January 2017 FAQs

What are the updated recommendations for the role of PCSK9 inhibitors in the management of hypercholesterolemia?

Introduction

A major risk factor for cardiovascular disease and stroke is hyperlipidemia.¹ Statins are considered the gold standard for the treatment of hyperlipidemia. The effectiveness of statins in lowering low-density lipoprotein cholesterol (LDL-C) and also decreasing the risk of morbidity and mortality due to atherosclerotic cardiovascular disease (ASCVD) has been shown in the literature by randomized controlled trials.² Despite the use of statins and other lipid-lowering drugs along with lifestyle modifications to decrease total cholesterol levels, certain patients lack a response to treatment and require alternative treatment modalities to help reduce the risk of cardiovascular disease.

In 2015, proprotein convertase subtilisin-like kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha) and alirocumab (Praluent) received Food and Drug Administration (FDA) approval for use as an adjunct to diet and add-on treatment to a maximally tolerated dose of statin therapy in patients with heterozygous familial hypercholesterolemia (HeFH) or clinical ASCVD.^3,4 In addition, evolocumab was approved for use in patients with homozygous familial hypercholesterolemia (HoFH).

The previous guideline update by the American College of Cardiology/American Health Association (ACC/AHA) for the management of hyperlipidemia did not adequately address non-statin therapies for the management of cholesterol.⁵ In 2016, an expert consensus was published to address the roles of non-statin therapy, including PCSK9 inhibitors.⁶ Even though gaps in knowledge remain as major organizations await the results of the cardiovascular outcome trials evaluating PCSK9 inhibitors, other organizations such as the National Lipid Association (NLA) have also addressed preliminary recommendations for PCSK9 inhibitors in their guidelines.^7,8 The purpose of this update is to discuss the recommendations for the place in therapy of PCSK-9 inhibitors in the management of hypercholesterolemia, as well as, address some of the questions posed in a previous FAQ on PCSK-9 inhibitors published in June 2015 (available here).

Recommendations from the American College of Cardiology

The aim of the American College of Cardiology expert consensus is to provide a practical guidance on the role of non-statin therapies for LDL-C reduction, including PCSK-9 inhibitors.⁶ The experts voice that the recommendations are not “firm triggers” since a traditional review was not performed for the addition of non-statin therapies. In addition, the decision to add non-statin therapies should take into consideration adherence to lifestyle modifications and statin therapy, statin intolerance, control of other risk factors, percentage LDL-C reduction from baseline and/or absolute on-treatment LDL-C measurement, clinician-patient discussion on risk and benefits, and response to treatment.

Initial statin therapy is guided by the statin benefit groups established in the 2013 ACC/AHA guidelines.⁵ Prior to the addition of a non-statin therapy, patient adherence to the statin should be assessed, and if goals are not attained an increase of the statin dose and intensity to the maximum tolerated dose is recommended. For patients who are statin intolerant, a referral to a lipid specialist should be considered, as well as, an attempt to intensify lifestyle and dietary modifications. After these interventions, if patients do not achieve a LDL-C response of ≥ 50% reduction or < 100 mg/dL, non-statin therapy can be considered based on a clinician-patient discussion on benefits and risks. Table 1 below summarizes the recommendations for non-statin therapy in patients who are unable to achieve goal LDL-C after treatment with a maximally tolerated statin.

Table 1. Summary of ACC/AHA Expert Consensus Recommendations.

Recommendations from the National Lipid Association

The NLA is taking a conservative approach towards the place in therapy for PCSK9 inhibitors until the results of cardiovascular outcomes trials are available.⁷ However, the recommendations do suggest that combination treatment with a statin and another lipid-altering agent (eg, ezetimibe, PCSK9 inhibitor) should be considered in patients not at goal non-HDL-C and LDL-C levels and with a high or very high ASCVD risk.⁸ NLA states that the use of PCSK9 inhibitors should be considered in patients with ASCVD who have LDL-C ≥100 mg/dL (non-HDL-C ≥130 mg/dL) and patients with HeFH without ASCVD who have LDL-C ≥130 mg/dL (non-HDL-C ≥160 mg/dL) who are unable to achieve LDL-C goals while on a maximally tolerated dose of statin with or without ezetimibe. In addition, based on clinical judgment and cost of treatment, PCSK9 inhibitors may be used for high-risk patients with ASCVD unable to achieve treatment goals (eg, LDL-C ≥70 mg/dL [non-HDL-C ≥100 mg/dL]) and in high or very high-risk patients with statin intolerance unable to achieve goal LDL-C with other non-statin therapies.

Literature Summary

The publication of the UIC Drug Information Group FAQ in June 2015, available here, provides a summary of studies for both evolocumab and alirocumab. Since the June 2015 FAQ publication, the results for the ODYSSEY OPTIONS II, ODYSSEY COMBO I, and the ODYSSEY ALTERNATIVE trials have been published. These trials are summarized in Table 2 below. New studies were not identified for evolocumab.

Table 2. Summary of alirocumab trials.

Cost of PCSK9 Inhibitors

The annual wholesale cost for treatment with alirocumab and evolocumab is $14,600 and $14,100, respectively.¹² According to the Institute for Clinical and Economic Review (ICER), approximately 3.5 to 15 million American may be eligible and considered for treatment with PCSK9 inhibitors.¹³ For patients on statin therapy or unable to tolerate statins, PCSK9 inhibitors can reduce LDL-C by 55% to 60%. Both alirocumab and evolocumab have a similar efficacy and safety profile.¹⁴ Given the high cost of the drugs, utilization considerations may include restricting prescribing to lipid management specialists (eg, cardiology), and limiting treatment to those who failed high-intensity statin and ezetimibe or have statin intolerance. ICER identifies an annual cost less than $2177 as a reasonable cost of treatment.

Dosing Considerations and Administration of PCSK9 Inhibitors

PCSK9 inhibitors are self-administered by the patient.^3,4 Since PSCK9 inhibitors are stored in the refrigerator, the drug should be left at room temperature for 30 to 40 minutes prior to administration to avoid discomfort during injection. Evolocumab can be stored at room temperature but must be used within 30 days. Depending on the indication, evolocumab can be administered either at a dose of 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously every 4 weeks. When evolocumab is administered once monthly, 3 consecutive injections using the 140 mg/mL formulation are required to provide the full 420 mg dose. On the other hand, alirocumab is available as a 75 mg/mL and 150 mg/mL injection. The initial dose is 75 mg subcutaneously every 2 weeks. If further LDL-C reduction is required, the dose can be increased to 150 mg subcutaneously every 2 weeks. Subcutaneous injection sites include the thigh, abdomen, or upper arm. The injection site should be rotated with each injection and should never be co-administered with another injectable drug. Alirocumab and evolocumab have not been studied in patients with renal and hepatic impairment and no dosage adjustment information is available.

Summary

This FAQ update provides an overview of new studies and recommendations and addresses unanswered questions regarding, cost and drug administration. Overall, at this time it seems that PCSK9 inhibitors are primarily recommended in high or very high risk patients with ASCVD who are unable to achieve target LDL-C after the use of maximally tolerated statins with or without other non-statin therapies, such as ezetimibe. The results of the cardiovascular outcomes trials, FOURIER evaluating evolocumab, and ODYSSEY Outcomes evaluating alirocumab, are expected to be complete in 2017. Both of these trials will be pivotal in determining whether the cost of the PCSK9 inhibitors justifies the primary outcome of interest, a decrease in cardiac events, and the implications of further updates to guideline recommendations.

January 2017

The information presented is current as of December 28, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

References

1. Mozaffarian D, Benjamin EJ, Go AS, et al. heart disease and stroke statistics – 2016 update: A report from the American Heart Association [published online ahead of print December 16, 2016]. Circulation. 2016;133:e38-360. doi: 10.1161/CIR.0000000000000350.

2. Banach M, Stulc T, Dent R, et al. Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement [published online ahead of print September 26, 2016]. Int J Cardiol. 2016;225:184-196. doi: 10.1016/j.ijcard.2016.09.075.

3. Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2015.

4. Repatha [package insert]. Thousand Oaks, CA: Amgen Inc; 2015.

5. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1-45.

6. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert Consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016;68(1):92-125.

7. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – executive summary. J Clin Lipidol. 2014;8(5):473-488.

8. Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol. 2015;9(6 Suppl):S1-S122 .

9. Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. [published online ahead of print November 14, 2015] Atherosclerosis. 2016;244:138-146. doi:10.1016/j.atherosclerosis.2015.11.010

10. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015;169(6):906-915.

11. Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-769.

12. Comparative Effectiveness Public Advisory Counsel. PCSK9 inhibitors for treatment of high cholesterol: effectiveness, value, and value based price benchmarks – Final Report. Institute for Clinical and Economic Review website. http://icer-review.org/wp-content/uploads/2015/04/Final-Report-for-Posting-11-24-15.pdf. Published November 24, 2015. Accessed December 21, 2016.

13. Stein M. ICER Draft report on effectiveness, value, and pricing benchmarks for pcsk9 inhibitors for high cholesterol posted for public comment. Institute for Clinical and Economic Review website.https://icer-review.org/announcements/pcsk9-draft-report-release/. Published September 8, 2015. Accessed December 21, 2016.

14. Tice JA, Kazi DS, Pearson SD. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors for treatment of high cholesterol levels: effectiveness and value. JAMA Intern Med. 2016;176(1):107-108.

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What literature supports the use of liposomal bupivacaine in transversus abdominis plane nerve blocks?

Introduction

Regional anesthesia may be used in addition to analgesia during surgical procedures to reduce a patient’s stress response and limit requirements and adverse effects of systemic analgesia and general anesthesia.¹ Various techniques are utilized, including peripheral nerve blocks, which provide temporary anesthesia to a region innervated by a specific nerve.¹ The transversus abdominis plane (TAP) block is a form of peripheral nerve blockade in which the injection of local anesthetic between the transversus abdominis and internal oblique muscles blocks sensory stimuli to the anterior abdominal wall. It is often used to provide anesthesia for minor superficial procedures of the lower abdominal wall (eg, laparotomy, appendectomy, hysterectomy, and prostatectomy).^1,2 Typically, 20 mL of a local anesthetic is injected into this space, which may be performed bilaterally. The use of TAP blocks has increased in recent years.³

Various local anesthetics have been studied in TAP blocks, including bupivacaine, levobupivacaine, lidocaine, and ropivacaine. In 2011, a liposomal formulation of bupivacaine was approved by the US Food and Drug Administration for administration into surgical sites to produce postsurgical analgesia.⁴ Its drug delivery system slowly delivers active drug to extend its effect. The procedures in which liposomal bupivacaine (LB) has been studied have expanded, and clinicians may inquire about literature supporting its use in TAP blocks, which is summarized in this article.

Prospective evaluations of LB TAP blocks

Early prospective evaluations of LB TAP block described small samples of patients who received bilateral administration in open umbilical hernia repair.⁵ Safety and efficacy were demonstrated at up to 72 hours, as well as high patient satisfaction with pain control. Since then, higher-quality studies have been performed, which provide evidence in various surgical procedures.

Overall, prospective evaluations have found that LB TAP block may improve outcomes compared to TAP block with non-LB alone or in combination with epinephrine, but have not provided evidence of superiority to other forms of regional anesthesia. Two prospective randomized controlled trials (RCTs) evaluated LB TAP block in nephrectomy.⁶ One in 59 patients compared LB and a combination of non-LB and epinephrine TAP block.⁶ The LB was associated with significantly lower median maximal pain scores at 24 to 48 hours (5 vs 6) and 48 to 72 hours (3 vs 5). Also, LB provided significant reductions in mean opioid use (105 vs 182 mcg fentanyl equivalents), median length of stay (LOS; 67.7 vs 78.1 hours), and incidence of nausea and vomiting (7 vs 15 patients). The authors suggested the 10.4-hour decreased LOS provided a net savings considering the cost of a vial of LB vs a medical/surgical unit bed. Compared to these findings, however, one RCT comparing LB to the combination of bupivacaine and dexamethasone found the combination TAP block required less intraoperative and postoperative opioids in partial nephrectomy.⁷

Other procedures in which LB TAP block has been evaluated have support from only one RCT each, which has generally found benefit. In hysterectomy, a comparison of LB to non-LB demonstrated significant improvements in total opioid use at up to 72 hours (24.9 vs 51.7 mg morphine equivalents [MME]), incidence of nausea and vomiting (25% vs 56.7%), and maximal pain scores in the post-anesthesia care unit (5.0 vs 6.0), at 0 to 24 hours (4.5 vs 7.0), 24 to 48 hours (4.0 vs 5.0), and 48 to 72 hours (3.0 vs 5.0).⁸

Compared to surgeries performed without TAP block, LB TAP block provided similar results in opioid use, pain scores, LOS, and incidence of ileus in 50 patients undergoing elective laparoscopic colectomy. ⁹ However, compared to epidural analgesia in 36 major open abdominal surgeries, TAP block with LB was associated with significantly higher postoperative pain scores at 4, 12, 24, and 48 hours, as well as higher total consumption of narcotics.¹⁰ The authors attributed this difference to the biphasic release profile of LB because results were not significantly different at later evaluation times of 72 and 96 hours.

Retrospective evaluations of LB TAP blocks

Retrospective research has also evaluated LB in TAP block, where comparisons to other local anesthetics again demonstrate some benefit with LB, although results for some outcomes are inconsistent. Compared to patients receiving 0.25% non-LB or 0.25% to 0.5% ropivacaine in colorectal surgery, LB was associated with lower pain scores at up to 48 hours postoperatively (all p<0.05), reduced consumption of intravenous (99.1 vs 64.6 MME; p=0.04) but not oral opioids, as well as total ketorolac doses (49 vs 18.3 mg; p<0.001).¹¹ However, there were no significant differences in postoperative LOS or total cost. Another comparison to continuous TAP block with 0.5% ropivacaine in anterior lumbar interbody fusion found single-injection LB TAP block produced significant reductions in opioid consumption (46%, 34%, and 34% at days 1, 2 and overall, respectively; all p<0.05), and 1-day reductions in return of bowel function and discharge (both p<0.01).¹² However, there was no difference in mean pain scores. Another evaluation in colectomy found reduced narcotic consumption with LB but no difference in pain scores, LOS, and ileus compared with non-LB bupivacaine.¹³

In addition to these active control evaluations, other retrospective research has compared LB TAP block with no TAP block, where findings are similarly conflicting. In elective laparoscopic colectomy, LB TAP block was not associated with differences in analgesic use, pain scores, or LOS.⁹ In contrast, another review in colectomy procedures did find significant reductions in total narcotic use and LOS.¹⁴ In abdominal wall reconstruction, LB TAP block was associated with significant reductions in MME requirements at days 0 (9.5 vs 16.5), 1 (26.7 vs 39.5), and 2 (29.6 vs 40.7). ¹⁵ Pain scores were also significantly reduced at each day (5.1 vs 7.0; 4.2 vs 5.5; and 3.9 vs 4.8, respectively), as well as median LOS (5.2 vs 6.8 days). It should be noted, however, that this TAP block mixture also contained non-LB, so effects cannot be solely attributed to LB.

Lastly, a retrospective comparison with epidural in patients undergoing open hysterectomy reported results that conflict with prospective comparison with epidural.^10,16 The TAP block with LB was associated with significant reductions in opioid use at up to 48 hours and pain scores at 24 to 48 hours, but no reduction in LOS. A manufacturer-sponsored cohort study in patients undergoing major lower abdominal surgery found TAP block with LB to be noninferior to both epidural and intravenous patient-controlled analgesia in pain scores (<1 point increase in pain scores), and additionally noninferior to epidural in opioid consumption (<20% increase in mean opioid consumption). ¹⁷

A limitation to prospective and retrospective evaluations of LB TAP block is that some results are available in abstract format only, which precludes a full analysis of methods and outcomes to determine reasons for conflicting results.^5,7,9,10 Additionally, protocols for opioid administration were not specified, and some trials did not blind clinicians administering the study drugs. ⁸ Lastly, small sample sizes (many of fewer than 100 patients) may not provide sufficient power to detect differences between groups. Overall, more rigorous prospective research can help better inform this question.

Dosage and preparation of LB TAP block

Some authors have proposed that diluting LB with 0.9% normal saline (NS) will aid its spread to tissues, which otherwise would be inhibited by its viscosity.⁶ Additionally, dilution increases the total volume administered, which may facilitate spread of anesthesia. Therefore, protocols of LB TAP blocks have included admixtures of the drug with NS.

Common doses of LB used in TAP block range from 133 to 266 mg (10 to 20 mL) of 1.3% LB diluted in NS to a total volume of 30 to 60 mL.^5,6,8,10,18 Most protocols distributed the 10- or 20-mL dose of LB between both sides of the abdominal wall, but one case series described use of 20 mL of LB per side. ¹⁹ Additionally, administration of separate injections of 5 mL LB and 5 mL NS has been described. ²⁰ One group of investigators included 0.25% non-LB in the admixture, of which 50 mL was added to 20 mL of LB and 150 mL of normal saline. Aliquots of 20 mL of the solution were administered at 5 points on each side of the abdominal wall.¹⁵ Another protocol diluted LB with only non-LB, including 20 mL of each (13.3 and 5 mg/mL, respectively) administered bilaterally.¹⁷

Conclusion

Various local anesthetics have been used in TAP blocks, including the newer liposomal formulation of bupivacaine. Because there is no consensus regarding the optimal type, dose, or volume to be used in TAP block, questions may arise regarding the safety and efficacy of LB in this practice.²¹ Currently, higher-quality research provides some evidence that LB TAP block may improve outcomes compared to non-LB alone or in combination with epinephrine, but LB may not be superior to other forms of regional anesthesia. Given the varying procedures and preparations of LB TAP block that have been studied and the conflicting findings in current literature, the efficacy and safety of LB TAP block may remain difficult to define until further higher-quality prospective research is available.

January 2017

The information presented is current as of December 2, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

References

1. Madison SJ, Ilfeld BM. Peripheral nerve blocks. In: Butterworth JF, Mackey DC, Wasnick JD, eds. Morgan & Mikhail's Clinical Anesthesiology. 5th ed. New York, NY: The McGraw-Hill Companies; 2013. http://mhmedical.com/content.aspx?aid=57237814. Accessed December 15, 2016.

2. Yeung B, Mueller J. Peripheral nerve blocks: Trunk and perineum. In: Freeman BS, Berger JS, eds. Anesthesiology Core Review: Part Two Advanced Exam. New York, NY: McGraw-Hill Education; 2016. http://mhmedical.com/content.aspx?aid=1135738603. Accessed December 15, 2016.

3. Abdallah FW, Chan VW, Brull R. Transversus abdominis plane block: a systematic review. Reg Anesth Pain Med. 2012;37(2):193-209.

4. Exparel [package insert]. San Diego, CA: Pacira Pharmaceuticals Inc; 2016.

5. Feierman DE, Kronenfeld M, Gupta PM, Younger N, Logvinskiy E. Evaluation of Exparel® use in a transversus abdominis plane (TAP) block for prolonged postoperative analgesia in subjects undergoing open umbilical hernia repair. Anesth Analg. 2013;116(Suppl 1).

6. Hutchins JL, Kesha R, Blanco F, Dunn T, Hochhalter R. Ultrasound-guided subcostal transversus abdominis plane blocks with liposomal bupivacaine vs. non-liposomal bupivacaine for postoperative pain control after laparoscopic hand-assisted donor nephrectomy: a prospective randomised observer-blinded study. Anaesthesia. 2016;71(8):930-937.

7. Faucher E, Curtis C. Comparison between bupivacaine extended-release liposome injection versus bupivacaine with dexamethasone in transversus abdominis plane block: A prospective randomized trial. Reg Anesth Pain Med. 2015;40(5).

8. Hutchins J, Delaney D, Vogel RI, et al. Ultrasound guided subcostal transversus abdominis plane (TAP) infiltration with liposomal bupivacaine for patients undergoing robotic assisted hysterectomy: A prospective randomized controlled study. Gynecol Oncol. 2015;138(3):609-613.

9. Jrebi N, Ogilvie J, Jaluta T, et al. The transversus abdominis plane block: A prospective randomized controlled trial using exparel. Dis Colon Rectum. 2015;58(5):e299-e300.

10. Turchaninov K, Ptacek T, Nicholas T. Comparison of epidural analgesia with bilateral dual transversus abdominis plane infiltration block with liposomal bupivacaine in patients with major open abdominal surgery. Reg Anesth Pain Med. 2015;40(5).

11. Stokes A, Adhikary S, Quintili A, et al. Liposomal bupivacaine use in transversus abdominis plane blocks reduces pain and postoperative intravenous opioid requirements after colorectal surgery. Dis Colon Rectum. 2016;59(5):e66-e67.

12. Vaughn B. Retrospective, controlled evaluation comparing a multimodal approach to pain management utilizing a bilateral continuous TAP block to bilateral TAP injections of liposomal bupivacaine following anterior lumbar interbody fusion. Reg Anesth Pain Med. 2015;40(5).

13. Jrebi N, Szeto P, Hoedema R, et al. Tap block with exparel decreases postoperative pain and narcotic use in elective colorectal patients. Dis Colon Rectum. 2014;57(5):e350.

14. Hutchins J, Madoff R, Melton G, Kwaan M, Ogilvie J. Post-operative pain control with transversus abdominis plane blocks with liposomal bupivacaine versus iv opioids in laparoscopic colorectal patients: A retrospective cohort study. Anesth Analg. 2014;118(5):S285.

15. Fayezizadeh M, Majumder A, Neupane R, Elliott HL, Novitsky YW. Efficacy of transversus abdominis plane block with liposomal bupivacaine during open abdominal wall reconstruction. Am J Surg. 2016;212(3):399-405.

16. Hutchins J. Transversus abdominis plane blocks with liposomal bupivacaine versus epidurals for post-operative pain control in patients undergoing total abdominal hysterectomy: A retrospective cohort study. Reg Anesth Pain Med. 2014;39(5):e242.

17. Ayad S, Babazade R, Elsharkawy H, et al. Comparison of transversus abdominis plane infiltration with liposomal bupivacaine versus continuous epidural analgesia versus intravenous opioid analgesia. PLoS One. 2016;11:e0153675.

18. Feierman DE, Kronenfeld M, Gupta PM, Younger N, Logvinskiy E. Liposomal bupivacaine infiltration into the transversus abdominis plane for postsurgical analgesia in open abdominal umbilical hernia repair: Results from a cohort of 13 patients. J Pain Res. 2014;7:477-482.

19. Oppenheimer AJ, Fiala TG, Oppenheimer DC. Direct transversus abdominis plane blocks with exparel during abdominoplasty [published online ahead of print November 5, 2015]. Ann Plast Surg. doi: 10.1097/SAP.0000000000000659.

20. Hutchins J, Delaney D, Vogel R, et al. Ultrasound guided subcostal transversus abdominis plane (TAP) infiltration with liposomal bupivacaine vs. bupivacaine in patients undergoing robotic assisted hysterectomy: A prospective randomized controlled trial. Anesth Analg. 2015;120(3):S345.

21. Urigel S, Jolter J. Transversus abdominis plan (TAP) blocks. AANA J. 2014;82(1):73-79.

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What evidence is available for using direct oral anticoagulants in HIT?

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a life-threatening thrombogenic complication that is associated with the use of heparin products such as unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).^1-3 Two types of HIT have been identified: type I and type II.³ Type I is a reversible reaction, which in general, occurs within 2 days of therapy and is not immune-related. This reaction occurs in about 10% to 20% of heparin-treated patients.

In contrast, type II is immune- mediated and life-threatening, but less common and occurs in about 1% to 5% of UFH-treated patients and 0.8% of LMWH-treated patients.³ This reaction is caused by IgG antibodies against complexes of platelet factor 4 (PF4) and heparin, which results in platelet activation through the formation of microparticles and production of thrombin. Patients present with a platelet count of <150,000 cells/mm³ or a ≥50% decrease in platelet count from baseline. The onset of the decline is typically 5 to 10 days after the initiation of heparin therapy and takes place over 1 to 3 days. However, if the patient had received heparin within the last 100 days, platelets can start to decline as early as a few hours after receiving heparin products. This process can lead to the development of thrombosis, which needs to be addressed with pharmacologic therapy.

The goal of managing patients with HIT is to reduce the risk of thrombosis and potential complications of thromboses.^1-4 The immediate treatment of HIT is discontinuation of all heparin-containing products. Additionally, treatment with an alternative anticoagulant should be initiated. In current practice, direct thrombin inhibitors (DTIs), bivalirudin, and argatroban are typically used at therapeutic doses in lieu of heparin-based products, because they lack cross-reactivity to heparin. The most current American College of Chest Physicians (CHEST) Guidelines for the treatment and prevention of HIT also recommend the use of fondaparinux, an indirect factor Xa inhibitor, for certain patients.⁴ All of the aforementioned treatment options are administered parenterally either through the intravenous or subcutaneous route.³ Often, patient-specific variables drive the specific choice of alternative anticoagulation.

Direct oral anticoagulants

Direct oral anticoagulants (DOACs) directly antagonize a single target in the clotting pathway.^5-7 They are subcategorized based on the factor they specifically target: thrombin (factor IIa) or factor Xa. The options available in the United States are factor Xa inhibitors, apixaban, edoxaban, and rivaroxaban, and a factor IIa inhibitor, dabigatran. Their approved indications vary based on the specific DOAC, but include prevention and treatment of venous thromboembolism (VTE) and prevention of stroke in nonvalvular atrial fibrillation.

DOAC Use in HIT

While at this time the DOACs are not approved by the Food and Drug Administration (FDA) for the treatment of HIT, they have some potential advantages over the current HIT treatment options.⁷ Fixed dose regimens, minimal monitoring, and decreased incidence of drug-drug interactions all represent potential benefits over the current treatment options. Additionally, DOACs could provide several oral treatment options that could be used for initial treatment.⁸ Lastly, due to DOACs’ molecular structure, they would not be expected to interact with anti-PF4/heparin antibodies.^7-12

In vitro studies have shown that dabigatran, apixaban, and rivaroxaban do not cause platelet activation like heparin products.^9-10,12 In a study by Krauel et al, the in vitro effects of dabigatran and rivaroxaban on PF4/heparin complexes and anti-PF4/heparin antibodies with platelets was studied.¹⁰ Investigators found that both dabigatran and rivaroxaban do not interact with PF4 or HIT antibodies, suggesting that these drugs could be safely used in patients with a history of HIT or potentially in the active treatment of HIT. In another study, Walenga et al examined whether apixaban can interact with HIT antibodies present via a (14)C-serotonin release assay and the heparin-induced platelet aggregation assay. ¹² It was found that apixaban did not interact with HIT antibodies and, thus, did not activate platelets.

While in vitro studies were initially completed to test the viability of using DOACs as an alternative anticoagulant in HIT, there is also evidence available on their use in vivo. Tables 1 and 2 provide a summary of the data available on the use of DOACs in patients with HIT. There is one prospective study on the use of rivaroxaban in patients with confirmed or suspected HIT.¹³ The primary outcome was incidence of symptomatic venous or arterial thromboembolism by 30 days. Out of the 22 patients, 1 patient with confirmed HIT had a recurrent, symptomatic VTE. Of the 10 patients with confirmed HIT and thrombocytopenia, 9 experienced platelet recovery over a mean time of 11 days. This prospective cohort study was limited by a small number of patients, but did conclude that rivaroxaban could be an effective treatment for HIT patients.

There are a few retrospective studies that have addressed DOAC use in HIT patients as well.^14-16 Between 3 retrospective studies, dabigatran, rivaroxaban, and apixaban were successfully used in either preventing thromboses or aiding platelet recovery. However, 2 of the studies initiated treatment with a DTI, argatroban or bivalirudin, before transitioning to a DOAC. ^15,16 Therefore, the clinical applicability of these findings need to be considered. Finally, a majority of the data available are case reports of patients treated with DOACs.^17-25 In these case reports, all patients had successful platelet recovery and no patients had a recurrent thrombus or drug-related adverse events such as a major or minor bleed.

Overall, existing data on DOAC use in HIT patients show positive results with good clinical outcomes and tolerability. While the current literature is limited by its strength of evidence, it is likely that randomized controlled trials will not be conducted due to the rarity of HIT. Additionally, the one prospective study available was terminated early due to slow recruitment showing that it is difficult to carry out prospective studies in this disease state. However, due to their potential advantages over current treatment options and improbability of platelet activation and antibody formation effect, DOACs may theoretically be a therapeutic option for HIT patients.

Table 1. Cohort studies evaluating the use of DOACs in HIT patients.^13-25

Table 2. Case series and reports describing the use of DOACs in HIT patients.^17-25

References

1. Greinacher A. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med. 2015;373(3):252-261.

2. Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355(8):809-817.

3. Rao KV. Drug-induced hematologic disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach. 9^th ed. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811451. Accessed November 17, 2016.

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Prepared by:

Kripa Patel, PharmD

PGY1 Pharmacy Practice Resident

January 2017

The information presented is current as November 8, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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