May 2019 FAQs

Is intravenous ketamine effective for treatment of headache disorders in the emergency department?

Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, is a dissociative anesthetic agent that is increasingly being used for its effect on pain.1 In 2017, the Drug Information Group reviewed the evidence for intravenous sub-dissociative-dose ketamine for pain in the emergency department, which can be accessed here. In addition to highlighting the efficacy of intravenous ketamine for pain, the 2017 review discusses important safety considerations. The purpose of this review is to expand on that review by evaluating the efficacy and safety of intravenous ketamine specifically for treatment of acute headache disorders in the emergency department.

Background

Headache is a frequent cause of emergency department visits among adults, and acute migraine accounts for over one million visits to the emergency department in the United States per year.2,3  A number of agents are used for acute management of migraine in the emergency department, including intravenous metoclopramide, intravenous prochlorperazine, and subcutaneous sumatriptan.3Ketamine is receiving increasing interest as an acute treatment for migraine.4,5 As an NMDA antagonist, ketamine is thought to reduce central sensitization and “wind-up” that leads to hyperalgesia.1,6,7 While higher doses lead to sedation, lower doses are considered sub-anesthetic and used for analgesic effects.1 Although ketamine is associated with a number of adverse events, generally, intravenous ketamine used for analgesia in sub-anesthetic doses is well-tolerated. More common adverse events associated with ketamine administration include cardiovascular effects such as tachycardia and psychomimetic effects such as delirium, hallucinations, and nightmares.1,8

Guideline Recommendations

The American Society of Regional Anesthesia and Pain Medicine (ASRA), the American Academy of Pain Medicine (AAPM), and the American Society of Anesthesiologists (ASA) published 2018 consensus guidelines on intravenous ketamine infusions for chronic pain.1 This guideline categorized the data for ketamine infusions in migraine headache pain as “weak or no evidence” (grade D, low level of certainty), and no evidence for intermediate or long-term pain improvement.

Previously, the American Headache Society (AHS) published 2016 evidence-based recommendations on the use of parenteral therapies for the treatment of adults with acute migraine in the emergency department.3 At the time of the AHS guideline recommendation, data for ketamine in migraine was based on the results of one class 3 (ie, lowest quality) randomized controlled trial.3,9 The trial found that ketamine (0.08 mg/kg) administered subcutaneously resulted in reduced pain intensity, but with fatigue and insobriety. Based on this study, the guideline authors determined they could make no recommendation on injectable ketamine.3 Since the publication of that guideline, additional studies have been published examining the role of intravenous ketamine for migraine or other headache disorders.

Literature review

Studies evaluating intravenous ketamine for acute migraine or headache are included in the Table.6,7,10,11 Four studies were identified, only two of which administered ketamine in the emergency department. Two randomized controlled trials found that intravenous ketamine 0.2 mg/kg or 0.3 mg/kg did not improve pain compared to placebo or prochlorperazole, respectively, when administered in emergency departments.6,10 Both of these studies were limited by small sample sizes. The first study by Etchison et al was conducted in patients with acute migraine and the second by Zitek et al was in patients with primary headaches. Two retrospective reviews of ketamine infusion were conducted in patients with refractory headaches.7,11 Both were at the same institution. Unlike the previously discussed randomized controlled trials, instead of receiving a bolus dose of ketamine the emergency department, the patients were admitted to the hospital for ketamine infusion over approximately 5 days. Both studies found that mean headache pain level decreased from baseline to end of therapy, and >70% of patients experienced at least a 2-point improvement in pain scale rating by discharge.

Safety

Neurologic adverse events occurred in studies. The trial by Etchison and colleagues observed higher Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) scores for generalized discomfort and fatigue with ketamine compared to placebo.6 The trial by Zitek et al conducted an interim analysis because providers expressed concern of severe dysphoria among patients treated with ketamine.10 The trial was stopped at this point because of the presumed superiority of prochlorperazine. Two patients in the ketamine group withdrew due to severe dysphoria. In the two studies, ketamine was administered over 1 and 2 minutes, respectively.6,10 However, as noted by both trials’ authors, a recent study by Motov et al found that administration of a 15-minute infusion of ketamine led to lower rates of feelings of unreality compared to administration by intravenous push.12 There were a number of common adverse events reported in the retrospective reviews, including nystagmus, confusion, sedation, nausea/vomiting, blurry vision, hallucinations, and vivid dreams. More serious adverse events included elevated liver enzymes, falls, and suicidality. Of note, in both retrospective reviews ketamine was administered at higher doses and for a longer duration compared to the studies conducted at emergency departments.

Table. Intravenous ketamine for the treatment of acute migraine or headache.6,7,10,11

Study design

Subjects

Interventions

Outcomes
RCTs
Etchison 20186

DB, SC, RCT

 N=34 adults (18 to 65 years) with acute migraine at the ED Ketamine 0.2 mg/kg IV administered over 1 minute (n=16)

Placebo (normal saline) (n=18)

 Primary:

  • NRS-11 pain scores: median change from baseline to 30 minutes was 1.0 (IQR, 0 to 2.25) with ketamine compared to 2.0 (IQR, 0 to 3.75) with placebo (difference, ‑1.0; IQR, -2 to 1; p=NS)

Secondary:

  • Change from baseline in categorical pain scores at 30 minutes, functional disability score at 30 minutes, and patient satisfaction at 60 minutes were not significantly different between groups

Safety:

  • SERSDA scores for generalized discomfort were higher with ketamine at baseline (p=0.0247) and 30 minutes (p=0.008), while SERSDA score for fatigue was higher with ketamine at 60 minutes (p=0.0216).
  • The most common side effects were fatigue, nausea, and generalized discomfort.
Zitek 201810

DB, MC, RCT

 N=54 adults (18 to 65 years) with primary headaches at the ED Ketamine 0.3 mg/kg IV administered over 2 minutes (plus ondansetron 4 mg IV) (n=25)

Prochlorperazine 10 mg IV administered over 2 minutes (plus diphenhydramine 25 mg IV) (n=29)

500 mL normal saline was administered to both groups.

 An unplanned interim analysis was performed after multiple providers in the EDs expressed concern of severe dysphoria with ketamine. At this time, the study was stopped because of the apparent superiority of prochlorperazine over ketamine.

Primary:

  • At 60 minutes, reduction in mean VAS pain score was higher with prochlorperazine (63.5 mm; 95% CI, 52.7 to 74.3 mm) vs ketamine (43.5 mm; 95% CI, 30.2 to 56.8 mm) (difference, 20.0 mm; 95% CI, 2.8 to 37.2 mm; p=0.03)

Secondary:

  • Reduction in mean VAS pain scores at 45 minutes was higher with prochlorperazine vs ketamine
  • Rescue medication use, subjective restlessness, hospital admissions, and headache at 24 to 48 hours were non-significantly lower with prochlorperazine vs ketamine
  • Satisfaction scores (0 to 10) at 24 to 48 hours were higher with prochlorperazine vs ketamine (mean difference, 3.4 points; 95% CI, 1.2 to 5.6)

Safety:

  • Two patients in the ketamine group withdrew due to dysphoria, and 1 patient in the prochlorperazine group withdrew due to akathisia
Retrospective reviews
Schwenk 201811

Retrospective review

 N=61 patients with refractory headache admitted for ketamine infusion therapy

97% of patients had migraine and 3% had cluster headache

 Ketamine infusion: typically started at 10 mg/h IV in most patients and increased by 5 mg/h every 3 to 4 h to a “soft upper limit” of 1 mg/kg/h Mean ketamine infusion length was 5.1 ± 0.1 days with a mean maximum infusion rate of 0.76 mg/kg/h

Outcomes:

  •  Mean headache pain level (0 to 10) improved from 7.5 ± 0.2 on admission to 3.4 ± 0.3 at end of treatment (p<0.001)
  • 77% of patients were immediate responders (at least a 2-point improvement on 0- to 10-point NRS in headache from beginning to end pain) and 40% were also sustained responders at the first office visit and 39% at the second office visit

Safety:

  • Common AEs (>10%) in immediate and nonresponders were nystagmus (75% and 54%, respectively), sedation (48% and 62%), nausea/vomiting (40% and 31%), blurry vision (35% and 46%), hallucinations (27% and 31%), and vivid dreams (10% and 23%)
  • One patient stopped ketamine due to nausea, blurry vision, and sedation
Pomeroy 20177

Retrospective review

 N=77 patients admitted with refractory chronic migraine or new daily persistent headache Ketamine infusion: 0.1 mg/kg/h IV, increased by 0.05 mg/kg/h hourly until pain relief, nystagmus, or mild inebriation. Infusion rate of 0.25 mg/kg/h was maintained for 6 hours before further dose increase (maximum dose: 1 mg/kg/h) (maximum duration: 5 days) Mean ketamine infusion length was 4.8 days (range, 2 to 9 days) and rate was 0.53 mg/kg/h (range, 0.08 to 1.25 mg/kg/h)

Outcomes:

  •  Mean headache pain level (0 to 10) improved from 7.1 (range, 2 to 10) on admission to 3.8 (range, 2 to 10) at discharge (mean difference, 3.253; 95% CI, 2.60 to 3.90; p<0.0001)
  • 71.4% of patients were acute responders and 27.3% were also sustained responders (at least a 2-point improvement on 11-point scale in headache from admission to discharge and from admission to first follow-up visit)

Safety:

  • Common AEs (>10%) included diplopia or blurred vision (36.4%), confusion (24.7%), hallucinations (20.8%), dysarthria (11.7%), and dizziness (11.7%).
  • One patient experienced suicidality, 1 patient experienced elevated liver enzymes, and 2 patients experienced falls
Abbreviations: AE=adverse event; CI=confidence interval; CO=crossover; DB=double-blind; ED=emergency department; IQR=interquartile range; IV=intravenous; MC=multicenter; NRS=Numerical Rating Scale; NS=non-significant; RCT=randomized controlled trial; SC=single-center; SERSDA=Side Effect Rating Scale for Dissociative Anesthetics; VAS=visual analog scale.

Conclusion

Overall, current data are lacking to support intravenous ketamine for migraine or headache in the emergency department. Two small randomized controlled trials did not find a benefit of intravenous ketamine administered as a bolus compared to placebo or prochlorperazine, respectively, when administered in the emergency department. Two separate retrospective reviews conducted at a single institution found that a longer ketamine infusion administered to admitted patients may improve pain in patients with severe refractory headaches; however, as retrospective reviews, these were of lower study quality. The exact role of intravenous ketamine should be further elucidated with higher quality studies.

References

1.         Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):521-546.

2.         Minor DS, Harrell T. Headache disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 19th ed.  New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=1861&sectionid=146063736. Accessed April 21, 2019.

3.         Orr SL, Friedman BW, Christie S, et al. Management of adults with acute migraine in the emergency department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies. Headache. 2016;56(6):911-940.

4.         Naeem F, Schramm C, Friedman BW. Emergent management of primary headache: a review of current literature. Curr Opin Neurol. 2018;31(3):286-290.

5.         Long BJ, Koyfman A. Benign headache management in the emergency department. J Emerg Med. 2018;54(4):458-468.

6.         Etchison AR, Bos L, Ray M, et al. Low-dose ketamine does not improve migraine in the emergency department: a randomized placebo-controlled trial. West J Emerg Med.2018;19(6):952-960.

7.         Pomeroy JL, Marmura MJ, Nahas SJ, Viscusi ER. Ketamine infusions for treatment refractory headache. Headache. 2017;57(2):276-282.

8.         Clinical Pharmacology powered by ClinicalKey. 2019. http://clinicalpharmacology.com/. Accessed April 21, 2019.

9.         Nicolodi M, Sicuteri F. Exploration of NMDA receptors in migraine: Therapeutic and theoretic implications. Int J Clin Pharmacol Res. 1995;15:181-189.

10.       Zitek T, Gates M, Pitotti C, et al. A comparison of headache treatment in the emergency department: prochlorperazine versus ketamine. Ann Emerg Med. 2018;71(3):369-377.e1.

11.       Schwenk ES, Dayan AC, Rangavajjula A, et al. Ketamine for refractory headache: a retrospective analysis. Reg Anesth Pain Med. 2018;43(8):875-879.

12.       Motov S, Mai M, Pushkar I, et al. A prospective randomized, double-dummy trial comparing intravenous push dose of low dose ketamine to short infusion of low dose ketamine for treatment of moderate to severe pain in the emergency department. Am J Emerg Med.2017;35(8):1095-1100.

Prepared by:
Patricia Hartke, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2019

The information presented is current as of April 22, 2019. 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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Does elevated INR in hospitalized patients with chronic liver disease suggest that anticoagulation is not necessary?

Introduction

The liver produces a number of proteins involved in hemostasis.1-6 Therefore, patients with chronic liver disease (CLD) experience a variety of hemostatic abnormalities. This may result in findings from hemostatic tests suggesting increased risk for bleeding, such as elevated international normalized ratio (INR).

These abnormal hemostatic indices may lead to the misconception that patients with CLD and elevated INR are at increased risk of bleeding, and therefore are “auto-anticoagulated,” and do not require otherwise indicated anticoagulation.1-3,7-9 However, concomitant dysfunctions in production of procoagulant proteins also occurs in CLD, which may increase the risk of thrombosis.4,6 Together, these actions lead to a “rebalancing” of hemostasis in patients with CLD.1-4,6-9 This review summarizes the underlying hemostatic pathology occurring in CLD, its effects on laboratory indices of hemostasis, and clinical considerations in hospitalized patients with CLD being considered for anticoagulation.

Effects of CLD on hemostasis

Patients with CLD experience changes in all aspects of hemostasis.4 These resulting changes are often referred to as a “rebalancing” of compensatory mechanisms, leading to an equilibrium that provides low risk of bleeding or thrombosis, even in patients with advanced liver disease experiencing multiple derangements in normal hemostasis.1-4,6-9

In normal primary hemostasis, a platelet plug is formed after platelets adhere to a site of vascular injury and, through assembling activated coagulation factors on their surface, support generation of thrombin.6,10 Patients with CLD may experience a functional decrease in the levels of circulating platelets due to their sequestration in the spleen, more rapid turnover, and, because of lower levels of hepatic thrombopoietin, underproduction of platelets.7 In normal secondary hemostasis, the cascade of coagulation proteases acts to cleave soluble fibrinogen by thrombin to insoluble fibrin, forming the fibrin mesh at the site of injury around the platelet plug.10 The production of all procoagulant factors except for factor VIII occurs in the liver, and is reduced in patients with CLD.3,4,7 Deficiencies of vitamin K-dependent factors II, VII, IX, and X also may be exacerbated in patients with liver disease who actively use alcohol.11

Contrasting these changes is the reduced production of anticoagulant factors, including protein C, protein S, and antithrombin, particularly in patients with cirrhosis.3 Additionally, patients with decompensated cirrhosis may be at elevated risk for thrombosis due to stasis in the portal circulation and lower extremity veins.2 In sum, changes to the hemostatic system in both anticoagulant and procoagulant systems occurs in CLD, increasing the risk of both bleeding and thrombosis, and results in a rebalanced equilibrium of hemostasis.5

Measures of hemostatic indices in CLD

Patients with CLD often have abnormal hemostatic indices, such as prolonged prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT).1,3 However, these tests are unreliable in CLD because they only reflect changes in procoagulant factors and do not measure anticoagulant effects. For example, the PT and INR were developed to identify dysregulation of procoagulant proteins I, II, V, VII, and X for use in patients treated with vitamin K antagonists.1

The inability of PT and INR to reflect changes in anticoagulant factors thus makes them unreflective of the true hemostatic status of a patient with CLD. Thus, these patients may still be at risk for thrombosis despite elevated INR, and these hemostatic indices should be interpreted with caution.1,3 Currently, there are no laboratory tests of hemostasis that accurately measure procoagulant and anticoagulant systems that would best address the shortcomings of PT and INR in patients with CLD.7

The deficiencies of PT and INR in measuring thrombotic risk in patients with CLD have been evaluated. One single-center retrospective cohort of adult inpatients with CLD evaluated development of venous thromboembolism (VTE) during hospital stay across quartiles of INR.9 Among 190 patients, the incidence of VTE did not significantly differ between quartiles, suggesting that INR is not predictive of VTE risk during hospitalization. Similarly, a single-center retrospective study identified that in multivariate analysis, INR was not a significant predictor of VTE in a cohort of 13,368 patients.12

Thromboprophylaxis in CLD

The aforementioned elements of dysregulated hemostasis may occur in combination with traditional risk factors for VTE, such as immobility, advanced age, and malignancy, suggesting thromboprophylaxis may be necessary in CLD.3 To date, high-quality studies of the effects of treatment and prophylaxis of VTE in CLD are unavailable because most trials exclude patients with underlying coagulopathies, including CLD.5 However, retrospective studies suggest that thromboprophylaxis in patients with CLD and compelling indications for anticoagulation is often still appropriate.2,5

The risk of bleeding with anticoagulation in hospitalized patients with CLD was found to not be significantly increased in several retrospective studies.2,13-17 Only one study in 256 patients with cirrhosis and baseline INR >1.5 identified the overall risk of hemorrhage was significantly elevated with pharmacologic thromboprophylaxis over no prophylaxis (17.5% vs 7.4%; p = 0.02).15 However, this finding appeared to be driven primarily by differences in minor hemorrhage (12.5% vs 4.5%; p = 0.02), while major hemorrhage did not differ between groups (5.0% vs 2.8%; p = 0.47).

Although the ability of thromboprophylaxis to reduce the risk of VTE in CLD has been evaluated in several studies, few have document significant efficacy. Only one single-center retrospective cohort study identified a protective effect of thromboprophylaxis (odds ratio, 0.34; 95% confidence interval, 0.04 to 0.88).13 Nonetheless, a general consensus is that thromboprophylaxis should not be withheld from patients with CLD who have compelling risk factors for thrombosis.1-5 Despite this, studies have documented that use of thromboprophylaxis is suboptimal in CLD. For example, several retrospective studies reported the rate of thromboprophylaxis in hospitalized patients with CLD ranged from approximately 25% to 55%, indicating challenges to implementing appropriate anticoagulation.9,14,16,18

The decision to use anticoagulation in patients with CLD may be aided by risk assessment tools for VTE. Although guidelines for VTE prevention do not specifically address patients with CLD, their recommendations are based on VTE risk stratification using the Padua Predictor Score (Table).19-23One evaluation of the Padua Score specifically in hospitalized patients with CLD found it was an effective risk assessment tool in this population.23 Patients identified as high-risk (Padua Score ≥4) had 12.7 times greater odds of VTE as low-risk patients (Padua Score <4). The authors concluded high-risk patients would benefit from pharmacological thromboprophylaxis. Based on these findings, the Padua Score has been recommended as an aid in assessing risk of VTE in hospitalized patients with CLD to better inform decisions regarding the appropriateness of thromboprophylaxis.2,5,23

Table. Padua Predictor Score.21
Risk factor

Points
Active cancer

3
Previous VTE (with exclusion of superficial vein thrombosis)

3
Reduced mobility

3
Already known thrombophilic condition

3
Recent (≤1 month) trauma and/or surgery

2
Elderly age (≥70 years)

1
Heart and/or respiratory failure

1
Acute MI and/or ischemic stroke

1
Acute infection and/or rheumatologic disorder

1
Obesity (BMI ≥30)

1
Ongoing hormonal treatment

1
Abbreviations: BMI=body mass index; MI=myocardial infarction; VTE=venous thromboembolism.

Conclusion

Elevated INR in patients with CLD can be deceiving. Rather than believing these patients are “auto-anticoagulated,” their hemostatic status should be considered “rebalanced” because of changes in production of both prothrombotic and antithrombic proteins. Common measures of hemostasis such as PT and INR may be prolonged, but these only measure prothrombotic factors without reflecting changes in antithrombotic factors. Further study in more rigorous controlled trials is warranted, but current evidence suggests the risk of bleeding is not increased with thromboprophylaxis in patients with CLD. Therefore, thromboprophylaxis should not be withheld from patients with CLD in the presence of thrombotic risk factors, even if tests of hemostasis are elevated.1,4 The Padua Predictor score may help determine the risk of VTE in patients with CLD, and ultimately, whether anticoagulation should be initiated.

References

1.         Weeder PD, Porte RJ, Lisman T. Hemostasis in liver disease: implications of new concepts for perioperative management. Transfus Med Rev. 2014;28(3):107-113.

2.         Dhar A, Mullish BH, Thursz MR. Anticoagulation in chronic liver disease. J Hepatol. 2017;66(6):1313-1326.

3.         Khoury T, Ayman AR, Cohen J, Daher S, Shmuel C, Mizrahi M. The complex role of anticoagulation in cirrhosis: An updated review of where we are and where we are going. Digestion. 2016;93:149-159.

4.         Barton CA. Treatment of coagulopathy related to hepatic insufficiency. Crit Care Med. 2016;44(10):1927-1933.

5.         Shah NL, Intagliata N. Hemostatic abnormalities in patients with liver disease. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate; 2019. https://www.uptodate.com/. Accessed April 15, 2019.

6.         Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365(2):147-156.

7.         Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013;11(9):1064-1074.

8.         Pincus KJ, Tata AL, Watson K. Risk of venous thromboembolism in patients with chronic liver disease and the utility of venous thromboembolism prophylaxis. Ann Pharmacother. 2012;46:873-878.

9.         Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010;137:1145-1149.

10.       Gale AJ. Continuing education course #2: current understanding of hemostasis. Toxicol Pathol. 2011;39:273-280.

11.       Shah NL, Intagliata NM, Northup PG, Argo CK, Caldwell SH. Procoagulant therapeutics in liver disease: a critique and clinical rationale. Nat Rev Gastroenterol Hepatol. 2014;11:675-682.

12.       Gulley D, Teal E, Suvannasankha A, Chalasani N, Liangpunsakul S. Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci. 2008;53(11):3012-3017.

13.       Barclay SM, Jeffres MN, Nguyen K, Nguyen T. Evaluation of pharmacologic prophylaxis for venous thromboembolism in patients with chronic liver disease. Pharmacotherapy. 2013;33(4):375-382.

14.       Moorehead KJ, Jeffres MN, Mueller SW. A retrospective cohort analysis of pharmacologic VTE prophylaxis and Padua Prediction Score in hospitalized patients with chronic liver disease. J Pharm Pract. 2017;30(1):58-63.

15.       Reichert JA, Hlavinka PF, Stolzfus JC. Risk of hemorrhage in patients with chronic liver disease and coagulopathy receiving pharmacologic venous thromboembolism prophylaxis. Pharmacotherapy. 2014;34(10):1043-1049.

16.       Smith CB, Hurdle AC, Kemp LO, Sands C, Twilla JD. Evaluation of venous thromboembolism prophylaxis in patients with chronic liver disease. J Hosp Med. 2013;8(10):569-573.

17.       Intagliata NM, Henry ZH, Shah N, Lisman T, Caldwell SH, Northup PG. Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding. Liver Int. 2014;34(1):26-32.

18.       Yang LS, Alukaidey S, Croucher K, Dowling D. Suboptimal use of pharmacological venous thromboembolism prophylaxis in cirrhotic patients. Intern Med J. 2018;48(9):1056-1063.

19.       Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-e325S.

20.       Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e227S-e277S.

21.       Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e195S-e226S.

22.       Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352.

23.       Bogari H, Patanwala AE, Cosgrove R, Katz M. Risk-assessment and pharmacological prophylaxis of venous thromboembolism in hospitalized patients with chronic liver disease. Thromb Res. 2014;134(6):1220-1223.

Prepared by:
Ryan Rodriguez, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2019

The information presented is current as April 5, 2019. 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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Is ticagrelor the optimal antiplatelet for patients with peripheral artery disease?

Antiplatelet agents

For many years aspirin was the sole antiplatelet agent used for both primary and secondary prevention of cardiovascular (CV) events.1 Although effective, the search for antiplatelet agents with improved efficacy and safety continued, and over the last 25 years, a number of antiplatelet agents with a variety of mechanisms have been studied. The antiplatelet agents known as the P2Y12 inhibitors have been particularly successful and are widely used as monotherapy and in combination with aspirin for dual antiplatelet therapy (DAPT).

Ticagrelor is a unique P2Y12 inhibitor approved by the Food and Drug Administration (FDA) as secondary prevention in patients with acute coronary syndrome (ACS).2 In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor significantly reduced the composite endpoint of death from vascular causes, myocardial infarction (MI), or stroke in patients with ACS compared with clopidogrel.3Some prescribers prefer ticagrelor to clopidogrel in ACS patients based on this study.4 However, the superiority of ticagrelor in other CV diseases such as peripheral artery disease (PAD) is less clear. Based on studies supporting improved efficacy of ticagrelor compared with clopidogrel in patients with other CV disorders, evaluation of its efficacy in PAD is worthwhile.

PAD

Peripheral artery disease is believed to affect about 8.5 million Americans.5 Although PAD can result in serious health-related problems, 40% of patients are without symptoms. Those who are symptomatic often experience claudication (pain or fatigue in the legs during exercise that is relieved in less than 10 minutes with rest).6,7 Patients may also present with acute or chronic limb ischemia.

PAD treatment

The primary treatment for symptomatic PAD is an antiplatelet agent. The American Heart Association/American College of Cardiology (AHA/ACC) guidelines for PAD recommend the use of antiplatelet agents in patients with symptomatic PAD.7 They also suggest considering antiplatelet therapy in those who are asymptomatic with an abnormal ankle-brachial index (ABI) score (≤ 0.90). The ABI is the ratio of the systolic blood pressure in the ankle to the blood pressure in the upper arm. The evidence for antiplatelet agents in other patients who are asymptomatic is less clear.

The AHA/ACC guidelines specifically recommend the use of aspirin at a dose of 75 to 325 mg/day or clopidogrel at a dose of 75 mg/day.7 The role of other antiplatelet agents was unclear at the time of writing.

Ticagrelor vs clopidogrel

Early evidence evaluating the use of ticagrelor compared with clopidogrel for PAD was obtained from a subgroup of patients enrolled in the PLATO trial.3,8 All patients in the PLATO trial had ACS and were treated with aspirin 75 to 100 mg/day (doses up to 325 mg/day were allowed for 6 months after stent placement). Patients were randomized to either ticagrelor (180 mg loading dose followed by 90 mg twice daily) or clopidogrel (300 to 600 mg loading dose followed by 75 mg/day). The primary endpoint was a composite of CV death, MI, or stroke.

There were 1144 patients with PAD enrolled in PLATO.8 The primary outcome occurred in more clopidogrel-treated patients (20.6%) than ticagrelor-treated patients (18.0%) although this failed to reach statistical significance (hazard ratio [HR], 0.846; 95% confidence interval [CI], 0.644 to 1.111; p=0.99). Major bleeding was not different between groups (14.8% with ticagrelor and 17.9% with clopidogrel; HR, 0.807; 95% CI, 0.593 to 1.099; p=0.09). Secondary outcomes such as death from any cause, CV death, MI, and stroke were not significantly different between groups. The findings of this analysis are limited by their post-hoc nature, and it was hoped that a randomized controlled trial designed specifically for PAD patients would clarify the role of ticagrelor.

Examining Use of Ticagrelor in PAD, EUCLID, was a randomized, double-blind trial in 13,885 patients with PAD.9 Patients in this study were at least 50 years of age with either previous revascularization of the lower limbs for symptomatic PAD at least 30 days prior to randomization or hemodynamic evidence of PAD with an ABI ≤ 0.80 at screening. Importantly, patients who required aspirin were excluded from the study. Patients were randomized to treatment with clopidogrel 75 mg/day or ticagrelor 90 mg twice daily. The primary efficacy endpoint was a composite of CV death, MI, or ischemic stroke, and the primary safety endpoint was major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) criteria.

Baseline characteristics were similar between groups and generally representative of the PAD population with a median age of 66 years and 72% male.9 Forty-three percent of patients were enrolled based on revascularization and 57% were enrolled based on abnormal ABI. Median follow up time was 30 months. The primary endpoint occurred in 10.8% of patients in the ticagrelor group compared with 10.6% of patients in the clopidogrel group (HR, 1.02; 95% CI, 0.92 to 1.13; p=0.65). The only statistically significant difference in efficacy was ischemic stroke which occurred in 1.9% of ticagrelor-treated patients compared with 2.4% of clopidogrel-treated patients (HR, 0.78; 95% CI, 0.62 to 0.98; p=0.03). Major bleeding was also similar between groups (1.6%; HR, 1.10; 95% CI, 0.84 to 1.43; p=0.49). However, more patients discontinued ticagrelor due to adverse events. Dyspnea was the leading cause of discontinuation due to adverse events with 4.8% and 0.8% of ticagrelor- and clopidogrel-treated patients discontinuing for this reason (p<0.001). A post-hoc analysis of patients with coronary artery disease (CAD) also failed to find a benefit with ticagrelor.10 The composite outcome of CV death, MI, or stroke occurred in 15.3% of patients treated with clopidogrel and 15.4% of patients treated with ticagrelor (HR, 1.02; 95% CI, 0.87 to 1.19; p=0.84).

Ticagrelor vs aspirin

Although the majority of evidence for ticagrelor in PAD comes from studies compared with clopidogrel, there is some evidence compared with aspirin. The PEGASUS-TIMI 54 (Prior Heart Attack Using Ticagrelor Compared to Placebo on A Background of Aspirin – Thrombolysis in Myocardial Infarction) trial randomized patients with previous MI to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo.11All patients received low-dose aspirin. Although the full study was quite large (N=21,162), only about 5% of patients had concomitant PAD.12 In the patients with PAD the addition of ticagrelor to aspirin reduced the primary composite endpoint of CV death, MI, or stroke from 19.3% with aspirin alone to 14.1% with ticagrelor 60 mg (HR, 0.69; 95% CI, 0.47 to 0.99; p=0.045), and to 16.3% with ticagrelor 90 mg (HR, 0.81; 95% CI, 0.57 to 1.15; p=0.24). The risk of major bleeding was similar among groups (1.6% to 1.8%).

Conclusion

Ticagrelor has been studied in PAD patients with (PLATO, PEGASUS-TIMI 54) or without (EUCLID) concomitant aspirin.8,9,12 Neither the PLATO nor EUCLID studies found ticagrelor to have superior efficacy or safety compared with clopidogrel in patients with PAD.8,9 However, the PEGASUS-TIMI 54 study of ticagrelor in combination with aspirin did find benefit to the combination therapy compared with aspirin alone.12 It should be noted that the PLATO and PEGASUS-TIMI 54 trials were not designed to differentiate the effects of ticagrelor in patients with PAD.3,11 Findings in PAD are from post-hoc analyses, and firm conclusions should not be drawn.8,12 On the contrary, EUCLID was a well-designed, prospective trial comparing ticagrelor to clopidogrel in patients with PAD.9 Thus, there is stronger evidence to refute the superiority of ticagrelor to clopidogrel in this study. In summary, evidence does not support the superiority of ticagrelor compared to clopidogrel in patients with PAD, but ticagrelor may be more effective than aspirin in these patients.

References

  1. Schafer AI. Antiplatelet therapy. ASH website. https://www.hematology.org/About/History/50-Years/1525.aspx. Published December 2008. Accessed April 22, 2019.
  2. Brilinta [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2019.
  3. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med. 2009;361(11):1045-1057.
  4. Cutlip D, Lincoff AM. Antiplatelet agents in acute non-ST elevation acute coronary syndromes. Cannon CP, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www-uptodate-com. Updated June 29, 2018. Accessed April 22, 2019.
  5. Peripheral arterial disease (PAD) fact sheet. Centers for Disease Control and Prevention website. https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_pad.htm. Updated June 16, 2016. Accessed April 22, 2019.
  6. Kohlman-Trigoboff D. Update: diagnosis and management of peripheral arterial disease. J NursePract. 2019;15(1):87-95.e1.
  7. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017;69(11):e71-e126.
  8. Patel MR, Becker RC, Wojdyla DM, et al. Cardiovascular events in acute coronary syndrome patients with peripheral arterial disease treated with ticagrelor compared with clopidogrel: data from the PLATO Trial. Eur J Prev Cardiol. 2015;22(6):734-742.
  9. Hiatt WR, Fowkes GR, Heizer G, et al for the EUCLID Trial Steering Committee and Investigators. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med.2017;376(1):32-40.
  10. Berger JS, Abramson BL, Lopes RD, et al for the EUCLID Trial Steering Committee and Investigators. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease and prior coronary artery disease: insights from the EUCLID trial. Vasc Med. 2018;23(6):523-530.
  11. Bonaca MP, Bhatt DL, Cohen M, et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800.
  12. Bonaca MP, Bhatt DL, Storey RF, et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease. J Am Coll Cardiol. 2016;67(23):2719-2728.

Prepared by:
Courtney Krueger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2019

The information presented is current as of April 22, 2019. 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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