July 2013 FAQs
July 2013 FAQs
Does azithromycin increase the risk of cardiovascular death?
Does azithromycin increase the risk of cardiovascular death?
Macrolide antibiotics have recently been in the spotlight for their association with cardiac death. The mechanism behind the cardiac death is believed to be QT interval prolongation.1 Medications associated with QT prolongation are often linked to torsades de pointes (TdP), which can result in sudden cardiac death.1-2 Erythromycin was the first macrolide to be associated with QT prolongation, but subsequent reports and studies have also described QT prolongation with clarithromycin and azithromycin.
In March 2012, the Food and Drug Administration (FDA) updated labeling for macrolide antibiotics to indicate the potential for QT prolongation and strengthened the warnings and precautions section with information related to TdP.3 Subsequently in May 2012, the FDA issued a statement on the increased risk of death with a 5-day course of azithromycin after results from a New England Journal of Medicine article by Ray and colleagues reported a small increase in cardiovascular deaths in persons treated with azithromycin compared to persons treated with amoxicillin, ciprofloxacin, or no drug therapy.3-5 In March 2013, the FDA issued an additional safety alert warning healthcare professionals to consider the cardiovascular safety concerns with azithromycin in patients with risk factors for cardiac events.4 Most recently, Svanström and colleagues revisited this topic and explored the cardiovascular risk with azithromycin use in the Danish population.6
We have previously summarized the study by Ray and colleagues ( http://dig.pharm.uic.edu/faq/2012/Jul/faq1.aspx).5 Briefly, the cohort study included adults enrolled in the Tennessee Medicaid program. Patients (347,795) with a 5-day course of azithromycin were compared to a control group of 1,391,672 patients with no prescription for antibiotics, a group of 1,348,672 patients with amoxicillin prescriptions, a group of 264,626 patients with ciprofloxacin prescriptions, and a group of 193,906 patients with prescriptions for levofloxacin. The primary endpoints were cardiovascular death and death from any cause. Patients were between the ages of 30 and 74 years and were excluded if they were considered at high risk for death from causes unrelated to a short-term exposure to a proarrhythmic medication, were hospitalized in the last 30 days, or resided in a nursing home within the last year.
Patients receiving azithromycin had an increased risk of cardiovascular mortality with 85.2 cases per 1 million courses compared with 29.8 per 1 million courses among patients with no antibiotic use (hazard ratio [HR] 2.88, 95% CI 1.79-4.63, p<0.001).5 Patients receiving azithromycin also had an increased risk of cardiovascular mortality compared with those receiving amoxicillin (HR 2.49, 95% 1.38-4.50, p=0.002) or ciprofloxacin (HR 3.49, 95% CI 1.32-9.26, p=0.01). In contrast, there was no increase in the risk of death for patients receiving amoxicillin or ciprofloxacin compared with no antibiotic use. The risk of cardiovascular mortality was similar between azithromycin and levofloxacin, with no significant difference seen. In addition to increased cardiovascular mortality, azithromycin was associated with an increased risk of death compared with no antibiotic or amoxicillin. The authors concluded that there was a small increase in cardiovascular deaths with azithromycin, but this was most evident in patients with a high baseline risk of cardiovascular disease, which accounted for 59% of the cardiovascular deaths during azithromycin therapy.5
A more recent study questioned whether the association of azithromycin with cardiovascular death can be generalized to populations that have relatively low cardiovascular risks compared with the population studied by Ray and colleagues.5,6 Svanström and colleagues retrospectively reviewed the chart of patients using azithromycin and compared them to those with no use of antibiotics or those with use of oral penicillin.6 The study population included all Denmark citizens between the ages of 18 and 64 years, but excluded those who had been hospitalized or had used any antibiotics within 30 days prior to the study date. The primary outcome was cardiovascular death, and the secondary outcome was death from noncardiovascular causes. Similar to Ray and colleagues, the timing of treatment was classified as current use (1 to 5 days) or recent use (6 to 10 days).5,6 This study also included past use (11 to 35 days), which was not evaluated in the previous study.
The study included 1,102,419 episodes of azithromycin use, 7,364,292 episodes of penicillin use, and 7,084,184 control episodes of no antibiotic use. 6 After propensity-score estimations and matching in a 1:1 ratio, 2,204,100 episodes were used in the analysis of azithromycin versus no use of antibiotics. The baseline characteristics of the groups were similar. The mean age ranged from 39.5 to 42 years among the groups, and few patients had acute coronary syndrome (1% to 2%), other ischemic disease (3%), or cerebrovascular disease (1% to 2%).
The risk of death from cardiovascular causes was significantly increased with current use of azithromycin (1.1 cases per 1000 patient-years) when compared to no antibiotics (0.4 cases per 1000 patient years, rate ratio [RR], 2.85; 95% CI 1.13-7.24).6 No significant risk was observed for recent or past use. Neither an unadjusted analysis nor a propensity score adjusted analysis associated azithromycin with a higher risk of cardiovascular death than penicillin. Current users of penicillin had 1.5 cases per 1000 patient years (RR compared with azithromycin 0.93, 95% CI 0.56-1.55). Again there was no risk difference for recent or past use. Noncardiovascular death was not increased with azithromycin compared with no antibiotic use (RR 1.60, 95% CI 1-2.54) or penicillin use (RR 0.75, 95% CI 0.55-10.1).
As compared with no antibiotics, Svanström and Ray both showed a significantly increased risk of cardiovascular death during current use of azithromycin. 5-6 The 2 studies found different outcomes when comparing the cardiovascular mortality with azithromycin to other antibiotics. In the study by Ray, azithromycin had increased mortality when compared to amoxicillin or ciprofloxacin. However, in the study by Svanström, when compared with penicillin, azithromycin was not associated with a significantly increased risk.
One explanation for the contrast seen between the studies is the different study populations. Ray and colleagues examined cardiovascular risk of death in a US Medicaid population with a higher baseline mortality risk versus a more general population in Denmark. The cardiovascular mortality rate per 1 million antibiotic courses was 85.2 in the study by Ray versus 15.4 in the study by Svanström. The authors hypothesized that the variation found in these studies was largely because the cardiovascular risk with azithromycin was greatest in patients with cardiovascular disease; thus, there were more cardiovascular deaths in this higher risk population.6 Furthermore, Ray and colleagues studied an older population with a mean age of 49 years compared to a mean age of 39 years in the Svanström study. Older patients may be more susceptible to drug-associated effects on the QT interval.7
The limitations of retrospective analyses must be considered in weighing the results of these studies. Unfortunately, a true cause and effect cannot be established with this type of study. Randomized controlled trials are required to establish a firm relationship, but these trials are often not large enough to detect a rare adverse event. In addition, some clinical trials for azithromycin have excluded patients with prolonged QT intervals, which eliminates patients that are at high risk for cardiovascular death.8
No true cause and effect relationship can be established between azithromycin use and cardiovascular mortality; however, the findings cannot be ignored. Healthcare professionals should consider individual patient risk factors for QT prolongation when prescribing azithromycin. Clinicians must consider the arrhythmogenic potential, not only of azithromycin, but also of concurrent medications.
1. Owens RC Jr. QT prolongation with antimicrobial agents: understanding the significance. Drugs. 2004;64(10):1091-1124.
2. Shaffer D, Singer S, Korvick J, Honig P. Concomitant risk factors in reports of torsades de points associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System. Clin Infect Dis. 2002;35(2):197-200.
3. FDA Statement regarding azithromycin (Zithromax) and the risk of cardiovascular death. U.S Food and Drug Administration website. http://www.fda.gov/Drugs/Drugsafety/ucm304372.htm. Updated 3/12/2013. Accessed May 5, 2013.
4. FDA Drug Safety Communication: azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms. U.S. Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm341822.htm. Updated 3/18/2013. Accessed May 5, 2013.
5. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881-1889.
6. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368(18):1704-1712.
7. Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Eur Heart J. 2000;21(15):1216-1231.
8. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-698.
Renee Thomas, PharmD
University of Illinois at Chicago
What safety risks prompted the labeling change that recommend against epidural administration of triamcinolone acetonide (Kenalog)?
What safety risks prompted the labeling change that recommend against epidural administration of triamcinolone acetonide (Kenalog)?
Epidural steroid injection (ESI) has been a treatment modality for low back pain (LBP) for decades.1 ESI is the administration of corticosteroids into the epidural space, around the spinal cord and spinal nerves. The beneficial effects of ESI are proposed to include decreased production of inflammatory mediators, depressed nerve conduction, and dilution of local concentrations of endogenous inflammatory cytokines.1,2 Given that LBP is now the second most common symptom-related cause for national physician office visits, ESI has become the most commonly performed intervention for LBP in the United States.1,3 Although minimally invasive and frequently used, inadvertent injection of drug into a vein or artery can result in serious complications, such as debilitating or fatal infarction of the brainstem or spinal cord.4
Corticosteroids commonly used in ESI include betamethasone, dexamethasone, methylprednisolone, and triamcinolone.5,6 Recently, a change in the product labeling of triamcinolone acetonide suspension for injection (Kenalog) stated that the product is not intended for intravenous, intramuscular, intraocular, epidural, or intrathecal use.7,8 This labeling change has caused confusion among physicians and pharmacists who have experience with the drug’s use in ESI and were unaware of reasons behind the labeling change.9
History of labeling revision of Kenalog
In June 2011, the warning and adverse events sections of the Kenalog package insert were updated to reflect the risk of injury with epidural administration.8 The update stated the product is intended for intra-articular and intralesional use only, and that intravenous, intramuscular, intraocular, epidural, and intrathecal administration are not recommended. In addition, the adverse events section of the label was updated to reflect information on reports of complications including spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke.
To communicate this important change, the Food and Drug Administration (FDA) issued a drug safety labeling change notification, but not a safety alert for human medical products, which typically contains more information on background, research, and recommendations in clear language.9,10 Thus, many clinicians were unaware of the notification and only discovered the change upon reviewing the product label. Reports have documented numerous cases of physicians who either were unaware of or overlooked the warning against epidural triamcinolone administration and continued this practice.9,10
Data on safety of ESI
The post-marketing safety data that prompted the manufacturer’s change to the Kenalog product labeling have not been published or released by the FDA. 9,10 Therefore, this source information is not currently available to describe the nature and frequency of adverse events associated with triamcinolone ESI. Although some published literature evaluating epidurally administered triamcinolone is available, it offers minimal insight into incidence rates of complications. Of 8 clinical trials of triamcinolone ESI in radiculopathy, sciatica, or post-laminectomy syndrome, 4 did not report information on adverse events and 3 reported no serious adverse events.11-18 Only 1 trial reported postdural puncture headache among 120 patients who received 3 weekly ESIs with triamcinolone.12 Thus, with such limited data from controlled trials, the incidence rate of serious complications due to triamcinolone ESI cannot be defined. Nevertheless, various case reports detail the nature of events, which have included spinal epidural lipomatosis, cauda equina syndrome, paraplegia, calcification, spinal cord infarction, intracranial hypotension, and pneumocephalus. 19-26
Corticosteroids as a class also lack high-quality evidence to describe the risk of adverse events associated with epidural administration, as clinical trials have generally not been well-designed and epidemiologic safety data have not been collected.27 Some useful data come from a national survey of physician members of the American Pain Society regarding their experience with adverse events following ESI.5 Of the 1340 surveyed physicians, 21.4% responded, revealing 78 total complications. Serious complications included 16 brain infarcts, 12 spinal cord infarcts, and 2 combined brain/spinal cord infarcts. Thirteen cases resulted in death. Corticosteroids were used in 70 of the reported complications, and when the type of corticosteroid was reported, use included methylprednisolone, betamethasone, and triamcinolone in 20, 3, and 3 complications, respectively. While data from this survey provide a useful perspective of types of complications, it does not allow estimation of risk via an incidence rate.
Drug characteristics affecting ESI safety
Results from the physician survey illustrate an important pharmaceutical consideration for corticosteroids used in ESI – their categorization as particulate versus non-particulate corticosteroids. Those considered more likely to aggregate into particles that may cause embolization following inadvertent injection into vertebral or foraminal arteries are termed particulate steroids; these include methylprednisolone and triamcinolone. 5,6,28 In contrast, those less likely to cause this complication are termed non-particulate steroids and are advocated by some as the corticosteroids of choice to reduce the risk of embolization.28 While dexamethasone is generally agreed to be a non-particulate steroid, classification of betamethasone has varied.5,29 Corticosteroids reported in the physician survey were all considered particulate steroids by the authors.5
Non-particulate corticosteroid preparations are considered to confer lower risk of embolism, as they contain particles smaller than red blood cells and exhibit low propensity to aggregate or pack.2,28 Microscopic analysis of steroid preparations has assessed such characteristics.28 Particles of triamcinolone (Kenalog) and betamethasone (Celestone Soluspan) equaled or exceeded the diameter of red blood cells and exhibited aggregation. Those of methylprednisolone (Depo-Medrol) were smaller than red blood cells and did not aggregate, although they were densely packed. Particle characteristics were most favorable in dexamethasone (Decadron), which showed sizes 10 times smaller than red blood cells and no aggregation.30 Dexamethasone has not yet been associated with complications of ESI, and even direct carotid artery injection in 8 rats did not cause any injury, while injection with Depo‑Medrol or Solu-Medrol in 15 of 19 rats caused cerebral hemorrhage.5,30,31 Importantly, randomized trials comparing outcomes of particulate versus non-particulate steroids have included few patients and not all reported safety outcomes.18,32,33 One of 3 trials reported no complications among 60 patients who completed the study, though 1 patient lost to follow-up inadvertently received drug intrathecally.32
Other pharmaceutical characteristics presumed to increase risk of injury include the presence of the neurotoxic preservatives polyethylene glycol (PEG) and benzyl alcohol.1 However, controversy has existed on which is the offending agent. Concentrations of PEG in corticosteroid preparations approximate 2.8% to 3%, while studies have shown changes in nerve conduction only at concentrations of 20% and greater.34 Additionally, benzyl alcohol is present in some preparations at concentrations of 0.9%, though injection of up to 9% produced only transient changes in animal models. 35 Some currently available corticosteroid preparations of methylprednisolone acetate contain PEG or benzyl alcohol, while some preparations of betamethasone, triamcinolone, and dexamethasone contain benzyl alcohol but not PEG.8,36-38
Importantly, drug characteristics are one of many considerations, including physical technique, to reduce the risk of complications with ESI. Ultimately, the selection of the type and dose of steroid used in ESI has long been based on clinician preference and no consensus is currently available on the optimum regimen.2
Triamcinolone acetonide, a corticosteroid that has been used in ESI, recently underwent a labeling change warning against its epidural administration due to the risk of serious complications. Adverse event reports that the manufacturer considered in submitting this labeling change have not been published. Additionally, high quality data are lacking to quantify the risk for serious complications with ESI, although numerous case reports describe the nature of complications, which may be serious or fatal. Until such data or consensus are available to determine the most appropriate steroid to use in ESI, risk may be reduced by use of non-particulate corticosteroids or preparations that do not include potentially neurotoxic preservatives.
1. Cohen SP, Bicket MC, Jamison D, Wilkinson I, Rathmell JP. Epidural steroids: a comprehensive, evidence-based review. Reg Anesth Pain Med. 2013;38(3):175-200.
2. Gharibo C, Koo C, Chung J, Moroz A. Epidural steroid injections: An update on mechanisms of injury and safety. Techniques Reg Anesth Pain Manage. 2009;13(4):266-271.
3. Epstein NE. The risks of epidural and transforaminal steroid injections in the Spine: Commentary and a comprehensive review of the literature. Surg Neurol Int. 2013;4(Suppl 2):S74-93.
4. Kloth DS, Calodney AK, Derby R, et al. Improving the safety of transforaminal epidural steroid injections in the treatment of cervical radiculopathy. Pain Physician. 2011;14(3):285-293.
5. Scanlon GC, Moeller-bertram T, Romanowsky SM, Wallace MS. Cervical transforaminal epidural steroid injections: more dangerous than we think? Spine. 2007;32(11):1249-1256.
6. Wilkinson IM, Cohen SP. Epidural steroid injections. Curr Pain Headache Rep. 2012;16(1):50-59.
7. KENALOG-10 [package insert].Princeton, NJ: Bristol-Myers Squibb Company; 2011. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ec04ecbb-2896-3feb-85fd-a64aba93b289.
8. Kenalog-10 (triamcinolone acetonide) injection and Kenalog-40 (triamcinolone acetonide) injection. Food and Drug Administration website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm262876.htm. Updated August 11, 2011. Accessed June 24, 2013.
9. Armstrong D. Bristol-Myers Warning Ignored on Steroid Shots Tied to Deaths. Bloomberg website. http://www.bloomberg.com/news/2012-01-25/bristol-myers-warning-ignored-on-steroid-shots-tied-to-deaths.html. Updated January 24, 2012. Accessed June 24, 2013.
10. Sadaka Associates. Deaths Reported After Doctors Ignored Kenalog Warning & FDA Failed To Adequately Warn. http://www.pharmawatchdog.com/deaths-reported-after-doctors-ignored-kenalog-warning-fda-failed-to-adequately-warn Updated January 31, 2012. Accessed June 24, 2013.
11. Rocco AG, Frank E, Kaul AF, Lipson SJ, Gallo JP. Epidural steroids, epidural morphine and epidural steroids combined with morphine in the treatment of post-laminectomy syndrome. Pain. 1989;36(3):297-303.
12. Arden NK, Price C, Reading I, et al. A multicentre randomized controlled trial of epidural corticosteroid injections for sciatica: the WEST study. Rheumatology (Oxford). 2005;44(11):1399-1406.
13. Kang SS, Hwang BM, Son HJ, et al. The dosages of corticosteroid in transforaminal epidural steroid injections for lumbar radicular pain due to a herniated disc. Pain Physician. 2011;14(4):361-370.
14. Lee JW, Park KW, Chung SK, et al. Cervical transforaminal epidural steroid injection for the management of cervical radiculopathy: a comparative study of particulate versus non-particulate steroids. Skeletal Radiol. 2009;38(11):1077-1082.
15. Becker C, Heidersdorf S, Drewlo S, De rodriguez SZ, Krämer J, Willburger RE. Efficacy of epidural perineural injections with autologous conditioned serum for lumbar radicular compression: an investigator-initiated, prospective, double-blind, reference-controlled study. Spine. 2007;32(17):1803-1808.
16. Kraemer J, Ludwig J, Bickert U, Owczarek V, Traupe M. Lumbar epidural perineural injection: a new technique. Eur Spine J. 1997;6(5):357-361.
17. Iversen T, Solberg TK, Romner B, et al. Effect of caudal epidural steroid or saline injection in chronic lumbar radiculopathy: multicentre, blinded, randomised controlled trial. BMJ. 2011;343:d5278.
18. Park CH, Lee SH, Kim BI. Comparison of the effectiveness of lumbar transforaminal epidural injection with particulate and nonparticulate corticosteroids in lumbar radiating pain. Pain Med. 2010;11(11):1654-1658.
19. Tok CH, Kaur S, Gangi A. Symptomatic spinal epidural lipomatosis after a single local epidural steroid injection. Cardiovasc Intervent Radiol. 2011;34 Suppl 2:S250-255.
20. Bilir A, Gulec S. Cauda equina syndrome after epidural steroid injection: a case report. J Manipulative Physiol Ther. 2006;29(6):492.e1-3.
21. Tripathi M, Nath SS, Gupta RK. Paraplegia after intracord injection during attempted epidural steroid injection in an awake-patient. Anesth Analg. 2005;101(4):1209-1211.
22. Darmoul M, Bouhaouala MH, Rezgui M. Calcification following intradiscal injection, a continuing problem?. Presse Med. 2005;34(12):859-860.
23. Ludwig MA, Burns SP. Spinal cord infarction following cervical transforaminal epidural injection: a case report. Spine. 2005;30(10):E266-268.
24. Huntoon MA, Martin DP. Paralysis after transforaminal epidural injection and previous spinal surgery. Reg Anesth Pain Med. 2004;29(5):494-495.
25. Dietrich CL, Smith CE. Epidural granuloma and intracranial hypotension resulting from cervical epidural steroid injection. Anesthesiology. 2004;100(2):445-447.
26. Simopoulos T, Peeters-asdourian C. Pneumocephalus after cervical epidural steroid injection. Anesth Analg. 2001;92(6):1576-1577.
27. Tonkovich-quaranta LA, Winkler SR. Use of epidural corticosteroids in low back pain. Ann Pharmacother. 2000;34(10):1165-1172.
28. Derby R, Lee SH, Date ES, Lee JH, Lee CH. Size and aggregation of corticosteroids used for epidural injections. Pain Med. 2008;9(2):227-234.
29. Manchikanti L, Cash KA, Pampati V, Wargo BW, Malla Y. Cervical epidural injections in chronic discogenic neck pain without disc herniation or radiculitis: preliminary results of a randomized, double-blind, controlled trial. Pain Physician. 2010;13(4):E265.
30. Berthelot JM, Le goff B, Maugars Y. Side effects of corticosteroid injections: What's new? [published online ahead of print January 22, 2013]. Joint Bone Spine. 2013. doi: 10.1016/j.jbspin.2012.12.001.
31. Dawley JD, Moeller-bertram T, Wallace MS, Patel PM. Intra-arterial injection in the rat brain: evaluation of steroids used for transforaminal epidurals. Spine. 2009;34(16):1638-1643.
32. Kim D, Brown J. Efficacy and safety of lumbar epidural dexamethasone versus methylprednisolone in the treatment of lumbar radiculopathy: a comparison of soluble versus particulate steroids. Clin J Pain. 2011;27(6):518-522.
33. Dreyfuss P, Baker R, Bogduk N. Comparative effectiveness of cervical transforaminal injections with particulate and nonparticulate corticosteroid preparations for cervical radicular pain. Pain Med. 2006;7(3):237-242.
34. Benzon HT, Gissen AJ, Strichartz GR, Avram MJ, Covino BG. The effect of polyethylene glycol on mammalian nerve impulses. Anesth Analg. 1987;66(6):553-559.
35. Deland FH. Intrathecal toxicity studies with benzyl alcohol. Toxicol Appl Pharmacol. 1973;25(2):153-156.
36. Depo-Medrol [package insert]. New York, NY: Pfizer; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ccb4d123-7b12-4aef-8ef0-f8d68c1a6547.
37. Celestone Soluspan [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7b5489a1-e30f-450f-bd2b-00d05fd52915.
38. Dexamethasone Sodium Phosphates [package insert]. Shirley, NY: American Regent, Inc.: 2009. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8ed678e2-8a6a-418d-af99-af46d54ae5c4.
What is the efficacy of prothrombin complex concentrates in the management of vitamin K antagonist-related major bleeding??
What is the efficacy of prothrombin complex concentrates in the management of vitamin K antagonist-related major bleeding?
Anticoagulation with a vitamin K antagonist (VKA) has been the mainstay of therapy for various arterial and venous thromboembolic disorders including atrial fibrillation (AF) and venous thromboembolism (VTE).1 Warfarin, a VKA, is frequently used in these patients due to availability of clinical evidence supporting its use and its familiarity among healthcare providers. Although effective, VKAs are associated with an increased risk for major bleeding. The incidence of major bleeding varies depending on the treatment indication and presence of patient and treatment-specific risk factors. The varying methodologies and definitions used in the literature make it difficult to accurately assess the event rate; however, the incidence of VKA-related major bleeding is low.
Risk of bleeding with VKAs is highly dependent on the international normalized ratio (INR).1,2 A significant increase in major hemorrhage is seen when the INR is > 4.5.2 In a meta-analysis of randomized controlled trials (RCTs) of patients treated with warfarin for AF, the rates of major bleeding ranged from 1.4% to 3.4% per year.3 A meta-analysis of major bleeding events with warfarin in patients treated for symptomatic VTE showed a similar occurrence with an incidence of 1.69% to 1.8% per year.4 Lastly, in patients treated with warfarin for prosthetic heart valves, bleeding events tended to be slightly higher and ranged from 0.3% to 8.3% per-patient year.5 Additionally, intracranial hemorrhage, in contrast to other bleeding episodes, is associated with significant morbidity and mortality rate of about 50%.1
Management of VKA-related bleeding
Rapid treatment of a VKA-related major hemorrhage is of vital importance.2 Treatment options include fresh frozen plasma (FFP), recombinant factor VIIa (rFVIIa), and prothrombin complex concentrates (PCCs; also referred to as Factor IX complexes), in addition to vitamin K (phytonadione). Fresh frozen plasma has been the mainstay of therapy, although all 3 treatment options have been used with varying degrees of success. The American College of Chest Physicians (ACCP) clinical practice guidelines currently recommend 4-factor PCCs over FFP for the reversal of VKA-related bleeding. These recommendations are grade 2C, indicating a weak recommendation based on low quality evidence where an uncertain balance of risk and benefit exists. This is due to the lack of well-designed RCTs comparing one agent to another.
Prothrombin complex concentrates
Prothrombin complex concentrates were first used for the treatment of patients with hemophilia B.6,7 Recently, they have gained attention in the treatment of VKA-related bleeding for their ability to rapidly and effectively correct the INR.6 Prothrombin complex concentrates are concentrated solutions derived from human plasma containing coagulation factors II, IX, X, and/or VII.7 They can be further divided into 3-factor and 4-factor PCCs depending on their factor VII content. Three-factor PCCs contain inactivated coagulation factors II, IX, and X, with minimal to no factor VII. Four-factor PCCs contain the same 3 coagulation factors with inactivated factor VII concentrations similar to their factor IX content. Both 3-factor and 4-factor PCCs have been studied for the treatment of major bleeding with VKAs, although none have been compared head-to-head.7 There are two 3-factor PCCs available in the United States—Profilnine SD and Bebulin. There is only one 4-factor PCC available in the United States, marketed under the name Kcentra and the only PCC in the United States that has a Food and Drug Administration (FDA)-approved indication for the management of VKA-associated major bleeding.8 Kcentra is also marketed under the name Beriplex P/N in 25 other counties. Another PCC, an activated PCC (aPCC, also referred to as Anti-inhibitor coagulant complex) is available in the United States under the name FEIBA NF. FEIBA NF differs from other PCCs in that it contains inactivated factors II, IX, and X and small amounts of activated factor VII.7
Table 1. Comparison of the 3- and 4-factor PCCs and aPCCs available in the United States.8,9
PCC Factor II Factor VII Factor IX Factor X Heparin Antithrombin III Protein C Protein S Bebulin 24-38 IU/mL <5 IU/mL 24-38 IU/mL 24-38 IU/mL <0.015 IU/IU factor IX – – – Profilnine SD NMT 150 units/100 factor IX units NMT 35 units/100 factor IX units 100 units NMT 100 units/100 factor IX units – – – – Kcentra 380-800 units/500 unit vial 200-500 units/500 unit vial 400-620 units/500 unit vial 500-1020 units/500 unit vial 8-40 units/500 unit vial 4-30 units/500unit vial 420-820 units/500 unit vial 240-680 units/500 unit vial FEIBANFa 1.3 IU/IU 0.9 IU/IU 1.4 IU/IU 1.1 IU/IU – – 1.1 IU/IU –
a Contains activated factor VII.
Abbreviations: aPCC, activated prothrombin complex concentrates; IU, international unit; NMT, no more than; PCC, prothrombin complex concentrate.
Literature review of efficacy of PCCs in treatment of VKA-related bleeding
A number of trials have been published evaluating the efficacy of PCCs, both 3- and 4-factor products, in the treatment of VKA-associated bleeding. All of the products in Table 1 have been evaluated in this setting and studies using products available in the United States are summarized in Tables 2 to 4 below. Currently, published trials on the efficacy of Kcentra in the reversal of VKA-associated bleeding are not available. However, as mentioned previously, Kcentra is marketed under the name Beriplex P/N in other countries and trials using Beriplex P/N are listed below as well. Information from data on file from the manufacturer for Kcentra is also summarized in Table 4.
Table 2. Efficacy of 3-factor PCCs for VKA-related bleeding.
Reference Study description INR/Bleeding site Patient population Outcomes (mean [range]) Holland et al10 (2009) Design: Retrospective analysis of 3-factor PCC + FFP using a PCC protocol
Treatment: One of 4 treatment groups: low-dose Profilnine SD 25 units/kg + FFP or high-dose 50 units/kg + FFP
Primary outcome: Reduction in INR from >5 to <3 within 24 hours of initial INR measurement
INR: All patients with INR >5
Patients with ICH were excluded
40 patients on warfarin therapy with INR >5 and major bleeding (n=29) or high risk for bleeding (n=11)
42 patients (including those with ICH) with INR >5 treated with FFP alone
Historical controls (n=42):
Pretreatment INR=9.4 (5.1-9.4)
Posttreatment (FPP alone) INR=2.3 (1.2-5)
62% of patients achieved primary outcome
Low-dose PCC alone (n=23):
Pretreatment INR=9 (5.2-15)
Posttreatment INR=4.6 (1.4-15)
55% of patients achieved primary outcome
High-dose PCC alone (n=17):
Pretreatment INR=8.6 (5.3-15)
Posttreatment INR=4.7 (1.4-15)
43% of patients achieved primary outcome
Low-dose PCC + FFP:
After addition of FFP, posttreatment INR=2.1 (1.6-3.3)
89% of patients achieved primary outcome
High-dose PCC + FFP:
After addition of FFP, posttreatment INR=2.0 (1.3-2.2)
93% of patients achieved primary outcome
Further reductions in INR were significant with addition of FFP (p=0.01 and p <0.01 for low- and high-dose PCC vs. PCC+FFP, respectively)
Chapman et al11 (2011) Design:
Retrospective chart review of trauma patients requiring anticoagulation reversal
Profilnine 20 units/kg ± FFP and vitamin K, with dose repeated based on INR
Time (in hours) to achieve an INR <1.5
INR >1.5 for inclusion
Bleeding was not an inclusion criteria
31 trauma patients included; 13 received PCC
Pretreatment INR=3.03 (1.8-8)
85% received concomitant FFP
36% received concomitant vitamin K
92 % of patients achieved an INR < 1.5
No PCC group:
Pretreatment INR=2.77 (1.7-5.3)
89% received FFP
61% received vitamin K
89% of patients achieved an INR <1.5
(p=nonsignificant for all between group comparisons)
Time (SD) to achieve INR <1.5 significantly shorter in the PCC group versus no PCC (16:59
[20:53] vs. 30:03 [23:10] hours; p = 0.048)
Three thromboembolic events occurred; 2 in the PCC group and one in the no PCC group
Of the 2 events that occurred in the PCC group, one was a catheter-associated DVT and the
other a femoral DVT in a patient with protein S deficiency and
history of pulmonary embolism
Baseline mean ISS scores were significantly higher in the PCC group versus the no PCC group
(17.8 vs. 9.1, p <0.001)
Abbreviations: DVT, deep vein thrombosis; FFP, fresh frozen plasma; ICH, intracranial hemorrhage; INR, international normalized ratio; ISS, injury severity score; PCC, prothrombin concentrate complex.
Table 3. Efficacy of the 4-factor aPCC in treatment of VKA-related bleeding.
Reference Study description INR/Bleeding site Patient population Outcomes (mean [range]) Wojcik et al12
Retrospective review of protocolized use of aPCC in VKA-related bleeding
Dose based on INR
<5, 500 units FEIBA;
≥5, 1000 units FEIBA with repeat dose (500 units) based on INR (if >1.5) 30 minutes after
Vitamin K 10 mg was given concomitantly
Normalization of the INR to
Patients stratified into 2 groups: INR < 5 and > 5
ICH (38.9%) and GI (23.6%) bleeding were the 2 most common sites for patients given aPCC
73 patients on warfarin with acute VKA-related bleeding
69 patients with similar characteristics who received FFP prior to availability of aPCC
Statistically significant difference in the number of patients with posttreatment INR
<1.4 in the aPCC group compared to FFP (50.7% vs. 33.3%; p=0.017)
Time to reach target INR was also significantly lower in the aPCC group versus FFP (2 vs. 25
aPCC group and INR <5 (n=51):
Pretreatment INR=2.6 (1.2-4.9)
Posttreatment INR=1.4 (1.1-3.2)
51.1% of patients achieved primary outcome versus 28.2% with FFP
aPCC group and INR ≥5 (n=21):
Pretreatment INR=12.8 (5.0-¥)
Posttreatment INR=1.5 (1.1-¥)
42.9% of patients achieved primary outcome versus 7.7% with FFP
All occurred in the aPCC group
One patient experienced a myocardial infarction 15 hours after aPCC administration; another
developed a catheter-associated DVT 2 weeks after aPCC
Abbreviations: aPCC, activated prothrombin complex concentrate; DVT, deep vein thrombosis; FFP, fresh frozen plasma; GI, gastrointestinal; ICH, intracranial hemorrhage; INR, international normalized ratio.
Table 4. Efficacy of 4-factor PCC in treatment of VKA-related bleeding.
Reference Study description INR/Bleeding site Patient population Outcomes (mean [range]) Pabinger et al13
Prospective, single-arm, multinational trial
Standard dose vitamin K followed by 25, 35, or 50 units/kg of Beriplex P/N for baseline INRs of 2-3.9, 4-6, or >6, respectively
Primary outcome :
INR normalization to <1.3 at 30 minutes after the end of PCC infusion
Clinical efficacy in stopping or preventing major hemorrhage as judged by investigators
Adverse events up to 90 days post-infusion
INR <4, n=26 patients (61%)
INR 4-6, n=7 patients (16%)
INR >6, n=10 patients (23%)
Other (bladder, hemarthrosis, intracranial, nasal, peritoneal, subdural)=14%
43 patients on VKAs with an INR >2 who required emergency surgical or diagnostic intervention (n=26) or had acute major bleeding (n=17)
Incision and drainage, and vascular surgery were most common procedures performed
Median baseline INR=3.2
Median posttransfusion INR=1.2
Primary outcome achieved in 40 patients (93%)
Remaining 3 patients achieved an INR of 1.4 at this time point
INR remained stable (median 1.2-1.3) for 48 hours postinfusion
Very good=40 patients (93%)
Satisfactory=2 patients (4.6%)
Questionable=1 patient (2.3%) with malignant bladder tumor and continued bleeding
25 patients (58%) experienced an ADR with 2 potential thromboembolic events
6 ADRs were considered serious; 3 patients died
Preston et al1
Open-label, noncomparative trial
Intravenous vitamin K 2 to 5 mg simultaneously with 25, 35, or 50 units/kg Beriplex P/N for baseline INRs of 2-3.9, 4-6, or >6, respectively
Primary outcome :
Rate of correction of warfarin-induced coagulopathy
Thrombovascular events, coagulation activation, DIC
Median (range) baseline INR=3.98 (2-27.6)
subdural hematoma, spontaneous hemorrhage, and emergency surgery (n=5 patients each)
42 patients requiring immediate reversal of VKA therapy
INR correction (<1.3) was seen in 78.5% of patients within 20 minutes
Remaining patients had INR values ranging from 1.3 to 1.9
No apparent evidence of DIC was seen
8 patients died, with one thromboembolic event seen; causes of death included heart failure, sepsis, acute pancreatitis, acute renal failure, severe
coronary atheroma, and ICH
Data on file (2013)
Prospective, randomized, open-label active-controlled, noninferiority trial
Plasma (n=104) or Kcentra (n=98) 25, 35, or 50 units/kg for baseline INRs of 2-<4, 4-6, or >6, respectively
Hemostatic efficacy as effective or not effective and INR reduction to <1.3 at 30 minutes post-infusion
212 patients with INR ≥2.0 with acute major bleeding and recent use of a VKA anticoagulant
Patients with a recent history of a thrombotic event, myocardial infarction, cerebrovascular accident, transient ischemic attack, unstable angina, severe
peripheral vascular disease, or DIC were excluded
72.4% effective hemostasis in the PCC group compared to 65.4% in the FFP group (difference 7.1%, 95% CI -5.8, 19.9), meeting noninferiority margin of
INR reduction to <1.3 at 30 minutes after infusion occurred in 62.2% and 9.6% of patients in the PCC and FFP group, respectively (difference
52.6%, 95% CI 39.4, 65.9)
Most common ADRs were hypotension, tachycardia, headache, nausea/vomiting, and arthralgia
9 (8.7%) in the PCC group experienced a potential thrombotic event (5 attributed to the PCC), compared to 6 patients (3 attributed to FFP) in the FFP group
Abbreviations: ADR, adverse drug reaction; CI, confidence interval; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; GI, gastrointestinal; ICH, intracranial hemorrhage; IM, intramuscular; INR, international normalized ratio; PCC, prothrombin concentrate complex; SC, subcutaneous; VKA, vitamin K antagonist.
Dosage and administration
Specific dosing and administration will depend on the PCC product used.7 The dose of PCC is based on the factor IX content.Both fixed-dosing strategies and dose based on body weight have been studied. Additionally, the dose administered depends on the baseline INR on presentation for some of the product formulations.8 For Kcentra, the dose depends on the presenting INR and patient weight, up to a maximum dosing weight of 100 kg (see Table 5). For the 3-factor PCCs, doses of 20 units/kg, 25 units/kg, and 50 units/kg have been used in clinical trials.10,11 FEIBA has been given as a fixed dose, based on INR, either 500 units or 1000 units.12
Table 5. Dosing information for Kcentra.8
Pretreatment International Normalized Ratio 2 to <4 4 to 6 >6 Dose (units of Factor IX/kg) 25 35 50 Maximum dose (units of Factor IX) 2500 3500 5000
The most concerning complication of PCC administration is thromboembolic events.6 Both 3- and 4-factor PCCs have been associated with such complications, with an event rate of up to 10% seen in clinical trials.8,10-13 Kcentra carries a box warning for this complication.8 Fatal and nonfatal venous and arterial events have occurred. The benefits of therapy should be carefully evaluated and compared to the potential risk of thrombosis.6,8 All patients should be monitored closely for any complication, especially those with a history of thromboembolism or at high risk for thromboembolic complications.
Vitamin K antagonist acute major hemorrhage is a rare, but serious complication of therapy that can be life-threatening if not treated appropriately. The mainstay of treatment has been the administration of FFP to acutely correct the coagulopathy, along with vitamin K for sustained normalization of the INR. Disadvantages of FFP include prolonged preparation and administration times, potential for viral transmission, transfusion-related acute lung injury (TRALI), large administration volumes, and need for blood type matching.6
Prothrombin complex concentrates may bypass the issues associated with FFP and offer clinicians an alternative treatment option. The 4-factor PCCs are now recommended over FFP in this setting according to the 2012 ACCP guidelines. Both 3- and 4-factor PCCs have been studied for the acute management of VKA-associated bleeding. The 3-factor PCCs available in the United States (Profilnine SD and Bebulin) have not been shown to be effective. Clinical trials have shown an incomplete response to treatment and inability to effectively normalize the INR, unless combined with FFP. In contrast, 4-factor PCCs, which until now have not been available in the United States, have shown good clinical utility in both retrospective and prospective clinical trials. The 4-factor PCC Kcentra has been shown to be noninferior to FFP in clinical hemostatic efficacy and superior to FFP in rapidly normalizing the INR, with complete reversal seen within 30 minutes after infusion in the majority of patients.15 Greater efficacy has also been seen with FEIBA, a 4-factor aPCC, versus FFP.12 Most adverse reactions to PCCs are minor, however, serious adverse effects in the form of arterial and venous thromboembolic events have occurred. As most patients treated with VKAs have clinical characteristics that predispose them to thromboembolic complications, the administration of a potential prothrombotic agent such as a PCC can predispose patients to new events.6 These events are seen more often in patients with multiple thrombotic risk factors and a history of a thromboembolic event, especially within the previous 3 months.8 Therefore, the risk for thromboembolic events with the use of any PCC agent should be weighed against the benefits of therapy, and caution should be used in high-risk patients.
1. Linkins LA. Bleeding risks associated with vitamin k antagonists. Blood Rev. 2013;27(3):111-118.
2. Holbrook A, Schulman S, Witt DM, et. al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9 th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e152S-184S.
3. Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med. 2012;172(8):623-631.
4. Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomized controlled trials. BMJ. 2012;13(345):e7498.
5. Salem DN, O’Gara PT, Madias C, Pauker SG. Valvular and structural heart disease: American college of chest physicians evidence-based clinical practice guidelines, 8th ed. Chest. 2008;133(6 Suppl):593S-629S.
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7. Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health Syst Pharm. 2013;70(10 Suppl 1):S12-21.
8. Kcentra [package insert]. Kankakee, IL: CSL Behring; April 2013.
9. Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm. 2012;69(17):1473-1484.
10. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009;49(6):1171-1177.
11. Chapman SA, Irwin ED, Beal AL, Kulinski NM, Hutson KE, Thorson MA. Prothrombin complex concentrate versus standard therapies for INR reversal in trauma patients receiving warfarin. Ann Pharmacother. 2011;45(7-8):869-875.
12. Wojcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med. 2009;2(4):217-225.
13. Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6(4):622-631.
14. Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol. 2002;116(3):619-624.
15. Data on File. CSL Behring, LLC. Last revised May 1, 2013.
Prepared by: Dejan Landup, PharmD
University of Illinois at Chicago