes that synthesized α- and dense-granules, and formed preplatelets without exogenous thrombopoietin.

The team noted that, unlike platelets themselves, these microparticles can be frozen, which will enable them to be stored and used for platelet production on an as-needed basis.

“Knowing that these microparticles have a biological function opens the door to other applications, including genetic therapies,” Dr Papoutsakis said. “We’re hopeful that our discovery can break the vicious cycle of [immune thrombocytopenia] as well as other conditions that cause reduced platelet count and cause life-threatening bleeding.”