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Jan 2019 FAQs

What clinical data are available comparing nicardipine to clevidipine in acute ischemic stroke?

What evidence is available to support the use of N-acetylcysteine for impulse control disorders?

What evidence supports the use of direct-acting oral anticoagulants in patients with cancer-related VTE?

Answers

What clinical data are available comparing nicardipine to clevidipine in acute ischemic stroke?

Introduction

Acute ischemic stroke is common in the United States (US), and is estimated to affect approximately 795,000 Americans each year.1  Although it has fallen from the third leading cause of death in the US to the fifth due to medical advancements in stroke care, it is still a frequent cause of disability.  Currently, the only pharmacologic treatment strategy with documented efficacy in acute ischemic stroke is administration of intravenous (IV) tissue plasminogen activator (tPA; alteplase) within the first 3 hours of symptom onset.  However, in patients who are eligible for reperfusion with alteplase, current, severe uncontrolled hypertension is a contraindication to therapy.2  Hypertension is common among patients with ischemic stroke, and can be the result of a sympathetic response, chronic hypertension, or other stroke-related factors.3  Patients with acute stroke and elevated blood pressures must be treated with IV antihypertensive agents to lower the blood pressure to ≤185 mmHg systolic and ≤110 mmHg diastolic in order to be eligible for thrombolytic therapy.4  If the blood pressure is not reduced to an appropriate range prior to therapy, the patient should not receive alteplase due to a potentially increased risk of intracerebral hemorrhage.4,5

Guideline Recommendations

The American Heart Association (AHA) and American Stroke Association (ASA) recently published an update to their existing guideline on early management of patients with acute ischemic stroke.5  Based on the existing evidence, the guideline recommends treatment of elevated blood pressure in patients who are otherwise appropriate candidates for IV alteplase, with an initial goal of <185 mmHg systolic and <110 mmHg diastolic prior to administration of alteplase.  In addition, the goal blood pressure should be below 180/105 within the first 24 hours after treatment with alteplase.  In patients who have an elevated blood pressure but are otherwise eligible for alteplase use, the guideline recommends treatment with either intravenous labetalol, nicardipine, or clevidipine, and suggests that other agents may be considered based on comorbid conditions.  No preference is given among the 3 recommended agents, although both nicardipine and clevidipine are calcium channel blockers.  The previous version of the guideline that was released in 2013 only recommended labetalol and nicardipine for this purpose, although clevidipine was approved by the FDA in 2008.6  Other guidelines on the management of stroke do not provide specific pharmacologic recommendations for blood pressure reduction.

Dosing Recommendations and Considerations in Stroke

Table 1 highlights the differences in dosing, pharmacokinetic properties, and adverse effects between nicardipine and clevidipine for blood pressure reduction in patients with acute ischemic stroke.  While both agents have an onset of action within minutes, clevidipine has a much quicker offset, which may allow for tighter blood pressure control than nicardipine.9  On the other hand, clevidipine is associated with more severe adverse effects, including acute renal failure and atrial fibrillation. In addition, clevidipine is supplied as a lipid emulsion product with a concentration of 0.5 mg/mL, whereas nicardipine is supplied as a premixed solution in a concentration of either 0.1 or 0.2 mg/mL.7,8  Because of the differences in duration, formulation, and adverse effect profiles between agents, it is difficult to determine if one agent is preferable over the other for the treatment of acute ischemic stroke. Therefore, a literature search was conducted for head-to-head data comparing the use of nicardipine and clevidipine for blood pressure reduction in patients with acute stroke.

Table 1. Nicardipine and clevidipine- dosing and other considerations in acute ischemic stroke.5,7-9

Nicardipine (Cardene)

Clevidipine (Cleviprex)

Generic available?

Yes

No

Initial dosing

5 mg/hr IV

1 to 2 mg/hr IV

Onset

1 minute

2 to 4 minutes

Duration

3 hours

5 to 15 minutes

Titration

Titrate up by 2.5 mg/hr every 5 to 15 minutes

Maximum: 15 mg/hr

Double dose every 2 to 5 min. until desired BP reached

Maximum: 21 mg/hr

Common adverse effects (>5%)

Headache (up to 14.6%)

Hypotension (5.6%)

Peripheral edema (5.9%)

Phlebitis (30.4%)

Headache (6.3%)

Acute renal failure (9%)

Nausea (up to 21%)

Atrial fibrillation (up to 36.1%)

Abbreviations: BP=blood pressure; IV=intravenous.

Evidence Summary

Trials comparing the use of nicardipine and clevidipine to treat hypertension in patients with stroke are summarized in Table 2. Overall, only 3 studies were identified, all of which are retrospective in nature.10-12  The primary outcome for each study involved the time to reach goal blood pressure, which was not found to be different between agents in any of the 3 studies.  In addition, none of the studies found differences in the need for rescue antihypertensive medications or in the number of documented adverse effects between nicardipine and clevidipine.  Two of the studies also evaluated additional clinical outcomes, including length of stay and in-hospital death, and found no difference between agents.10,11  All 3 studies concluded that nicardipine and clevidipine are equal with regards to safety and efficacy, and that either agent may be used to treat hypertension in patients with stroke.  The studies by Rosenfeldt and Finger both noted that clevidipine is associated with less fluid delivery than nicardipine, and may be a favorable option in patients who require fluid restriction.10,12  The authors of both studies also noted that clevidipine is a lipid emulsion, which may further limit its use in certain patient populations.

Table 2. Studies comparing the use of nicardipine and clevidipine for blood pressure reduction in patients with acute stroke.10-12

Study design and duration

Subjects

Interventions

Results

Authors’ conclusions

Rosenfeldt 201810

Retrospective chart review

N=119 adults with acute stroke treated for acute blood pressure reduction

Nicardipine (n=60)

Clevidipine (n=59)

  • No difference in achievement of goal systolic blood pressure (SBP) at 1 hour after initiation of infusion between nicardipine and clevidipine (73.3% vs. 66.1%, respectively; p=0.39)
  • No difference in achievement of goal SBP at 6 hours after initiation of infusion between nicardipine and clevidipine (95% vs 98.3%, respectively; p=0.62)
  • No difference in a composite endpoint (in-hospital death, 30-day readmission, rebleeding on 24-hour CT scan, and hematoma expansion in those with intracerebral hemorrhage) between nicardipine and clevidipine (41.6% vs 50.8%, respectively; p=0.41)
  • No differences in safety outcomes (such as hypotension, tachycardia, incidence of AKI, and bradycardia) were found between the 2 agents
  • In most cases, it is likely that nicardipine and clevidipine are equivalent options for reduction of blood pressure in patients with acute stroke
  • Disadvantages of treatment with clevidipine include increased cost, lipid delivery, and adverse effects, although it does deliver less fluid and may be beneficial in patients who are fluid restricted

Allison 201711

Retrospective, observational cohort study

N=210 adult patients admitted to the ED that required a continuous infusion for acute BP management in AIS or ICH

Nicardipine 5 mg/h, titrated by nursing discretion every 15 mins to a max dose of 15 mg/h (n=140)

Clevidipine 2 mg/h, increased by doubling the dose every 90 seconds until a rate of 12 mg/h was reached, then increasing by 4 mg/h to a max dose of 32 mg/h (n=70)

Patients may have also received doses of labetalol 10mg IV throughout the first 24 hours

  • Significant reduction in SBP at the initiation of continuous infusion with nicardipine (SBP=184 mmHg) vs clevidipine (SBP=199 mmHg); p=0.002
  • No difference in mean time from initiation of infusion to goal SBP between agents (74 mins with nicardipine vs 50 mins with clevidipine; p=0.101)
  • No difference in safety outcomes, including hypotension, between groups
  • No difference in length of stay or death prior to discharge between groups; p=0.452
  • Due to the lack of differences between agents, either agent may be used for controlling BP in patients with acute stroke

Finger 201712

Retrospective chart review

N=57 adult patients with a primary neurological injury dictating specific blood pressure goals while in the NSICU

Nicardipine (n=38)

Clevidipine (n=19)

  • No difference in time to target SBP for nicardipine (median 46 mins) vs clevidipine (median 30 mins); p=0.13
  • No difference in median percentage of time spent within target SBP range with nicardipine (78%) vs clevidipine (79%); p=0.64
  • Median duration of clevidipine infusion was about 10 hours longer than nicardipine, but resulted in significantly lower administration volumes per patient
  • Safety outcomes, such as hypotension and tachycardia, were similar between groups
  • Antihypertensive therapy should be individualized in neurocritical care patients based on patient characteristics and pharmacokinetic properties of the agent
  • Clevidipine is another viable option in this patient population

Abbreviations:AIS=acute ischemic stroke; AKI=acute kidney injury; BP=blood pressure; CT=computed tomography; ED=emergency department; ICH=intracerebral hemorrhage; NSICU=neuroscience intensive care unit

Conclusion

Current guidelines from AHA and ASA on management of acute ischemic stroke recommend treatment of hypertension with either nicardipine, clevidipine, or labetalol.  Nicardipine and clevidipine are both calcium channel blockers, with notable differences in their titration, duration, formulation, and adverse effect profiles. The existing literature, which consists of 3 small, retrospective studies, suggests that either agent can be utilized for the treatment of hypertension in stroke based on similarities in efficacy and safety.  Therefore, until larger, randomized trials are conducted, the decision to use one agent over the other should be based on patient-specific factors, such as fluid and lipid status, as well as the potential adverse effects associated with each agent. 

References

  1. Siegel J, Pizzi MA, Brent Peel J, et al. Update on neurocritical care of stroke. Curr Cardiol Rep. 2017;19(8):67.
  2. Activase [package insert]. South San Francisco, CA: Genentech, Inc.; 2018.
  3. Oliveira Filho J, Mullen MT. Initial assessment and management of acute stroke. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 6, 2018.
  4. Oliveira Filho J, Samuels OB. Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 6, 2018.
  5. Powers WJ, Rabinstein AA, Ackerson T, et al.; American Heart Association Stroke Council. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.
  6. Jauch EC, Saver JL, Adams HP Jr, et al.; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.
  7. Cardene [package insert]. Deerfield, IL: Baxter Healthcare Corporation; 2018.
  8. Cleviprex [package insert]. Cary, NC: Chiesi USA, Inc.; 2017.
  9. Micromedex Solutions [database online]. Greenwood Village, CO: Truven Health Analytics; 2018. https://www.micromedexsolutions.com/micromedex2/librarian/. Accessed December 6, 2018.
  10. Rosenfeldt Z, Conklen K, Jones B, Ferrill D, Deshpande M, Siddiqui FM. Comparison of nicardipine with clevidipine in the management of hypertension in acute cerebrovascular diseases. J Stroke Cerebrovasc Dis. 2018;27(8):2067-2073.
  11. Allison TA, Bowman S, Gulbis B, Hartman H, Schepcoff S, Lee K. Comparison of clevidipine and nicardipine for acute blood pressure reduction in patients with stroke. J Intensive Care Med. 2017 Jan 1:885066617724340. doi: 10.1177/0885066617724340.
  12. Finger JR, Kurczewski LM, Brophy GM. Clevidipine versus nicardipine for acute blood pressure reduction in a neuroscience intensive care population. Neurocrit Care. 2017;26(2):167-173.

Prepared by:

Jessica Zacher, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois At Chicago College of Pharmacy

January 2019

The information presented is current as of December 6, 2018. 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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What evidence is available to support the use of N-acetylcysteine for impulse control disorders?

Introduction

Impulse control disorders can be broadly characterized as disorders that involve difficulty resisting excessive/harmful urges or behaviors; this difficulty leads to significant social impairment and impaired occupational functioning.1 The Diagnostic and Statistical Manual of Mental Disorders (DSM) IV formally recognized several disorders as impulse control disorders, including pathological gambling (now referred to as gambling disorder, or GD), kleptomania (KM), trichotillomania (TTM), intermittent explosive disorder (IED), and pyromania.2,3 Some of these disorders were reclassified when the DSM-V was published in 2013: TTM was placed on the same spectrum as obsessive-compulsive disorders (OCD), while GD was reclassified as an addictive disorder.3 Additionally, excoriation disorder (ED, also referred to as skin picking disorder) was formally recognized in the DSM-V; previously, this diagnosis would have fallen under “impulse control disorders not otherwise specified.” Despite these classification changes, all of the disorders mentioned above share some similar characteristics: these include repetitive engagement in a behavior despite adverse consequences, decreased control over the behavior, an increased craving prior to engagement in the behavior, and a pleasant feeling during the performance of the behavior.1 The remainder of this article will focus specifically on TTM, ED, and GD, since these are the impulse control disorders where N-acetylcysteine has been systematically studied.

Trichotillomania is characterized by recurrent episodes of pulling out one’s hair; it occurs in approximately 0.6 to 3.4% of the general population.4 Excoriation disorder, also known as skin picking disorder, dermatillomania, psychogenic excoriation, or neurotic excoriation, presents with recurrent picking of the skin, which may lead to skin lesions and significant distress or functional impairment.5 This disorder occurs in approximately 1.4 to 5.4% of the general population. Gambling disorder occurs in approximately 1.2 to 7.1% of the general population; it is defined by recurrent, maladaptive gambling behavior that leads to significant distress.6

There are currently no Food and Drug Administration (FDA)-approved medications for the treatment of these disorders; however, studies have shown that certain medications may be beneficial for patients with TTM, ED, and GD. Olanzapine and clomipramine have been shown to decrease the severity of TTM in placebo-controlled trials.4 In ED, selective serotonin reuptake inhibitors (SSRIs), particularly fluoxetine, escitalopram, fluvoxamine, and sertraline, have shown promising results in reducing skin-picking symptoms.5 Medications that have shown the most benefit in treating GD include opioid antagonists (naltrexone and nalmefene) and SSRIs (paroxetine and fluvoxamine).6 For all these disorders, N-acetylcysteine has also been explored as a potential pharmacologic treatment option.

Potential Role of N-acetylcysteine

N-acetylcysteine is derived from the amino acid L-cysteine.7 It has been shown to reduce oxidative stress by increasing glutamate and glutathione production; it may also affect dopamine release from the presynaptic terminals and reverse mitochondrial dysfunction. In patients with OCD, there is an upregulation of glutamate release from presynaptic neurons. When N-acetylcysteine is administered, it increases extrasynaptic glutamate levels even further, resulting in a negative feedback loop on presynaptic receptors and ultimately decreasing the amount of glutamate that is released. It is hypothesized that this action on glutaminergic transmission allows N-acetylcysteine to aid in the reduction of compulsive behaviors, such as those associated with TTM, ED, and GD.

Literature Review

Table 1 summarizes the trials examining N-acetylcysteine in the treatment of ED, TTM, and GD.8-13 Efficacy was assessed using disorder-specific symptom severity scales in most trials. The 1 randomized trial in ED used the Yale-Brown Obsessive Compulsive Scale Modified for Neurotic Excoriation (NE-YBOCS) as its primary efficacy measure; scores on the NE-YBOCS range from 0 to 40, with higher numbers indicating increased symptom severity.8 Two trials in TTM used scores on the Massachusetts General Hospital Hairpulling Scale (MGH-HPS) as their primary efficacy outcome; scores on this scale range from 0 to 28, with higher numbers indicating increased severity.9,10 The 2 trials conducted in patients with GD used the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) to measure efficacy; like the NE-YBOCS, scores on this scale range from 0 to 40, with higher numbers indicating greater severity.11,12 N-acetylcysteine was found to be effective in all studies except one: in a study of pediatric TTM patients age 8 to 17 years, N-acetylcysteine was not found to be beneficial as an add-on treatment.8 However, this study was small and not fully powered, as study enrollment was terminated early.

Some patient populations were excluded from the trials; common exclusion criteria included thoughts of suicide, history of seizures, asthma, current pregnancy/inadequate contraception, and history of bipolar disorder, dementia, or psychotic disorders.8-12 Dosing for N-acetylcysteine varied substantially across studies. For ED, doses ranged from 450 to 3000 mg/day; doses for TTM ranged from 600 to 2400 mg/day, while doses for GD ranged from 600 to 3000 mg/day.8-13 Doses were generally started low and titrated based on observed efficacy and tolerability. Larger studies are required to determine the optimal dosing of N-acetylcysteine in the treatment of these disorders.

Table 1. N-acetylcysteine for the treatment of impulse control disorders.8-13

Study Design and Duration

Subjects

Interventions

Results

Conclusions

Excoriation Disorder

Grant et al,

20168

Randomized, double-blind, placebo-controlled trial

12 weeks

N=66 adults age 18 to 65 years with a primary, current DSM-5 diagnosis of excoriation disorder

N-acetylcysteine 1200 mg/day initially, with titration to 2400 mg/day at week 3 and 3000 mg/day at week 6 (n=35)

Placebo (n=31)

  • Mean NE-YBOCS score in the N-acetylcysteine group decreased from 18.9 to 11.5 at 12 weeks, while mean NE-YBOCS score in the placebo group decreased from 17.9 to 14.1 at 12 weeks (difference in final NE-YBOCS score, -3.767; p=0.048)
  • Of the 53 patients who completed the study, 15/32 (47%) in the N-acetylcysteine group were much or very much improved as measured by the Clinical Global Impression-Severity scale, while only 4/21 (19%) in the placebo group were much or very much improved (p=0.03)
  • Adverse events in the N-acetylcysteine group included nausea (14%), dry mouth (3%), constipation (6%), and dizziness (3%); in the placebo group, the only adverse effect experienced was nausea (3%)

N-acetylcysteine  significantly reduced skin-picking symptoms compared to placebo

Miller et al,

201313

Open-label pilot study

12 weeks

N=35 patients age 5 to 39 years with confirmed Prader-Willi syndrome and persistent skin-picking behavior for more than 1 year

N-acetylcysteine 450 to 1200 mg once daily

  • 25 patients (71%) had complete resolution of self-mutilation behaviors, with no open lesions and improvement of all existing lesions
  • 10 patients (29%) did not have complete resolution of skin-picking behavior, but had reduced numbers of active lesions (only 1 to 2 active lesions remained)

N-acetylcysteine shows a promising effect in the treatment of skin picking in patients with Prader-Willi syndrome, but placebo-controlled studies are required in order to confirm the results of this study

Trichotillomania

Bloch et al,

20139

Randomized, double-blind placebo-controlled, add-on study

12 weeks  

N=39 patients age 8 to 17 years with a primary diagnosis of trichotillomania and hair pulling behaviors that have lasted for at least 6 months

All patients were required to be on a stable medication and psychotherapy regimen

N-acetylcysteine 600 mg at dinner initially, with titration to 600 mg twice daily at week 2, 600 mg in the morning and at dinner at week 3, and finally 1200 mg twice daily at week 4 (n=20)

Placebo (n=19)

  • After 12 weeks of treatment, mean MGH-HPS score decreased from 13.15 to 10.70 in the N-acetylcysteine group and 16.58 to 13.53 in the placebo group (p=0.55 for difference between groups at 12 weeks)
  • No significant difference was observed in any other measure of hairpulling severity
  • Adverse events were similar across treatment groups with the exception of nausea, which was more commonly reported in the placebo group (63% vs. 30%); 1 patient receiving N-acetylcysteine reported a full-body rash that resolved with discontinuation of N-acetylcysteine

N-acetylcysteine had no benefit as an add-on treatment in children with trichotillomania: however, this trial was not adequately powered to detect a treatment difference

Grant et al,

200910

Randomized, double-blind, placebo-controlled study

12 weeks

N=50 adults age 18 to 65 years with a primary DSM-IV diagnosis of trichotillomania

N-acetylcysteine 1200 mg/day for 6 weeks, then 2400 mg/day (n=25)

Placebo (n=25)

  • After 12 weeks of treatment, mean MGH-HPS total score decreased from 17.6 to 10.4 in the N-acetylcysteine group and 16.7 to 16.0 in the placebo group  (p<0.001 for difference between groups at 12 weeks)
  • At week 12, 56% of patients receiving N-acetylcysteine were much or very much improved according to the Clinical Global Impression improvement scale; only 16% of patients taking placebo were much or very much improved (p=0.003)
  • No adverse events were reported in the N-acetylcysteine group

N-acetylcysteine is safe and more effective than placebo in the treatment of trichotillomania

Pathological Gambling/Gambling Disorder

Grant et al,

201411

Randomized, placebo-controlled trial

12 weeks

N=28 adults age 18 to 75 years with co-occurring DSM-IV diagnoses of nicotine dependence and pathological gambling for at least 6 months prior to study entry

N-acetylcysteine 1,200 mg/day with titration to 3,000 mg/day based on clinical judgment (n=13)

Placebo (n=15)

All patients additionally received smoking cessation treatment (weeks 0 through 6) and 6 sessions of imaginal desensitization plus motivational interviewing for pathological gambling (weeks 6 through 12)

  • Mean PG-YBOCS total score at baseline was 20.4 for placebo and 23.5 for N-acetylcysteine; at week 6, mean PG-YBOCS score was 16.3 for placebo and 17.4 for N-acetylcysteine, and at week 12, mean PG-YBOCS score was 5.5 for placebo and 7.5 for N-acetylcysteine (p=NS between groups at all time points)
  • At week 24 (12 weeks after study treatment was stopped), mean PG-YBOCS score was 6.4 in patients who had received placebo and 1.0 in patients who had received N-acetylcysteine (p=0.043)

N-acetylcysteine may be useful to augment behavioral therapy in patients with pathological gambling and co-existing nicotine dependence

Grant et al,

200712

Open-label pilot study

8 weeks

Additional 6-week double-blind discontinuation phase in patients with a 30% reduction in PG-YBOCS total score at 8 weeks

N=27 adults age 18 to 75 years with a primary diagnosis of pathological gambling based on DSM-IV criteria and a score of 15 or greater on the PG-YBOCS scale

Open-label pilot study:

  • N-acetylcysteine 600 mg/day for 2 weeks, then 1200 mg/day for 2 weeks, then 1800 mg/day (n=27)

Double-blind discontinuation phase:

  • N-acetylcysteine, same dose patient was receiving at completion of the open label phase (n=6)
  • Placebo (n=7)
  • At the end of the open-label phase, PG-YBOCS scores had decreased from a mean of 20.3 at baseline to a mean of 11.8 (p<0.001)
  • 51.9% of patients were very much improved according to the Clinical Global Impression improvement scale
  • 16 patients (59.3%) were classified as responders (≥30% decrease in PG-YBOCS total score), and 13 entered the double-blind discontinuation phase
  • At the end of the 6-week double-blind discontinuation phase, the PG-YBOCS total score was 7.2 for N-acetylcysteine and 10.6 for placebo (p=0.095)
  • 83.3% of patients assigned to N-acetylcysteine still met responder criteria at 6 weeks, while only 28.6% of patients receiving placebo still met responder criteria at 6 weeks (p=0.078)
  • 2 subjects reported mild flatulence during the open-label phase; no other adverse events were reported

The results of this small, open-label study show a positive effect of N-acetylcysteine in the treatment of pathological gambling

Abbreviations: DSM=Diagnostic and Statistical Manual of Mental Disorders; MGH-HPS=Massachusetts General Hospital Hairpulling Scale; NE-YBOCS=Yale-Brown Obsessive Compulsive Scale Modified for Neurotic Excoriation; NS=not significant; PG-YBOCS=Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling.

Conclusion

Studies examining N-acetylcysteine in the treatment of TTM, ED, and GD have generally shown positive results, but the overall quantity and quality of evidence is limited. Most studies were small, and thus underpowered to examine the adverse effects and tolerability of N-acetylcysteine. Additionally, most studies did not assess the long-term effects of N-acetylcysteine; in all available studies, patients were treated with N-acetylcysteine for 12 weeks or less. A number of the studies were unblinded or lacked a control group, which may have led to bias on the part of the patients or the investigators. Therefore, although the results from available trials are promising, larger randomized controlled trials are needed to fully examine the effects of N-acetylcysteine in TTM, ED, and GD, as well as confirm its safety and determine optimal dosing strategies.

References

  1. Schreiber L, Odlaug BL, Grant JE. Impulse control disorders: updated review of clinical characteristics and pharmacological management. Front Psychiatry. 2011;2:1. doi: 10.3389/fpsyt.2011.00001.
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
  4. Franca K, Kumar A, Castillo D, et al. Trichotillomania (hair pulling disorder): clinical characteristics, psychosocial aspects, treatment approaches, and ethical considerations [published online ahead of print August 28, 2018]. Dermatol Ther. doi:10.1111/dth.12622.
  5. Lochner C, Roos A, Stein DJ. Excoriation (skin-picking) disorder: a systematic review of treatment options. Neuropsychiatr Dis Treat. 2017;13:1867-1872.
  6. Choi SW, Shin YC, Kim DJ, et al. Treatment modalities for patients with gambling disorder. Ann Gen Psychiatry. 2017;16:23. doi:10.1186/s12991-017-0146-2.
  7. Racz R, Sweet BV, Sohoni P. Oral acetylcysteine for neuropsychiatric disorders. Am J Health Syst Pharm. 2015;72(11):923-929.
  8. Grant JE, Chamberlain SR, Redden SA, Leppink EW, Odlaug BL, Kim SW. N-acetylcysteine in the treatment of excoriation disorder: a randomized clinical trial. JAMA Psychiatry. 2016;73(5):490-496.
  9. Bloch MH, Panza KE, Grant JE, Pittenger C, Leckman JF. N-acetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial. J Am Acad Child Adolesc Psychiatry. 2013;52(3):231-240.
  10. Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania. Arch Gen Psychiatry. 2009;66(7):756-763.
  11. Grant JE, Odlaug BL, Chamberlain SR, et al. A randomized, placebo-controlled trial of N-acetylcysteine plus imaginal desensitization for nicotine-dependent pathological gamblers. J Clin Psychiatry. 2014;75(1):39-45.
  12. Grant JE, Kim SW, Odlaug BL. N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry. 2007;62(6):652-657.
  13. Miller JL, Angulo M. An open-label pilot study of N-acetylcysteine for skin picking in Prader-Willi syndrome. Am J Med Genet A. 2014;164A(2):421-424.

Prepared by:

Ioana Balta, PharmD Candidate 2020

College of Pharmacy

University of Illinois at Chicago

Reviewed by:

Laura Koppen, PharmD, BCPS

Clinical Assistant Professor

College of Pharmacy

University of Illinois at Chicago

January 2019

The information presented is current as of October 19, 2018. 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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What evidence supports the use of direct-acting oral anticoagulants in patients with cancer-related VTE?

Introduction

Cancer is a strong risk factor for venous thromboembolism (VTE), increasing the risk for this outcome by four to six times compared to patients without cancer.1  Patients with cancer who experience VTE should receive anticoagulation with low-molecular weight heparin (LMWH) for acute treatment and secondary prophylaxis.2,3  Guidelines prefer LMWH over vitamin K antagonists (VKAs) in this setting because of some evidence of greater efficacy and the practical challenges with VKAs in this population, such as drug interactions, insufficient absorption, and need for perioperative discontinuation.4  Nonetheless, many patients with cancer-related VTE are treated with VKAs, potentially because of the ease of administration and lower cost with oral therapy.4,5

The availability of direct-acting oral anticoagulants (DOACs), including apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban, has led to expanded study and use in a variety of patient populations.  Some findings indicate improved efficacy and safety of DOACs compared with VKAs and LMWH, leading to their preference in specific settings.6  These findings, along with the practical advantages of reduced monitoring requirements and oral administration, have raised questions regarding the potential for use of DOACs in cancer-related VTE.

Therapy of Acute Cancer-related VTE

Guideline recommendations for antithrombotic therapy in patients with cancer and VTE have evolved significantly over recent years as more data on DOAC safety and efficacy have become available.  In 2012, the 9th edition of the American College of Chest Physicians (ACCP) guideline recommended LMWH over VKA therapy in patients with cancer and VTE.7  For patients not treated with LMWH, the guideline recommended VKA therapy over the DOACs then available, dabigatran and rivaroxaban.  The latter recommendation was rooted in the paucity of data available at that time regarding DOAC use in cancer-related VTE, but the potential was noted for their greater preference and better outcomes.  Shortly thereafter, in 2013, the American Society of Clinical Oncology (ASCO) published guidelines on VTE treatment.2  Again, LMWH was preferred, and DOAC use was not recommended due to insufficient evidence.

In 2016, the recognition of the suitability of DOACs for treatment of cancer-related VTE started to become apparent.  The 2016 ACCP guideline (10th edition) on antithrombotic therapy for VTE disease still suggests LMWH over VKA in patients with VTE and cancer, but in patients not treated with LMWH, there is no preference for either VKA therapy or DOACs then available (apixaban, edoxaban, dabigatran, and rivaroxaban).3  Among DOACs, no particular agent is recommended, and product selection is dependent on clinical factors. This guideline recognized the similar reduction in risk for recurrent VTE between DOACs and VKAs, including in patients with cancer, although LMWH may be more effective than both oral options.

Most recently, guidelines from the Scientific and Standardization Committee of the International Society for Thrombosis and Hemostasis (ISTH) specifically address the role of DOACs in the treatment of cancer-related VTE.8  These guidelines have moved toward a preference for DOAC therapy, recommending their use in patients with cancer and acute VTE who have a low risk of bleeding and no risk of drug-drug interactions. Alternatively, LMWH is recommended. Similarly, the National Comprehensive Cancer Network guideline on cancer-associated venous thromboembolic disease now lists rivaroxaban along with LMWH as monotherapy options for treatment of VTE.9

Trials of Apixaban and Rivaroxaban in Cancer-related VTE

The recommendations for use of DOACs in cancer-related VTE from the ISTH draw mostly on evidence from two randomized clinical trials (RCTs) comparing DOACs with LMWH.8,10,11  The HOKUSAI-VTE Cancer RCT (n=1050) compared 6 to 12 months of therapy with subcutaneous (SC) dalteparin for at least 5 days followed by edoxaban 60 mg once daily versus continued dalteparin in patients with cancer-related VTE.10  The primary endpoint of recurrent VTE or major bleeding was noninferior with edoxaban therapy (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.70 to 1.36). Among these component endpoints, edoxaban lowered the risk of recurrent VTE numerically but not significantly, while significantly increasing major bleeding (6.9% vs 4.0%; risk difference, 2.9%; 95% CI, 0.1 to 5.6), which was more likely among patients with gastrointestinal cancer.

The SELECT-D trial (n=203) compared 6 months of therapy with SC dalteparin to oral rivaroxaban.11  After 3 weeks of rivaroxaban 15 mg twice daily, the dose was reduced to 20 mg once daily for the remainder of the trial.  The primary endpoint of VTE recurrence was significantly reduced with rivaroxaban versus dalteparin (4% vs 11%, respectively; HR, 0.43; 95% CI, 0.19 to 0.99). Rates of major bleeding were not significantly different (4% vs 6%, respectively), although clinically relevant non-major bleeding (CRNMB) was significantly increased with rivaroxaban (13% vs 4%, respectively; HR, 3.76; 95% CI, 1.63 to 8.69). Again, patients with esophageal or gastroesophageal cancer appeared to be at greater risk of major bleeding.

A meta-analysis of HOKUSAI-VTE Cancer and SELECT-D showed similar findings, with a marginally significant reduction in 6-month recurrent VTE with DOAC therapy versus LMWH (relative risk [RR], 0.65 95% CI, 0.42 to 1.01), and a higher risk of major bleeding (RR, 1.74; 95% CI, 1.05 to 2.88).12  Mortality did not differ between DOAC and LMWH therapy.

The HOKUSAI and SELECT-D RCTs provide high-quality evidence regarding DOAC use for acute VTE in patients with cancer, and now the AVERT RCT provides information on their role in the prevention of VTE.13 Thromboprophylaxis in this population has not been routinely recommended in ambulatory patients with cancer because the risks and inconveniences of parenteral therapy were not believed to outweigh their modest benefit.13,14  However, thromboprophylaxis is recommended to be considered for very select patients at high risk.2  The AVERT RCT studied such patients, who were initiating chemotherapy and were at intermediate to high risk of VTE (defined by Khorana score ≥2).13  The trial found apixaban 2.5 mg twice daily was noninferior and superior to placebo in reducing VTE risk (4.2% vs 10.2%; HR, 0.41; 95% CI, 0.26 to 0.65). Consistent with other trials, AVERT found apixaban significantly increased the risk of major bleeding (3.5% vs 1.8%; HR, 2.00; 95% CI, 1.01 to 3.95), although CRNMB did not differ.

Subgroup Analyses of DOACs in Cancer-related VTE

The HOKUSAI-VTE Cancer and SELECT-D trials represent the highest quality evidence available in treatment of patients with cancer-associated VTE because they specifically recruited these patients, but their findings are limited to edoxaban and rivaroxaban. Nonetheless, information on the safety and efficacy of other DOACs can be gleaned from subgroup analyses of cancer patients from their RCTs in treatment of acute VTE. While the numbers of patients with active cancer at any time during these trials were relatively low, subgroup analyses suggest trends toward greater efficacy with DOACs compared with standard care, though none found statistical evidence of superiority (Table).15-20

Data from these subgroups as well as from HOKUSAI-VTE Cancer and SELECT-D were used in a meta-analysis that estimated the efficacy and safety of DOAC versus standard care (LMWH or warfarin) in cancer-related VTE.16 Overall, the use of a DOAC significantly reduced the risk of VTE recurrence (RR, 0.64; 95% CI, 0.46 to 0.88), while there was no significant difference in risk of CRNMB (RR, 1.00; 95% CI, 0.75 to 1.33) or major bleeding (RR, 1.31; 0.71 to 2.44). While these results are encouraging, a limitation to this analysis is that the large HOKUSAI-VTE Cancer trial contributed most data for the analysis.

Table. Subgroup analyses of thrombotic and bleeding outcomes with DOACs vs standard care in patients with cancer-related VTE.16-20,a

Trial

RE-COVER-I & -II 17

RE-MEDY 16

EINSTEIN-DVT & -PE18

AMPLIFY19

HOKUSAI-VTE20

DOAC

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Control

Warfarin

Enoxaparin followed by warfarin

Enoxaparin followed by warfarin

Warfarin

Patients with cancer (n)

335

119

597

159

771

Recurrent VTE

5.2% vs 7.4%

3.3% vs 1.6%

5.1% vs 7.1%

3.7% vs 6.4%

3.7% vs 7.1%

Major bleeding

-

-

2.8% vs 5.0%

2.3% vs 5.0%

-

Major & CRNM bleeding

-

-

15.2% vs 15.8%

12.6% vs 22.5%

18.8% vs 25.9%

aIncidence rates reported as DOAC vs standard care.

Abbreviations: CRNM=clinically-relevant non-major; DOAC=direct-acting oral anticoagulant; VTE=venous thromboembolism.

Future Directions

Findings from HOKUSAI-VTE Cancer, SELECT-D, and AVERT significantly clarified the role of DOACs for treatment and prevention of cancer-related VTE. Nonetheless, some gaps in knowledge remain. For example, the findings from HOKUSAI and SELECT-D that patients with gastrointestinal cancer were at higher risk of bleeding is concerning, and further study may help confirm or refute this risk. Additionally, these trials contribute most of the current knowledge on this topic, and their results should not be extrapolated to a class-wide effect of other DOACs. For these other DOACs, subgroup analyses of apixaban and dabigatran RCTs should be considered preliminary until further data are available.1 Lastly, betrixaban has not been studied in cancer-related VTE and no clinical trials in this population are currently registered.21

Conclusion

Overall, findings from trials in patients with cancer-related VTE and from subgroups of patients with cancer in trials of VTE indicate trends toward greater efficacy with DOACs versus comparators in reducing recurrent VTE at the cost of significantly greater bleeding risk. The highest quality evidence is available for edoxaban and rivaroxaban, which have been studied in RCTs in patients with cancer-related VTE. Data on apixaban and dabigatran are limited to subgroup analyses from VTE trials. In addition, the AVERT trial showed benefit with apixaban for the prevention of VTE in cancer patients at high VTE risk. Guidelines are beginning to prefer DOACs over LMWH because of these emerging data and these drugs’ greater convenience. Further studies may shed light on the appropriate use of DOACs in this population, and may continue to reshape guideline recommendations. 

References

1.         Franco-Moreno A, Cabezon-Gutierrez L, Palka-Kotlowsa M, Villamayor-Delgado M, Garcia-Navarro M. Evaluation of direct oral anticoagulants for the treatment of cancer-associated thrombosis: an update. J Thromb Thrombolysis. 2018.

2.         Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(17):2189-2204.

3.         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.

4.         Witt DM, Clark NP. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: The McGraw-Hill Companies; 2014. accesspharmacy.mhmedical.com/content.aspx?aid=57503018.

5.         Delate T, Witt DM, Ritzwoller D, et al. Outpatient use of low molecular weight heparin monotherapy for first-line treatment of venous thromboembolism in advanced cancer. Oncologist. 2012;17:419-427.

6.         Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest. 2018;154(5):1121-1201.

7.         Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e419S-e494S.

8.         Khorana AA, Noble S, Lee AYY, et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16(9):1891-1894.

9.         Anonymous. Cancer-associated venous thromboembolic disease. National Comprehensive Cancer Network website. https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Published August 27, 2018. Accessed December 21, 2018.

10.       Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615-624.

11.       Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36(20):2017-2023.

12.       Li A, Garcia DA, Lyman GH, Carrier M. Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis. Thromb Res. 2019;173:158-163.

13.       Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer [published online ahead of print December 4, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1814468.

14.       Di Nisio M, Porreca E, Candeloro M, De Tursi M, Russi I, Rutjes AW. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev. 2016;12:CD008500.

15.       Schulman S, Kakkar AK, Goldhaber SZ, et al. RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-772.

16.       Al Yami MS, Badreldin HA, Mohammed AH, Elmubark AM, Alzahrani MY, Alshehri AM. Direct oral anticoagulants for the treatment of venous thromboembolism in patients with active malignancy: a systematic review and meta-analysis. J Thromb Thrombolysis. 2018;46:145-153.

17.       Schulman S, Goldhaber SZ, Kearon C, et al. Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost. 2015;114:150-157.

18.       Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21.

19.       Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost. 2015;13(12):2187-2191.

20.       Raskob GE, van Es N, Segers A, et al. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016;3(8):e379-387.

21.       US National Institutes of Health. Clinicaltrials.gov website. https://clinicaltrials.gov/. Accessed December 26, 2018.

Prepared by:

Ryan Rodriguez, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

January 2019

The information presented is current as December 20, 2018. 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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