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Munchausen syndrome by adult proxy: A review of the literature

Author(s)

Mark B. Warren, MD

Maria I. Lapid, MD

J. Michael Bostwick, MD

Asher first described Munchausen syndrome by proxy over 60 years ago. Like the famous Baron von Munchausen, the persons affected have always traveled widely; and their stories like those attributed to him, are both dramatic and untruthful.[1] Munchausen syndrome is a psychiatric disorder in which a patient intentionally induces or feigns symptoms of physical or psychiatric illness to assume the sick role. In 1977, Meadow described the first case in which a caregiverperpetrator deliberately produced physical symptoms in a child for proxy gratification.[2] Unlike malingering, in which external incentives drive conscious symptom falsification, Munchausen syndrome by proxy (MSBP) is associated with fulfillment of the abuser's own psychological need for garnering praise from medical staff for devoted care given a sick child.[3, 4]

MSBP was once considered vanishingly rare. Many experts now believe it is more common, with a reported annual incidence of 0.4/100,000 in children younger than 16 years, and 2/100,000 in children younger than 1 year.[5] It is a disorder in which a parent, often the mother (94%99%)[6] and often with training or interest in the medical field,[5] is the perpetrator. The medical team caring for her child often views her as unusually helpful, and she is frequently psychiatrically ill with disorders such as depression, personality disorder, or prior personal history of somatoform or factitious disorder.[7, 8] The perpetrator typically inflicts physical harm, although occasionally she may simply lie about symptoms or tamper with laboratory samples.[5] The most common methods of inflicting harm are poisoning and suffocation. Overall mortality is 6% to 9%.[6, 9]

Although a large body of literature addresses pediatric cases, there is little to guide clinicians when victims are adults. An obvious reason may be that MSBP with adult proxies (MSB‐AP) has been reported so rarely, although we believe it is under‐recognized and more common than thought. The primary objective of this review was to identify all published cases of MSB‐AP, and synthesize them to characterize victims and perpetrators, modes of deceit, and relationships between victims and perpetrators so that clinicians will be better equipped to recognize such cases or at least include MSB‐AP in the differential of possibilities when symptoms and history are inconsistent.

METHODS

The Mayo Clinic Rochester Institutional Review Board approved this study. The databases of Ovid MEDLINE, Ovid EMBASE, PubMed, Web of Knowledge, and PsychINFO were searched from inception through April 2014 to identify all published cases of Munchausen by proxy in patients 18 years or older. The following search terms were used: Munchausen syndrome by proxy, factitious disorder by proxy, Munchausen syndrome, and factitious disorder. Reports were included when they described single or multiple cases of MSBP with victims aged at least 18 years. The search was not limited to articles published in English. Bibliographies of selected articles were reviewed for reports identifying additional cases.

RESULTS

We found 10 reports describing 11 cases of MSB‐AP and 1 report describing 2 unique cases of MSB‐AP (Tables 1 and 2). Two case reports were published in French[10, 11] and 1 in Polish.[12] Sigal et al.[13] describes 2 different victims with a common perpetrator, and another report[14] describes the same perpetrator with a third victim. One case, though cited as MSB‐AP in the literature was excluded because it did not meet the criteria for the disorder. In this case, the wife of a 28‐year‐old alcoholic male poured acid on him while he was inebriated, ostensibly to vent frustration and coerce him into sobriety.[15, 16]

Table 1.Munchausen Syndrome by Adult Proxy CasesVictim Descriptions
Author	Gender	Age, y	Presenting Features	Occupation/Education	Outcome
NOTE: Abbreviations: F, female; M, male; NP, not provided.
Sigal M et al. (1986)[13]	F	20s	Abscesses (skin)	NP	Death
	F	21	Abscesses (skin)	Child care	Paraplegia
Sigal MD et al. (1991)[14]	M	NP	Rash	NP	Abuse stopped
Smith NJ et al. (1989)[19]	M	69	None	Retired businessman	Continued fabrication
Krebs MO et al. (1996)[10]	M	40s	Coma	Businessman	Abuse stopped
Ben‐Chetrit E et al. (1998)[20]	F	73	Coma	NP	Abuse stopped
Feldman KW et al. (1998)[8]	F	21	NP	Developmental delay	NP
Chodorowsk Z et al. (2003)[12]	F	80	Syncope	NP	Abuse stopped
Strubel D et al. (2003)[11]	F	82	None	NP	NP
Granot R et al. (2004)[21]	M	71	Coma	NP	Abuse stopped
Deimel GW et al. (2012)[17]	F	23	Rash	High school graduate	Continued abuse
Deimel GW et al. (2012)[17]	F	21	Recurrent bacteremia	College student	Death
Singh A et al. (2013)[22]	F	79	Fluid overload/false symptom history	Retired	Continued

Table 2.Munchausen Syndrome by Adult Proxy CasesPerpetrator Descriptions
Author	Gender	Age, y	Relationship	Occupation	Mode of Abuse	Outcome When Confronted
NOTE: Abbreviations: F, female; M, male; NP, not provided. a Same person. b Benzodiazepines. c Sleeping pills mixed with alcohol.
Sigal M et al. (1986)[13]	M	26	Husbanda	Businessman	Poisoningb followed by subcutaneous gasoline injection	Confession and incarceration
	M	29	Boyfrienda	Businessman	Poisoningb followed by subcutaneous gasoline injection	Confession and incarceration
Sigal MD et al. (1991)[14]	M	34	Cellmatea	Worked in medical clinic where incarcerated	Poisoningc followed by subcutaneous turpentine injection	Confession and attempted murder conviction
Smith NJ et al. (1989)[19]	F	55	Companion	Nurse	False history of hematuria, weakness, headaches	Denial
Krebs MO et al. (1996)[10]	F	47	Wife	Nurse	Tranquilizer injections	Confession and placed on probation
Ben‐Chetrit E et al. (1998)[20]	F	NP	Daughter	Nurse	Insulin injections	Denial
Feldman KW et al. (1998)[8]	F	NP	Mother	Business woman	False history of Batten's disease	NP
Chodorowsk Z et al. (2003)[12]	F	NP	Granddaughter	NP	Poisoningb	Denial
Strubel D et al. (2003)[11]	M	NP	Son	NP	False history of memory loss	NP
Granot R et al. (2004)[21]	F	NP	Wife	Hospital employee	Poisoningb	Confession
Deimel GW et al. (2012)[17]	F	NP	Mother	Unemployed chronic medical problems	Toxin application to skin	Denial
Deimel GW et al. (2012)[17]	F	NP	Mother	Medical office receptionist	Intravenous injection unknown substance	Denial
Singh A et al. (2013)[22]	M	NP	Son	NP	Fluid administration in context of fluid restriction/erratic medication administration/falsifying severity of symptoms	Denial

Of the 13 victims, 9 (69%) were women and 4 (31%) were men. Of the ages reported, the median age was 69 years and the mean age was 51 (range, 2182 years). Exact age was not reported in 3 cases. Lying about signs and symptoms, but not actually inducing injury, occurred in 3 cases (23%), whereas in 10 cases (77%), the victims presented with physical findings, including coma (3), rash (2), skin abscesses (2), syncope (1), recurrent bacteremia (1), and fluid overload (1). Seven (54%) of the victims were poisoned, 2 via drug injection and 5 by beverage/food contamination. A perpetrator sedated 3 victims and subsequently injected them, 2 with gasoline and another with turpentine. Two of the victims were involved in business, 1 worked in childcare, 1 attended beauty school after graduating from high school, 1 attended college, and 1 was developmentally delayed. Victim education or occupation was not reported in 7 cases.

Of the 11 perpetrators, 8 (73%) were women, and 3 (27%) were men (note that the same male perpetrator had 3 victims). Median age was 34 years (range, 2655 years), although exact age was not reported in 4 cases. The perpetrator was the victim's mother in 3 cases, wife in 2 cases, son in 2 cases, and daughter, granddaughter, husband, companion, boyfriend, or prison cellmate in 1 case each. Five (38%) worked in healthcare.

All of the perpetrators were highly involved, even overly involved, in the care of their victims, frequently present, sometimes hovering, in hospital settings, and were viewed as generally helpful, if not overintrusive, by hospital staff. When confronted, 3 perpetrators confessed, 3 denied abuse that then ceased, and 4 more denied abuse that continued, culminating in death in 1 case. In 1 case, the outcome was not reported.[8] At least 3 victims remained with their perpetrators. Two perpetrators were criminally charged, 1 receiving probation and the other incarceration. The latter began abusing his cellmate, behavior that did not stop until he was confronted in prison.

CONCLUSION/DISCUSSION

Our primary objective was to locate and review all published cases of MSB‐AP. Our secondary aim was to describe salient characteristics of perpetrators, victims, and fabricated diseases in hopes of helping clinicians better recognize this disorder.

Our review shows that perpetrators were exclusively the victims' caregivers, including mothers, wives, husbands, daughters, granddaughters, or companions. These perpetrators, many with healthcare backgrounds, were attentive, helpful, and excessively present. In the majority of cases, hidden physical abuse yielded visible disease. Less commonly, perpetrators lied about symptoms rather than actually creating signs of disease. The most common mode of disease instigation involved poisoning through beverage/food contamination or subcutaneous injection. Geriatric and developmentally delayed persons appeared particularly vulnerable to victimization. Of the 13 victims, 5 were geriatric and 1 was developmentally delayed.

The adult cases we report are similar to child cases in that the perpetrators are caregivers; however, the caregivers of the adults are a more diverse group. Other similarities between adult and child cases are that physical signs occur more often than simply falsifying information, and poisoning is the most common method of disease fabrication. Suffocation, although common in child cases, has not been reported in adults. Though present in only a minority of cases, another feature distinguishing these cases from those reported in the pediatric literature is the presence of collusion between the perpetrator and victim. When MSBP was first described, Meadow believed that victims would reach an age at which the disorder would cease because they would fight back or report the abuse.[2] In 7 of the adult cases, the victims were unknowingly poisoned; however, in 2 cases,[17] the victims knew what their mothers were doing to them and yet denied that they were harming them. To explain this collusion, Deimel et al. proposed Stockholm syndrome, a condition in which a victim holds a perpetrator in high regard, despite experiencing at their hands what others might consider brainwashing and torture.

The data from the individual cases are sometimes frustratingly incomplete, with inconsistent reporting of dyad demographics and outcomes across the 13 cases, which compromises efforts to compare and contrast them. However, because no published studies have thoroughly reviewed all existing cases of MSB‐AP, we believe our review provides important insights into this condition by consolidating available information. It is our hope that by characterizing perpetrators, victims, and common presentations, we will raise awareness about this condition among healthcare providers so that it may be included in the differential diagnosis when they encounter this dyad: a patient's medical problems do not respond as expected to therapy and a caregivers appears overly involved or attention seeking.

The diagnosis of a factitious disorder often presents an immense clinical challenge and generally involves a multidisciplinary approach.[18] In addition to the incomplete data for existing cases in the literature, we recognize the ongoing difficulties in precise diagnosis of this disorder. Because a hallmark of pathology is secrecy at the outset and often denial, and even abrupt transition of care, upon confrontation, it is often very difficult, especially early on, to uncover patterns of perpetration, let alone posit a motive. We recognize that there may be some perpetrators who are motivated by something other than purely psychological end points, such as financial reward or even sexual victimization. And when alternate care venues are sought, clinicians are often left wondering. Further, the damage that may come to a therapeutic relationship by prematurely diagnosing MSB‐AP is important to keep in mind. Hospitalists who suspect MSB‐AP should consult psychiatry. Although MSB‐AP is a diagnosis of exclusion and often based on circumstantial evidence, psychiatry can assist in diagnosing this disorder and, in the event of a confession, provide immediate therapeutic intervention. Social services can aid in a vulnerable adult investigation for patients who do not have capacity.

When Meadow first described MSBP, he ended his article by asking Is this degree of falsification rare or is it under‐recognized? Time has answered Meadow's question. Now we ask the same question with regard to MSB‐AP, is it rare or under‐recognized? We must remain vigilant for this disorder. Early recognition can prevent healthcare providers from unknowingly perpetuating victimization by treating caregiver‐induced pathology as if legitimate, thereby satisfying the perpetrator's psychological needs. Despite Meadow's assertion that proxies outgrow their victimization, our review warns that advanced age does not preclude vulnerability and in some cases, may actually increase it. In the future, the incidence and prevalence of MSB‐AP is likely to increase as medical technology allows greater survival of cognitively impaired populations who are dependent on others for care. The elderly and developmentally delayed may be especially at risk.

ACKNOWLEDGMENTS

Disclosures: M.C.B., M.B.W., and M.I.L. report no conflicts of interest. J.M.B. receives payment for lectures, including service on speakers bureaus, from nonprofit continuing medical education organizations and universities for occasional lectures; however, this funding is not relevant to this review.

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References

Asher R. Munchausen syndrome. Lancet. 1951(1):339–341.
Meadow R. Munchausen syndrome by proxy. The hinterland of child abuse. Lancet. 1977;2(8033):343–345.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. 4th ed. Washington, DC: American Psychiatric Press; 2000.
Ayoub CC, Alexander R, Beck D, et al. Position paper: definitional issues in Munchausen by proxy. Child Maltreat. 2002;7(2):105–111.
McClure RJ, Davis PM, Meadow SR, Sibert JR. Epidemiology of Munchausen syndrome by proxy, non‐accidental poisoning, and non‐accidental suffocation. Arch Dis Child. 1996;75(1):57–61.
Rosenberg DA. Web of deceit: a literature review of Munchausen syndrome by proxy. Child Abuse Negl. 1987;11(4):547–563.
Bass C, Jones D. Psychopathology of perpetrators of fabricated or induced illness in children: case series. Br J Psychiatry. 2011;199(2):113–118.
Feldman KW, Hickman RO. The central venous catheter as a source of medical chaos in Munchausen syndrome by proxy. J Pediatr Surg. 1998;33(4):623–627.
Schreier HA, Libow JA. Munchausen syndrome by proxy: diagnosis and prevalence. Am J Orthopsychiatry. 1993;63(2):318–321.
Krebs MO, Bouden A, Loo H, Olie JP. Munchhausen syndrome by proxy between two adults [in French]. Presse Med. 1996;25(12):583–586.
Strubel D, Docher C, LaPierre M. Munchhausen syndrome by proxy in an old woman [in French]. Revue Geriatr. 2003;28:425–428.
Chodorowsk Z, Anand JS, Porzezinska B, Markiewicz A. Consciousness disturbances: a case report of Munchausen by proxy syndrome in an elderly patient [in Polish]. Przegl Lek. 2003;60(4):307–308.
Sigal MD, Altmark D, Carmel I. Munchausen syndrome by adult proxy: a perpetrator abusing two adults. J Nerv Ment Dis. 1986;174(11):696–698.
Sigal M, Altmark D, Gelkopf M. Munchausen syndrome by adult proxy revisited. Isr J Psychiatry Relat Sci. 1991;28(1):33–36.
Alicandri‐Ciufelli M, Moretti V, Ruberto M, Monzani D, Chiarini L, Presutti L. Otolaryngology fantastica: the ear, nose, and throat manifestations of Munchausen's syndrome. Laryngoscope. 2012;122(1):51–57.
Somani VK. Witchcraft's syndrome: Munchausen's syndrome by proxy. Int J Dermatol. 1998;37(3):229–230.
Deimel GW, Burton MC, Raza SS, Lehman JS, Lapid MI, Bostwick JM. Munchausen syndrome by proxy: an adult dyad. Psychosomatics. 2012;53(3):294–299.
Bass C, Halligan P. Factitious disorders and malingering: challenges for clinical assessment and management. Lancet. 2014;383(9926):1422–1432.
Smith NJ, Ardern MH. More in sickness than in health: a case study of Munchausen by proxy in the elderly. J Fam Ther. 1989;11(4):321–334.
Ben‐Chetrit E, Melmed RN. Recurrent hypoglycaemia in multiple myeloma: a case of Munchausen syndrome by proxy in an elderly patient. J Intern Med. 1998;244(2):175–178.
Granot R, Berkovic SF, Patterson S, Hopwood M, Mackenzie R. Idiopathic recurrent stupor: a warning. J Neurol Neurosurg Psychiatry. 2004;75(3):368–369.
Singh A, Coppock M, Mukaetova‐Ladinska EB. Munchausen by proxy in older adults: A case report. Maced J Med Sci. 2013;6(2):178–181.

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Issue

Journal of Hospital Medicine - 10(1)

Page Number

32-35

Read more about Munchausen Syndrome by Adult Proxy

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Original Research

Author(s)

Mark B. Warren, MD

Maria I. Lapid, MD

J. Michael Bostwick, MD

Author(s)

Mark B. Warren, MD

Maria I. Lapid, MD

J. Michael Bostwick, MD

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Files

Article PDF

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METHODS

RESULTS

Table 1.Munchausen Syndrome by Adult Proxy CasesVictim Descriptions
Author	Gender	Age, y	Presenting Features	Occupation/Education	Outcome
NOTE: Abbreviations: F, female; M, male; NP, not provided.
Sigal M et al. (1986)[13]	F	20s	Abscesses (skin)	NP	Death
	F	21	Abscesses (skin)	Child care	Paraplegia
Sigal MD et al. (1991)[14]	M	NP	Rash	NP	Abuse stopped
Smith NJ et al. (1989)[19]	M	69	None	Retired businessman	Continued fabrication
Krebs MO et al. (1996)[10]	M	40s	Coma	Businessman	Abuse stopped
Ben‐Chetrit E et al. (1998)[20]	F	73	Coma	NP	Abuse stopped
Feldman KW et al. (1998)[8]	F	21	NP	Developmental delay	NP
Chodorowsk Z et al. (2003)[12]	F	80	Syncope	NP	Abuse stopped
Strubel D et al. (2003)[11]	F	82	None	NP	NP
Granot R et al. (2004)[21]	M	71	Coma	NP	Abuse stopped
Deimel GW et al. (2012)[17]	F	23	Rash	High school graduate	Continued abuse
Deimel GW et al. (2012)[17]	F	21	Recurrent bacteremia	College student	Death
Singh A et al. (2013)[22]	F	79	Fluid overload/false symptom history	Retired	Continued

Table 2.Munchausen Syndrome by Adult Proxy CasesPerpetrator Descriptions
Author	Gender	Age, y	Relationship	Occupation	Mode of Abuse	Outcome When Confronted
NOTE: Abbreviations: F, female; M, male; NP, not provided. a Same person. b Benzodiazepines. c Sleeping pills mixed with alcohol.
Sigal M et al. (1986)[13]	M	26	Husbanda	Businessman	Poisoningb followed by subcutaneous gasoline injection	Confession and incarceration
	M	29	Boyfrienda	Businessman	Poisoningb followed by subcutaneous gasoline injection	Confession and incarceration
Sigal MD et al. (1991)[14]	M	34	Cellmatea	Worked in medical clinic where incarcerated	Poisoningc followed by subcutaneous turpentine injection	Confession and attempted murder conviction
Smith NJ et al. (1989)[19]	F	55	Companion	Nurse	False history of hematuria, weakness, headaches	Denial
Krebs MO et al. (1996)[10]	F	47	Wife	Nurse	Tranquilizer injections	Confession and placed on probation
Ben‐Chetrit E et al. (1998)[20]	F	NP	Daughter	Nurse	Insulin injections	Denial
Feldman KW et al. (1998)[8]	F	NP	Mother	Business woman	False history of Batten's disease	NP
Chodorowsk Z et al. (2003)[12]	F	NP	Granddaughter	NP	Poisoningb	Denial
Strubel D et al. (2003)[11]	M	NP	Son	NP	False history of memory loss	NP
Granot R et al. (2004)[21]	F	NP	Wife	Hospital employee	Poisoningb	Confession
Deimel GW et al. (2012)[17]	F	NP	Mother	Unemployed chronic medical problems	Toxin application to skin	Denial
Deimel GW et al. (2012)[17]	F	NP	Mother	Medical office receptionist	Intravenous injection unknown substance	Denial
Singh A et al. (2013)[22]	M	NP	Son	NP	Fluid administration in context of fluid restriction/erratic medication administration/falsifying severity of symptoms	Denial

CONCLUSION/DISCUSSION

ACKNOWLEDGMENTS

METHODS

RESULTS

Table 1.Munchausen Syndrome by Adult Proxy CasesVictim Descriptions
Author	Gender	Age, y	Presenting Features	Occupation/Education	Outcome
NOTE: Abbreviations: F, female; M, male; NP, not provided.
Sigal M et al. (1986)[13]	F	20s	Abscesses (skin)	NP	Death
	F	21	Abscesses (skin)	Child care	Paraplegia
Sigal MD et al. (1991)[14]	M	NP	Rash	NP	Abuse stopped
Smith NJ et al. (1989)[19]	M	69	None	Retired businessman	Continued fabrication
Krebs MO et al. (1996)[10]	M	40s	Coma	Businessman	Abuse stopped
Ben‐Chetrit E et al. (1998)[20]	F	73	Coma	NP	Abuse stopped
Feldman KW et al. (1998)[8]	F	21	NP	Developmental delay	NP
Chodorowsk Z et al. (2003)[12]	F	80	Syncope	NP	Abuse stopped
Strubel D et al. (2003)[11]	F	82	None	NP	NP
Granot R et al. (2004)[21]	M	71	Coma	NP	Abuse stopped
Deimel GW et al. (2012)[17]	F	23	Rash	High school graduate	Continued abuse
Deimel GW et al. (2012)[17]	F	21	Recurrent bacteremia	College student	Death
Singh A et al. (2013)[22]	F	79	Fluid overload/false symptom history	Retired	Continued

Table 2.Munchausen Syndrome by Adult Proxy CasesPerpetrator Descriptions
Author	Gender	Age, y	Relationship	Occupation	Mode of Abuse	Outcome When Confronted
NOTE: Abbreviations: F, female; M, male; NP, not provided. a Same person. b Benzodiazepines. c Sleeping pills mixed with alcohol.
Sigal M et al. (1986)[13]	M	26	Husbanda	Businessman	Poisoningb followed by subcutaneous gasoline injection	Confession and incarceration
	M	29	Boyfrienda	Businessman	Poisoningb followed by subcutaneous gasoline injection	Confession and incarceration
Sigal MD et al. (1991)[14]	M	34	Cellmatea	Worked in medical clinic where incarcerated	Poisoningc followed by subcutaneous turpentine injection	Confession and attempted murder conviction
Smith NJ et al. (1989)[19]	F	55	Companion	Nurse	False history of hematuria, weakness, headaches	Denial
Krebs MO et al. (1996)[10]	F	47	Wife	Nurse	Tranquilizer injections	Confession and placed on probation
Ben‐Chetrit E et al. (1998)[20]	F	NP	Daughter	Nurse	Insulin injections	Denial
Feldman KW et al. (1998)[8]	F	NP	Mother	Business woman	False history of Batten's disease	NP
Chodorowsk Z et al. (2003)[12]	F	NP	Granddaughter	NP	Poisoningb	Denial
Strubel D et al. (2003)[11]	M	NP	Son	NP	False history of memory loss	NP
Granot R et al. (2004)[21]	F	NP	Wife	Hospital employee	Poisoningb	Confession
Deimel GW et al. (2012)[17]	F	NP	Mother	Unemployed chronic medical problems	Toxin application to skin	Denial
Deimel GW et al. (2012)[17]	F	NP	Mother	Medical office receptionist	Intravenous injection unknown substance	Denial
Singh A et al. (2013)[22]	M	NP	Son	NP	Fluid administration in context of fluid restriction/erratic medication administration/falsifying severity of symptoms	Denial

CONCLUSION/DISCUSSION

ACKNOWLEDGMENTS

References

Asher R. Munchausen syndrome. Lancet. 1951(1):339–341.
Meadow R. Munchausen syndrome by proxy. The hinterland of child abuse. Lancet. 1977;2(8033):343–345.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. 4th ed. Washington, DC: American Psychiatric Press; 2000.
Ayoub CC, Alexander R, Beck D, et al. Position paper: definitional issues in Munchausen by proxy. Child Maltreat. 2002;7(2):105–111.
McClure RJ, Davis PM, Meadow SR, Sibert JR. Epidemiology of Munchausen syndrome by proxy, non‐accidental poisoning, and non‐accidental suffocation. Arch Dis Child. 1996;75(1):57–61.
Rosenberg DA. Web of deceit: a literature review of Munchausen syndrome by proxy. Child Abuse Negl. 1987;11(4):547–563.
Bass C, Jones D. Psychopathology of perpetrators of fabricated or induced illness in children: case series. Br J Psychiatry. 2011;199(2):113–118.
Feldman KW, Hickman RO. The central venous catheter as a source of medical chaos in Munchausen syndrome by proxy. J Pediatr Surg. 1998;33(4):623–627.
Schreier HA, Libow JA. Munchausen syndrome by proxy: diagnosis and prevalence. Am J Orthopsychiatry. 1993;63(2):318–321.
Krebs MO, Bouden A, Loo H, Olie JP. Munchhausen syndrome by proxy between two adults [in French]. Presse Med. 1996;25(12):583–586.
Strubel D, Docher C, LaPierre M. Munchhausen syndrome by proxy in an old woman [in French]. Revue Geriatr. 2003;28:425–428.
Chodorowsk Z, Anand JS, Porzezinska B, Markiewicz A. Consciousness disturbances: a case report of Munchausen by proxy syndrome in an elderly patient [in Polish]. Przegl Lek. 2003;60(4):307–308.
Sigal MD, Altmark D, Carmel I. Munchausen syndrome by adult proxy: a perpetrator abusing two adults. J Nerv Ment Dis. 1986;174(11):696–698.
Sigal M, Altmark D, Gelkopf M. Munchausen syndrome by adult proxy revisited. Isr J Psychiatry Relat Sci. 1991;28(1):33–36.
Alicandri‐Ciufelli M, Moretti V, Ruberto M, Monzani D, Chiarini L, Presutti L. Otolaryngology fantastica: the ear, nose, and throat manifestations of Munchausen's syndrome. Laryngoscope. 2012;122(1):51–57.
Somani VK. Witchcraft's syndrome: Munchausen's syndrome by proxy. Int J Dermatol. 1998;37(3):229–230.
Deimel GW, Burton MC, Raza SS, Lehman JS, Lapid MI, Bostwick JM. Munchausen syndrome by proxy: an adult dyad. Psychosomatics. 2012;53(3):294–299.
Bass C, Halligan P. Factitious disorders and malingering: challenges for clinical assessment and management. Lancet. 2014;383(9926):1422–1432.
Smith NJ, Ardern MH. More in sickness than in health: a case study of Munchausen by proxy in the elderly. J Fam Ther. 1989;11(4):321–334.
Ben‐Chetrit E, Melmed RN. Recurrent hypoglycaemia in multiple myeloma: a case of Munchausen syndrome by proxy in an elderly patient. J Intern Med. 1998;244(2):175–178.
Granot R, Berkovic SF, Patterson S, Hopwood M, Mackenzie R. Idiopathic recurrent stupor: a warning. J Neurol Neurosurg Psychiatry. 2004;75(3):368–369.
Singh A, Coppock M, Mukaetova‐Ladinska EB. Munchausen by proxy in older adults: A case report. Maced J Med Sci. 2013;6(2):178–181.

References

Asher R. Munchausen syndrome. Lancet. 1951(1):339–341.
Meadow R. Munchausen syndrome by proxy. The hinterland of child abuse. Lancet. 1977;2(8033):343–345.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. 4th ed. Washington, DC: American Psychiatric Press; 2000.
Ayoub CC, Alexander R, Beck D, et al. Position paper: definitional issues in Munchausen by proxy. Child Maltreat. 2002;7(2):105–111.
McClure RJ, Davis PM, Meadow SR, Sibert JR. Epidemiology of Munchausen syndrome by proxy, non‐accidental poisoning, and non‐accidental suffocation. Arch Dis Child. 1996;75(1):57–61.
Rosenberg DA. Web of deceit: a literature review of Munchausen syndrome by proxy. Child Abuse Negl. 1987;11(4):547–563.
Bass C, Jones D. Psychopathology of perpetrators of fabricated or induced illness in children: case series. Br J Psychiatry. 2011;199(2):113–118.
Feldman KW, Hickman RO. The central venous catheter as a source of medical chaos in Munchausen syndrome by proxy. J Pediatr Surg. 1998;33(4):623–627.
Schreier HA, Libow JA. Munchausen syndrome by proxy: diagnosis and prevalence. Am J Orthopsychiatry. 1993;63(2):318–321.
Krebs MO, Bouden A, Loo H, Olie JP. Munchhausen syndrome by proxy between two adults [in French]. Presse Med. 1996;25(12):583–586.
Strubel D, Docher C, LaPierre M. Munchhausen syndrome by proxy in an old woman [in French]. Revue Geriatr. 2003;28:425–428.
Chodorowsk Z, Anand JS, Porzezinska B, Markiewicz A. Consciousness disturbances: a case report of Munchausen by proxy syndrome in an elderly patient [in Polish]. Przegl Lek. 2003;60(4):307–308.
Sigal MD, Altmark D, Carmel I. Munchausen syndrome by adult proxy: a perpetrator abusing two adults. J Nerv Ment Dis. 1986;174(11):696–698.
Sigal M, Altmark D, Gelkopf M. Munchausen syndrome by adult proxy revisited. Isr J Psychiatry Relat Sci. 1991;28(1):33–36.
Alicandri‐Ciufelli M, Moretti V, Ruberto M, Monzani D, Chiarini L, Presutti L. Otolaryngology fantastica: the ear, nose, and throat manifestations of Munchausen's syndrome. Laryngoscope. 2012;122(1):51–57.
Somani VK. Witchcraft's syndrome: Munchausen's syndrome by proxy. Int J Dermatol. 1998;37(3):229–230.
Deimel GW, Burton MC, Raza SS, Lehman JS, Lapid MI, Bostwick JM. Munchausen syndrome by proxy: an adult dyad. Psychosomatics. 2012;53(3):294–299.
Bass C, Halligan P. Factitious disorders and malingering: challenges for clinical assessment and management. Lancet. 2014;383(9926):1422–1432.
Smith NJ, Ardern MH. More in sickness than in health: a case study of Munchausen by proxy in the elderly. J Fam Ther. 1989;11(4):321–334.
Ben‐Chetrit E, Melmed RN. Recurrent hypoglycaemia in multiple myeloma: a case of Munchausen syndrome by proxy in an elderly patient. J Intern Med. 1998;244(2):175–178.
Granot R, Berkovic SF, Patterson S, Hopwood M, Mackenzie R. Idiopathic recurrent stupor: a warning. J Neurol Neurosurg Psychiatry. 2004;75(3):368–369.
Singh A, Coppock M, Mukaetova‐Ladinska EB. Munchausen by proxy in older adults: A case report. Maced J Med Sci. 2013;6(2):178–181.

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Managing snoring: When to consider surgery

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Duc A. Tien, MD

Alan Kominsky, MD

Snoring can range in significance from disturbing a bed partner to being a symptom of obstructive sleep apnea, a risk factor for cardiac disease and stroke. Snoring that is unrelated to obstructive sleep apnea may respond to a combination of nonsurgical treatments. However, if the problem persists despite conservative therapy, then surgical options may be considered.

This article explores why people snore, provides guidance for evaluating it and ruling out obstructive sleep apnea, and describes the available surgical treatments. Snoring associated with obstructive sleep apnea requires a different surgical treatment strategy that is beyond the scope of this article.

WHY PEOPLE SNORE

Humans go through four stages of sleep in each sleep cycle (and four or five cycles per night), and each stage has unique physiologic characteristics. As we progress deeper into sleep with each successive stage, the skeletal muscles of the body relax and eventually become atonic, except for the respiratory and ocular muscles. Soft tissues of the upper aerodigestive tract also lose their muscular tone.

Snoring is an undesirable vibratory sound that originates from the soft tissues of the upper respiratory tract during sleep, as airflow causes the relaxed tissues to vibrate.

The upper airway can be obstructed by the nasal septum, inferior nasal turbinates, adenoids, tonsils, uvula, soft palate, and base of the tongue—and often by more than one (Figure 1).³ In rare cases, obstruction can occur at the level of the larynx, such as from a tumor, laryngomalacia, or a laryngeal defect.

A SPECTRUM OF SLEEP-DISORDERED BREATHING

The American Academy of Sleep Medicine’s International Classification of Sleep Disorders¹ defines a number of sleep disorders. In clinical practice, the first-line diagnostic test for sleep disorders is polysomnography.

Snoring is only one sign of sleep-disordered breathing; others are excessive daytime somnolence, restless sleep, and witnessed apnea.

Considerable evidence links obstructive sleep apnea with serious medical problems including hypertension, coronary artery disease, heart failure, cardiac arrhythmia, and stroke.² Others include mood disorders, decreased libido, and cognitive impairment, with changes in attention, concentration, executive function, and fine-motor coordination.⁴ Therefore, ruling out obstructive sleep apnea is essential before pursuing interventions for primary snoring, although both disorders may warrant surgery.

PATIENT HISTORY

Most patients who present to the office because of snoring have snored for many years. Many seek medical attention at the request of a long-suffering bed partner.

Associated symptoms in primary snoring may include mouth breathing, chronic nasal congestion, and morning dry throat. Witnessed apnea, frequent awakenings during sleep, restless sleep, daytime somnolence, frequents naps, and memory impairment may be signs of more significant sleep-disordered breathing, such as obstructive sleep apnea.

The Epworth sleepiness scale may help quantify the severity of daytime somnolence.⁵ It is measured in a short questionnaire in which the patient indicates, on a scale of 0 to 3, his or her likelihood of dozing in a variety of situations.

The STOP-BANG questionnaire consists of eight yes-no questions:

Snore: Have you been told that you snore?
Tired: Are you often tired during the day?
Obstruction: Do you know if you stop breathing, or has anyone witnessed you stop breathing while you are asleep?
Pressure: Do you have high blood pressure or are you on medication to control high blood pressure?
Body mass index: Is your body mass index higher than 35 kg/m²?
Age: Are you age 50 or older?
Neck: Do you have a neck circumference greater than 17 inches (men) or greater than 16 inches (women)?
Gender: Are you male?

A score of three or higher has shown a sensitivity of 93% for detecting moderate obstructive sleep apnea and 100% for severe obstructive sleep apnea.⁶

SEARCHING FOR ANATOMIC CAUSES OF SNORING

A thorough physical examination should be done, focusing on potential anatomic causes of snoring. Nasal septal deviation or inferior turbinate hypertrophy with mucosal congestion may contribute to chronic mouth breathing secondary to nasal obstruction. Patients with a body mass index over 35 kg/m² and neck circumference over 17 inches (16 inches in women) are at higher risk of obstructive sleep apnea.

Indirect mirror examination or flexible transnasal endoscopy may reveal obstructing or persistent adenoid lymphoid tissue, particularly in young adults. Transnasal endoscopy may also reveal dynamic collapse of the palate and lateral oropharyngeal wall or fullness of the tongue base with subsequent narrowing of the oropharynx.

Figure 2. Friedman grading of the palate and tongue. The mouth is examined with the tongue in a neutral, relaxed position.

Examination of the oral cavity may reveal a disproportionately large tongue, a narrow opening into the oropharynx, or tonsillar hypertrophy. The Friedman classification (Figure 2), also called the modified Mallampati scale, can be used to describe the findings on physical examination of the palate and tongue in a systematic way. There are four grades of increasing severity, and the higher the grade, the less likely that surgery will succeed in patients with obstructive sleep apnea.⁷ The mouth is examined with the tongue in a relaxed position; in contrast, the original Mallampati classification, which is often used by anesthesiologists in assessing the oral airway, is assessed with the tongue protruding.

During flexible endoscopy, asking the patient to attempt to recreate the snoring can sometimes reveal the causative anatomic structure, which is usually the soft palate.

SLEEP STUDIES

A full diagnostic workup should include a sleep study if obstructive sleep apnea cannot be ruled out by the history and examination. Sleep studies include either polysomnography in a sleep laboratory or a home sleep test. They allow the clinician to further evaluate the severity of sleep-disordered breathing and to distinguish primary snoring from obstructive sleep apnea. This is particularly important if elective surgical intervention is planned. Sleep studies can also be used to evaluate for other sleep disorders.

Apnea is considered obstructive when polysomnography reveals episodes of no oral or nasal airflow with continued inspiratory effort, evidenced by abdominal or thoracic muscle activity. Hypopnea is defined as a 30% or greater reduction in airflow lasting at least 10 seconds, with an associated 4% or greater oxygen desaturation.¹ The combined number of apnea and hypopnea events per hour, or apnea-hypopnea index, is used clinically to quantify the severity of sleep-disordered breathing.

Primary snoring is diagnosed if the apnea-hypopnea index is 5 or less. Obstructive sleep apnea is considered mild when the apnea-hypopnea index is greater than 5 but less than 15, moderate from 15 to 30, and severe if over 30.

LIMITED ROLE FOR IMAGING

Cephalometric radiography (plain radiography of the airways) has limited value in the workup of primary snoring and is discouraged. Imaging is most useful in assessing craniofacial skeletal abnormalities. Lateral airway images can help in diagnosing adenoid hypertrophy in children. However, flexible nasopharyngoscopy can obtain this information by direct visualization with no radiation exposure.

Computed tomography and magnetic resonance imaging are seldom used in the workup of snoring because they do little to guide therapeutic intervention, are expensive, and, in the case of computed tomography, expose the patient to unnecessary radiation. Imaging does a have a role when planning surgical intervention of obstruction that involves the maxillofacial skeleton.

NONSURGICAL MANAGEMENT

The primary goal of therapy for snoring is to eliminate or reduce noise levels.

Although no study to date has analyzed the efficacy of nonsurgical management, several treatments are aimed at the root causes of snoring in an attempt to decrease it.

Intranasal topical steroids reduce inflammation of the nasal mucosa that occurs with allergic and nonallergic rhinitis, thereby opening up the nasal airway. They may reduce snoring in a small number of cases. These drugs must often be used in the long term to maintain their efficacy.

Devices. Other than continuous positive airway pressure (CPAP), the only currently available nonsurgical device approved by the US Food and Drug Administration for the treatment of snoring and obstructive sleep apnea is an oral dental appliance, which is customized to the patient’s dentition to relieve upper-airway obstruction by soft tissues of the oral cavity. The lower jaw is forced anteriorly, pulling the tongue and attached soft tissues forward. Custom-fitted oral appliances are an effective option for mild to moderate sleep apnea and associated snoring, and are more effective than thermoplastic “boil-and-bite” devices.⁸ These can easily be used in patients who have primary snoring.

Over-the-counter remedies such as nasal strips and head-positioning pillows have not been shown to be efficacious for snoring.⁹

Weight loss. Patients should be encouraged to join a weight-management program if overweight.

Sleep on the side, not on the back. Changing the sleep position may be useful in patients who have positional symptoms. Snoring is often worse in the supine position because gravity acting on the palate and tongue causes narrowing of the airway. “Positional therapy” employs devices to force patients to sleep in a lateral decubitus position to counter the effects of gravity.

Alcohol cessation. Alcohol has a relaxing effect on the muscles of the upper-respiratory tract, and abstaining from alcohol may therefore reduce snoring.

INDICATIONS FOR SURGERY

Surgery can decrease the noise level of snoring and thus bring relief for the patient’s bed partner.

Assessment of the upper airway may suggest the appropriate treatment, depending on whether the patient has nasal obstruction, adenoid hypertrophy, or palatal movement. A sleep study, if not previously done, should be done before surgery to rule out obstructive sleep apnea.

Many patients opt for surgery after noninvasive forms of treatment have proven ineffective or difficult to tolerate. When medical therapy for snoring has been unsuccessful, a discussion of the benefits, risks, and alternatives to surgery must take place between the patient and the surgeon.

SURGICAL PROCEDURES

Septoplasty

Septoplasty—straightening the nasal septum to improve the nasal airway—is an outpatient procedure. Although a deviated septum alone is not often the sole cause of snoring, most otolaryngologists agree that the septum should be addressed before or concomitantly with any palatal surgery for sleep-disordered breathing.

Nasal congestion often comes from a deviated bony or cartilaginous septum, enlarged turbinates, or bone spurs. Septal deviation may be developmental or the result of trauma to the nose.

Complications of septoplasty are rare but include septal perforation, scar-band formation, septal hematoma, epistaxis, and infection.

Radiofrequency ablation of the inferior turbinates

Hypertrophy of the inferior turbinate is the most common cause of nasal obstruction, followed by structural deformity of the nasal airway by septal deviation.³ Many patients report fixed or fluctuating nasal congestion and chronic mouth-breathing. The causes of turbinate congestion or enlargement include allergic rhinitis, upper-respiratory infection, and chronic rhinitis. In most cases, turbinate hypertrophy occurs at the level of the submucosa.

Radiofrequency ablation uses radiofrequency energy to generate heat at approximately 85°C (185°F) to create finely controlled coagulative lesions. The lesions are naturally resorbed in 3 to 8 weeks, inducing fibrosis, reducing excess tissue volume, and thus opening the airway. The procedure can be repeated several times to achieve optimal results. Radiofrequency ablation can also be used to reduce anatomic obstruction in other parts of the airway, such as the soft palate and the base of tongue.

Submucosal radiofrequency ablation of the inferior turbinate is a simple office-based procedure. It is often combined with septoplasty to optimize the nasal airway.

Mild to moderate edema with subsequent nasal obstruction and thick mucus formation can be expected the first week after the procedure. The risk of postoperative bleeding and infection is low. When performed with septoplasty, there is a low risk that scar tissue, or synechiae, may form between the turbinate and the septum.

Radiofrequency ablation of the palate

The soft palate is the most common anatomic source of snoring, and radiofrequency ablation can be applied to it as well. As with radiofrequency ablation in other areas, coagulative necrosis leads to fibrosis, and the soft tissue eventually contracts in volume with increased stiffness, thereby resulting in less tissue elasticity and vibration.

Carroll et al¹⁰ reported that nasal surgery combined with radiofrequency ablation of either the palate or the base of the tongue completely resolved snoring (according to the patient’s bed partner) in 42% of cases and improved it in 52%, with few complications. Also, patients who received more than one radiofrequency ablation application were more than twice as likely to have resolution of their snoring.

A systematic review of palatal radiofrequency ablation for snoring found that it is safe with minimal complication rates and reduces snoring in short-term follow-up.¹¹ The authors reviewed 30 studies: two randomized controlled trials, four clinical controlled trials, and 24 prospective uncontrolled studies. The only placebo-controlled randomized controlled trial found soft-palate radiofrequency ablation to be superior to placebo. In these studies, follow-up varied from 6 weeks to 26 months. However, the relapse rate was as high as 50% at a mean follow-up time of 13.2 months.

Thus, most of the information in this review has come from observational studies with short follow-up time. In another study, however, the authors presented a 5-year follow-up of palatal radiofrequency ablation that showed persistent and satisfying reduction of snoring.¹²

Injection snoreplasty

Alternative procedures have been used to reduce palatal flutter that leads to snoring.

Injection snoreplasty was first described by Brietzke and Mair al in 2001.¹³ Sodium tetradecyl sulfate, a sclerotherapy agent, is injected directly into the submucosal layer of the soft palate to induce scarring and reduce or eliminate snoring caused by the soft palate.

In a cohort study of 25 patients, the subjective success rate was 75% (13 patients) as far out as 19 months.¹⁴ In a separate cohort of 17 patients, home polysomnography with audio recordings was done before and after treatment in patients who underwent injection snoreplasty. Twelve (17%) of these patients had a significant reduction in the proportion of palatal snoring, loudness, and flutter frequency. Long-term success and snoring relapse rates of injection snoreplasty were reported to be similar to those of other current treatments.¹⁴

Pillar implants

The Pillar implant (Medtronic) was approved by the US Food and Drug Administration in 2002 for snoring and in 2004 for mild to moderate obstructive sleep apnea.

The implant, made of a woven polyester material, is designed to reduce vibration of the soft palate by increasing its stiffness. The implant induces a chronic inflammatory response that is thought to result in the formation of a fibrous capsule, which may also play a role in palatal stiffening. Three thin implants are inserted into the paramedian soft palate in a parallel orientation. This is an outpatient procedure done in the office.

The short-term benefits of the Pillar implant procedure have been well documented.^15,16 A meta-analysis of seven case-controlled studies that included 174 patients found the Pillar implant significantly decreased the loudness of snoring by 59%.¹⁵ The major disadvantage of Pillar implants was their high extrusion rate, which was reported to be 9.3%.¹⁵ While statistically significant improvement has been shown at up to 1 year, a recent longitudinal study suggests a clinical deterioration in snoring scale scores by 4 years after the procedure.¹⁶

Laser-assisted uvulopalatoplasty

Laser-assisted uvulopalatoplasty is a staged office-based procedure that involves removal of excess uvular mucosa and the creation of transpalatal vertical troughs to widen the retropalatal airway for the treatment of snoring and mild obstructive sleep apnea. The treatment typically requires about three sessions. It aims to mimic the palatal appearance of uvulopalatopharyngoplasty used to treat obstructive sleep apnea and has been proposed to have similar surgical outcomes in properly selected patients.

Krespi and Kaeker,¹⁷ in 1994, were among the first to describe the technique in the United States.

Kyrmizakis et al,¹⁸ in a retrospective study of 59 patients with habitual snoring who underwent laser-assisted uvulopalatoplasty, showed that a significant number of patients benefited from the procedure. During a follow-up ranging from 6 months to 5 years (mean 40 months), 91.5% of the patients with habitual snoring reported significant short-term improvement based on a posttreatment questionnaire, and 79.7% reported long-term subjective improvement.

Unfortunately, most of the studies have been small, and thus there is some controversy about the efficacy of laser-assisted uvulopalatoplasty, particularly in patients with obstructive sleep apnea. The most significant complication during healing is pain, which may deter patients from completing the full course of treatment.

References

American Academy of Sleep Medicine. International Classification of Sleep Disorders – Second Edition (ICSD-2). American Academy of Sleep Medicine 2005, 0965722023 978-0965722025.
Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003; 290:1906–1914.
Clemente CD. Anatomy: A Regional Atlas of the Human Body. Philadelphia; Lippincott Williams & Wilkins; 2010:752.
Jackson ML, Howard ME, Barnes M. Cognition and daytime functioning in sleep-related breathing disorders. Prog Brain Res 2011; 190:53–68.
Damiani MF, Quaranta VN, Falcone VA, et al. The Epworth Sleepiness Scale: conventional self vs physician administration. Chest 2013; 143:1569–1575.
Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008; 108:812–821.
Friedman M, Ibrahim H, Bass L. Clinical staging for sleep-disordered breathing. Otolaryngol Head Neck Surg 2002; 127:13–21.
Vanderveken OM, Devolder A, Marklund M, et al. Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea. Am J Respir Crit Care Med 2008; 178:197–202.
Michaelson P, Mair EA. Popular snore aids: do they work? Otolaryngol Head Neck Surg 2004; 130:649–658.
Carroll W, Wilhoit CS, Intaphan J, Nguyen SA, Gillespie MB. Snoring management with nasal surgery and upper airway radiofrequency ablation. Otolaryngol Head Neck Surg 2012; 146:1023–1027.
Bäck LJ, Hytönen ML, Roine RP, Malmivaara AOV. Radiofrequency ablation treatment of soft palate for patients with snoring: a systematic review of effectiveness and adverse effects. Laryngoscope 2009, 119:1241–1250.
DeVito A, Frassinet S, Panatta ML, Montevecchi F, Canzi P, Vicini C. Multilevel radiofrequency ablation for snoring and OSAHS patients therapy: long-term outcomes. Eur Arch Otolaryngol 2012; 269:321–330.
Brietzke SE, Mair EA. Injection snoreplasty: how to treat snoring without all the pain and expense. Otolaryngol Head Neck Surg 2001; 124:503–510.
Brietzke SE, Mair EA. Injection snoreplasty: extended follow-up and new objective data. Otolaryngol Head Neck Surg 2003; 128:605–615.
Choi JH, Kim SN, Cho JH. Efficacy of the Pillar implant in the treatment of snoring and mild-to-moderate obstructive sleep apnea: a meta-analysis. Laryngoscope 2013; 123:269–276.
Rotenberg BW, Luu K. Four-year outcomes of palatal implants for primary snoring treatment: a prospective longitudinal study. Laryngoscope 2012; 122:696–699.
Krespi YP, Kacker A. Laser-assisted uvulopalatoplasty revisited. Otolaryngol Clin North Am 2003; 36:495–500.
Kyrmizakis DE, Chimona TS, Papadakis CE, et al. Laser-assisted uvulopalatoplasty for the treatment of snoring and mild obstructive sleep apnea syndrome. J Otolaryngol 2003; 32:174–179.

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WHY PEOPLE SNORE

Snoring is an undesirable vibratory sound that originates from the soft tissues of the upper respiratory tract during sleep, as airflow causes the relaxed tissues to vibrate.

A SPECTRUM OF SLEEP-DISORDERED BREATHING

Snoring is only one sign of sleep-disordered breathing; others are excessive daytime somnolence, restless sleep, and witnessed apnea.

PATIENT HISTORY

Most patients who present to the office because of snoring have snored for many years. Many seek medical attention at the request of a long-suffering bed partner.

The STOP-BANG questionnaire consists of eight yes-no questions:

Snore: Have you been told that you snore?
Tired: Are you often tired during the day?
Obstruction: Do you know if you stop breathing, or has anyone witnessed you stop breathing while you are asleep?
Pressure: Do you have high blood pressure or are you on medication to control high blood pressure?
Body mass index: Is your body mass index higher than 35 kg/m²?
Age: Are you age 50 or older?
Neck: Do you have a neck circumference greater than 17 inches (men) or greater than 16 inches (women)?
Gender: Are you male?

A score of three or higher has shown a sensitivity of 93% for detecting moderate obstructive sleep apnea and 100% for severe obstructive sleep apnea.⁶

SEARCHING FOR ANATOMIC CAUSES OF SNORING

During flexible endoscopy, asking the patient to attempt to recreate the snoring can sometimes reveal the causative anatomic structure, which is usually the soft palate.

SLEEP STUDIES

LIMITED ROLE FOR IMAGING

NONSURGICAL MANAGEMENT

The primary goal of therapy for snoring is to eliminate or reduce noise levels.

Although no study to date has analyzed the efficacy of nonsurgical management, several treatments are aimed at the root causes of snoring in an attempt to decrease it.

Over-the-counter remedies such as nasal strips and head-positioning pillows have not been shown to be efficacious for snoring.⁹

Weight loss. Patients should be encouraged to join a weight-management program if overweight.

Alcohol cessation. Alcohol has a relaxing effect on the muscles of the upper-respiratory tract, and abstaining from alcohol may therefore reduce snoring.

INDICATIONS FOR SURGERY

Surgery can decrease the noise level of snoring and thus bring relief for the patient’s bed partner.

SURGICAL PROCEDURES

Septoplasty

Nasal congestion often comes from a deviated bony or cartilaginous septum, enlarged turbinates, or bone spurs. Septal deviation may be developmental or the result of trauma to the nose.

Complications of septoplasty are rare but include septal perforation, scar-band formation, septal hematoma, epistaxis, and infection.

Radiofrequency ablation of the inferior turbinates

Submucosal radiofrequency ablation of the inferior turbinate is a simple office-based procedure. It is often combined with septoplasty to optimize the nasal airway.

Radiofrequency ablation of the palate

Injection snoreplasty

Alternative procedures have been used to reduce palatal flutter that leads to snoring.

Pillar implants

The Pillar implant (Medtronic) was approved by the US Food and Drug Administration in 2002 for snoring and in 2004 for mild to moderate obstructive sleep apnea.

Laser-assisted uvulopalatoplasty

Krespi and Kaeker,¹⁷ in 1994, were among the first to describe the technique in the United States.

WHY PEOPLE SNORE

Snoring is an undesirable vibratory sound that originates from the soft tissues of the upper respiratory tract during sleep, as airflow causes the relaxed tissues to vibrate.

A SPECTRUM OF SLEEP-DISORDERED BREATHING

Snoring is only one sign of sleep-disordered breathing; others are excessive daytime somnolence, restless sleep, and witnessed apnea.

PATIENT HISTORY

Most patients who present to the office because of snoring have snored for many years. Many seek medical attention at the request of a long-suffering bed partner.

The STOP-BANG questionnaire consists of eight yes-no questions:

Snore: Have you been told that you snore?
Tired: Are you often tired during the day?
Obstruction: Do you know if you stop breathing, or has anyone witnessed you stop breathing while you are asleep?
Pressure: Do you have high blood pressure or are you on medication to control high blood pressure?
Body mass index: Is your body mass index higher than 35 kg/m²?
Age: Are you age 50 or older?
Neck: Do you have a neck circumference greater than 17 inches (men) or greater than 16 inches (women)?
Gender: Are you male?

A score of three or higher has shown a sensitivity of 93% for detecting moderate obstructive sleep apnea and 100% for severe obstructive sleep apnea.⁶

SEARCHING FOR ANATOMIC CAUSES OF SNORING

During flexible endoscopy, asking the patient to attempt to recreate the snoring can sometimes reveal the causative anatomic structure, which is usually the soft palate.

SLEEP STUDIES

LIMITED ROLE FOR IMAGING

NONSURGICAL MANAGEMENT

The primary goal of therapy for snoring is to eliminate or reduce noise levels.

Although no study to date has analyzed the efficacy of nonsurgical management, several treatments are aimed at the root causes of snoring in an attempt to decrease it.

Over-the-counter remedies such as nasal strips and head-positioning pillows have not been shown to be efficacious for snoring.⁹

Weight loss. Patients should be encouraged to join a weight-management program if overweight.

Alcohol cessation. Alcohol has a relaxing effect on the muscles of the upper-respiratory tract, and abstaining from alcohol may therefore reduce snoring.

INDICATIONS FOR SURGERY

Surgery can decrease the noise level of snoring and thus bring relief for the patient’s bed partner.

SURGICAL PROCEDURES

Septoplasty

Nasal congestion often comes from a deviated bony or cartilaginous septum, enlarged turbinates, or bone spurs. Septal deviation may be developmental or the result of trauma to the nose.

Complications of septoplasty are rare but include septal perforation, scar-band formation, septal hematoma, epistaxis, and infection.

Radiofrequency ablation of the inferior turbinates

Submucosal radiofrequency ablation of the inferior turbinate is a simple office-based procedure. It is often combined with septoplasty to optimize the nasal airway.

Radiofrequency ablation of the palate

Injection snoreplasty

Alternative procedures have been used to reduce palatal flutter that leads to snoring.

Pillar implants

The Pillar implant (Medtronic) was approved by the US Food and Drug Administration in 2002 for snoring and in 2004 for mild to moderate obstructive sleep apnea.

Laser-assisted uvulopalatoplasty

Krespi and Kaeker,¹⁷ in 1994, were among the first to describe the technique in the United States.

References

American Academy of Sleep Medicine. International Classification of Sleep Disorders – Second Edition (ICSD-2). American Academy of Sleep Medicine 2005, 0965722023 978-0965722025.
Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003; 290:1906–1914.
Clemente CD. Anatomy: A Regional Atlas of the Human Body. Philadelphia; Lippincott Williams & Wilkins; 2010:752.
Jackson ML, Howard ME, Barnes M. Cognition and daytime functioning in sleep-related breathing disorders. Prog Brain Res 2011; 190:53–68.
Damiani MF, Quaranta VN, Falcone VA, et al. The Epworth Sleepiness Scale: conventional self vs physician administration. Chest 2013; 143:1569–1575.
Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008; 108:812–821.
Friedman M, Ibrahim H, Bass L. Clinical staging for sleep-disordered breathing. Otolaryngol Head Neck Surg 2002; 127:13–21.
Vanderveken OM, Devolder A, Marklund M, et al. Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea. Am J Respir Crit Care Med 2008; 178:197–202.
Michaelson P, Mair EA. Popular snore aids: do they work? Otolaryngol Head Neck Surg 2004; 130:649–658.
Carroll W, Wilhoit CS, Intaphan J, Nguyen SA, Gillespie MB. Snoring management with nasal surgery and upper airway radiofrequency ablation. Otolaryngol Head Neck Surg 2012; 146:1023–1027.
Bäck LJ, Hytönen ML, Roine RP, Malmivaara AOV. Radiofrequency ablation treatment of soft palate for patients with snoring: a systematic review of effectiveness and adverse effects. Laryngoscope 2009, 119:1241–1250.
DeVito A, Frassinet S, Panatta ML, Montevecchi F, Canzi P, Vicini C. Multilevel radiofrequency ablation for snoring and OSAHS patients therapy: long-term outcomes. Eur Arch Otolaryngol 2012; 269:321–330.
Brietzke SE, Mair EA. Injection snoreplasty: how to treat snoring without all the pain and expense. Otolaryngol Head Neck Surg 2001; 124:503–510.
Brietzke SE, Mair EA. Injection snoreplasty: extended follow-up and new objective data. Otolaryngol Head Neck Surg 2003; 128:605–615.
Choi JH, Kim SN, Cho JH. Efficacy of the Pillar implant in the treatment of snoring and mild-to-moderate obstructive sleep apnea: a meta-analysis. Laryngoscope 2013; 123:269–276.
Rotenberg BW, Luu K. Four-year outcomes of palatal implants for primary snoring treatment: a prospective longitudinal study. Laryngoscope 2012; 122:696–699.
Krespi YP, Kacker A. Laser-assisted uvulopalatoplasty revisited. Otolaryngol Clin North Am 2003; 36:495–500.
Kyrmizakis DE, Chimona TS, Papadakis CE, et al. Laser-assisted uvulopalatoplasty for the treatment of snoring and mild obstructive sleep apnea syndrome. J Otolaryngol 2003; 32:174–179.

References

American Academy of Sleep Medicine. International Classification of Sleep Disorders – Second Edition (ICSD-2). American Academy of Sleep Medicine 2005, 0965722023 978-0965722025.
Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003; 290:1906–1914.
Clemente CD. Anatomy: A Regional Atlas of the Human Body. Philadelphia; Lippincott Williams & Wilkins; 2010:752.
Jackson ML, Howard ME, Barnes M. Cognition and daytime functioning in sleep-related breathing disorders. Prog Brain Res 2011; 190:53–68.
Damiani MF, Quaranta VN, Falcone VA, et al. The Epworth Sleepiness Scale: conventional self vs physician administration. Chest 2013; 143:1569–1575.
Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008; 108:812–821.
Friedman M, Ibrahim H, Bass L. Clinical staging for sleep-disordered breathing. Otolaryngol Head Neck Surg 2002; 127:13–21.
Vanderveken OM, Devolder A, Marklund M, et al. Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea. Am J Respir Crit Care Med 2008; 178:197–202.
Michaelson P, Mair EA. Popular snore aids: do they work? Otolaryngol Head Neck Surg 2004; 130:649–658.
Carroll W, Wilhoit CS, Intaphan J, Nguyen SA, Gillespie MB. Snoring management with nasal surgery and upper airway radiofrequency ablation. Otolaryngol Head Neck Surg 2012; 146:1023–1027.
Bäck LJ, Hytönen ML, Roine RP, Malmivaara AOV. Radiofrequency ablation treatment of soft palate for patients with snoring: a systematic review of effectiveness and adverse effects. Laryngoscope 2009, 119:1241–1250.
DeVito A, Frassinet S, Panatta ML, Montevecchi F, Canzi P, Vicini C. Multilevel radiofrequency ablation for snoring and OSAHS patients therapy: long-term outcomes. Eur Arch Otolaryngol 2012; 269:321–330.
Brietzke SE, Mair EA. Injection snoreplasty: how to treat snoring without all the pain and expense. Otolaryngol Head Neck Surg 2001; 124:503–510.
Brietzke SE, Mair EA. Injection snoreplasty: extended follow-up and new objective data. Otolaryngol Head Neck Surg 2003; 128:605–615.
Choi JH, Kim SN, Cho JH. Efficacy of the Pillar implant in the treatment of snoring and mild-to-moderate obstructive sleep apnea: a meta-analysis. Laryngoscope 2013; 123:269–276.
Rotenberg BW, Luu K. Four-year outcomes of palatal implants for primary snoring treatment: a prospective longitudinal study. Laryngoscope 2012; 122:696–699.
Krespi YP, Kacker A. Laser-assisted uvulopalatoplasty revisited. Otolaryngol Clin North Am 2003; 36:495–500.
Kyrmizakis DE, Chimona TS, Papadakis CE, et al. Laser-assisted uvulopalatoplasty for the treatment of snoring and mild obstructive sleep apnea syndrome. J Otolaryngol 2003; 32:174–179.

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Managing snoring: When to consider surgery

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The treatment of snoring begins with a thorough history and physical examination.
Polysomnography is almost always necessary to rule out other sleep disorders, such as obstructive sleep apnea. This is particularly important if an elective surgical intervention is planned.
Surgical procedures for snoring include septoplasty with or without radiofrequency ablation of the upper airway, injection snoreplasty, Pillar implants, and laser-assisted uvulopalatoplasty.
Although studies indicate that these procedures are effective, no well-controlled study has compared one procedure against another. The choice of procedure is often determined by the expertise of the surgeon, and the outcome is highly dependent on the skill of the surgeon.

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Keeping up with immunizations for adults

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A 58-year-old man with a history of irritable bowel syndrome and diabetes presents for an evaluation in early November. He is taking metformin and insulin glargine 10 units. He smokes 1 pack per day. He believes that his childhood immunizations were completed, but he has no records. He thinks his last “shot” was 15 years ago when he cut his hand on some wood.

Which immunizations, if any, would be most appropriate for this patient?

The explosion of new vaccines, new formulations, and new combinations made available in recent years makes managing immunizations a challenge. This article reviews common immunizations and current recommendations for their appropriate use.

Immunization recommendations (Table 1) are made predominantly by the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC). The last 15 years have seen the arrival of new vaccines (eg, varicella, hepatitis A, pneumococcal, and human papillomavirus), new formulations (eg, intranasal influenza), and new combinations.

To keep clinicians abreast of new indications, the ACIP issues immunization schedules annually for children and adults, available online and downloadable for easy reference.¹ For adults, the ACIP provides schedules based on age and medical condition. The schedule for medical conditions offers specific information regarding immunization and pregnancy, human immunodeficiency virus (HIV) infection, kidney failure, heart disease, asplenia, and other conditions. The ACIP also provides guidance on contraindications; for example, pregnant and immunocompromised patients should not receive the live-attenuated vaccines, ie, zoster, varicella, and combined measles, mumps, and rubella [MMR]).

Adult awareness of vaccines is low, as are vaccination rates: in people older than 60, the vaccination rate is about 70% for influenza, 60% for pneumococcus, 50% for tetanus, and 15% for zoster. The lack of vaccine awareness and the availability of new vaccines and indications have made it difficult to manage immunizations in the primary care setting. The electronic medical record is useful for tracking patient vaccine needs. Ideally, keeping up with immunizations should be a routine part of visits provided by a physician’s care team and does not always require direct physician coordination.

TETANUS, DIPHTHERIA, PERTUSSIS EVERY 10 YEARS

Tetanus (also called “lockjaw”) is a nervous system disorder characterized by muscle spasms. Caused by infection with Clostridium tetani, it is a rare disease in the United States thanks to widespread immunization, and it causes fewer than 50 cases annually. Worldwide, the incidence is about 1 million cases a year with 200,000 to 300,000 deaths.

Diphtheria (formerly sometimes called “throat distemper”) is caused by the gram-positive bacillus Corynebacterium diphtheriae and can occur as a respiratory illness or as a milder cutaneous form. The last outbreak in the United States was in Seattle in the 1970s, with the last reported case in 2003. The ACIP recommends booster shots for tetanus and diphtheria every 10 years following completion of the primary series.

Pertussis or whooping cough, caused by Bordetella pertussis infection, is a highly contagious disease increasingly seen in adults in the United States. It causes few deaths but high morbidity, with coughing that can persist up to 3 months. Coughing can be severe enough to cause vomiting, a characteristic sign.

In July 2012, the CDC reported that the United States was at a 50-year high for pertussis, with 18,000 cases reported and 8 deaths.² In Washington State alone, more than 2,520 cases had been seen through June 16 of that year, a 1,300% increase over the previous year. Rates were high in older children and adolescents despite previous vaccination, suggesting an early waning of immunity.

The ACIP recommends a single dose of the combination of high-dose tetanus and low-dose diphtheria and pertussis vaccines (Tdap) for all adults regardless of age and for all pregnant women with each pregnancy between 27 and 36 weeks of gestation. A dose of Tdap counts as the tetanus-diphtheria booster shot that is recommended every 10 years.

The patient described above is due for his tetanus-diphtheria booster and so should be given Tdap.

MEASLES, MUMPS, RUBELLA FOR THOSE BORN AFTER 1957

Measles remains a problem in the developing world, with an estimated average of 330 deaths daily. The number of cases fell 99% in the United States following the vaccination program that started in the early 1960s. Before the measles vaccine was available, an estimated 90% of children acquired measles by age 15.

The clinical syndrome consists of fever, conjunctivitis, cough, rash, and the characteristic Koplik spots—small white spots occurring on the inside of cheeks early in the disease course.

During the first 5 months of 2014, the CDC reported 334 cases of measles in the United States in 18 states, with most people affected being unvaccinated.³ In comparison, from 2001 to 2008, the number of cases averaged 56 annually.

Many of the recent cases were associated with infections brought from the Philippines. The increased number of measles cases underscores the need for vaccination to prevent measles and its complications.

Mumps is an acute, self-limited viral syndrome, and parotitis is the hallmark. Vaccination led to a 99% decline in cases in the United States. Although complications are rare, they can be serious and include orchitis (with risk of sterility), meningoencephalitis, and deafness.

Mumps outbreaks still occur, especially in close-contact settings such as schools, colleges, and camps. During the first half of 2014, central Ohio had more than 400 cases linked to The Ohio State University.

Rubella, also known as German measles, is a generally mild infection but is associated with congenital rubella syndrome. If a woman is infected with rubella in the first trimester of pregnancy, the risk of miscarriage is greater than 80%, as is the risk of birth defects, including hearing loss, developmental delay, growth retardation, and cardiac and eye defects.

Recommendations for MMR vaccination. People born before 1957 are considered immune to measles and usually to mumps. Health care workers should document immunity before assuming no vaccination is needed.

People born in 1957 or after should have one dose of MMR vaccine unless immunity is documented or unless there is a contraindication such as immunosuppression. A second dose is recommended for those born in or after 1957 who are considered to be at high risk: eg, health care workers, students entering college, and international travelers. The second dose should be given 4 weeks after the first.

Women of childbearing age should be screened for immunity to rubella. Susceptible women should receive MMR, although not during pregnancy and not if they may get pregnant within 4 weeks.

The patient described above was born before 1957, and so he is probably immune to measles and mumps.

HEPATITIS B FOR THOSE AT RISK

Hepatitis B vaccination is recommended for all adolescents and adults at increased risk: eg, men who have sex with men, intravenous drug users, people with multiple sexual partners, health care workers, patients with end-stage renal disease on hemodialysis, patients with chronic liver disease, and those with diabetes (age < 60).

Immunization consists of a series of three shots (at 0, 1–2, and 4–6 months). Booster doses are not recommended. Postvaccination testing for immunity is available and is recommended for health care workers, patients on hemodialysis, patients with HIV infection or who are otherwise immunocompromised, and sexual partners of people who are positive for hepatitis B surface antigen. Nonresponders should be revaccinated with the entire three-shot schedule. Hepatitis B vaccination is safe in pregnancy.

The patient described above has diabetes and so is a candidate for vaccination.

HEPATITIS A: A SLIGHTLY DIFFERENT RISK GROUP

Hepatitis A vaccination is recommended only for at-risk populations: international travelers; intravenous drug users; men who have sex with men; patients with clotting disorders, chronic liver disease, or hepatitis C infection; international adoptees; and laboratory personnel working with hepatitis A virus. The vaccination is given in two doses with a minimum interval of 6 months between doses.

A hepatitis A and hepatitis B combination vaccine (Twinrix) is also available. It is given in three doses, at 0, 1, and 6 months.

ANNUAL INFLUENZA VACCINE FOR ALL

In 2010, the ACIP recommended a policy of universal annual vaccination for everyone age 6 months and older. Some patients are at especially high risk themselves or are at high risk of exposing others and so are given higher priority during vaccine shortages—ie, patients who are immunosuppressed or have other medical risk factors, health care workers, household members of at-risk patients, and pregnant women after 13 weeks of gestation.

There are few contraindications, so almost everyone should be encouraged to receive the influenza vaccine. The flu shot does not cause the flu, but it may cause soreness at the injection site. Those with severe egg allergy should not receive the standard flu shot; a recombinant vaccine that does not use egg culture is available.

The standard flu shot is an inactivated influenza vaccine. In the past, most formulations were trivalent, but quadrivalent formulations are becoming more common. Special high-dose formulations are believed to elicit a better immune response and can be recommended for people over age 65. Intradermal and intramuscular formulations are available.

An intranasal live-attenuated influenza vaccine is also available and may be used for people ages 2 through 49. It should not be given to immunosuppressed people or to pregnant women.

Our patient should get a flu shot.

PNEUMOCOCCAL VACCINE FOR THOSE AGE 65 AND OLDER OR AT RISK

Two formulations are now available for pneumococcal immunization. The standard is a 23-valent polysaccharide vaccine (PPSV23; Pneumovax) indicated for people age 65 and older.

Patients under age 65 can receive PPSV23 if they have chronic lung disease, chronic cardiovascular disease, diabetes, chronic liver disease, or alcoholism or are a resident of a nursing home or an active smoker.

Our patient is a candidate for PPSV23 since he smokes and has diabetes.

The other formulation is a conjugate 13-valent vaccine (PCV13; Prevnar 13). Patients over age 19 at high risk should be given PCV13 plus the PPSV23 8 weeks later. Those who already received PPSV23 should be given PCV13 vaccine more than 1 year later. Candidates for PCV13 are those with immunocompromising conditions (including chronic renal failure and nephrotic syndrome), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants.

The current revaccination schedule for PPSV23 is as follows:

One-time revaccination 5 years after the first dose in patients with chronic renal failure, nephrotic syndrome, asplenia, or an immunosuppressive condition
One-time revaccination for patients age 65 or older if they were younger than 65 when first immunized (with one or two doses of PPSV23) and 5 years have passed
No revaccination is needed for people vaccinated with PPSV23 after age 65.

HUMAN PAPILLOMAVIRUS VACCINE

Human papillomavirus is the most common sexually transmitted infection in the United States and is strongly associated with cervical cancer. Immunization is now indicated for both sexes, generally between the ages of 9 and 26. Two vaccines are available: the quadrivalent formulation (Gardasil) for males or females and the bivalent formulation (Cervarix) for females only.

Immunization should be given in three doses: at 0, 1 to 2 months, and 6 months. It can be given to patients who are immunocompromised as a result of infection (including HIV infection), disease, or medications, or who have a history of genital warts, an abnormal Papanicolaou test, or a positive human papillomavirus DNA test.

It is hoped that immunization will lead to a significant decrease in cervical cancer rates. Eradication is unlikely because other papillomavirus strains also can lead to cancer, so cancer screening is still warranted. For men who have sex with men, it is hoped that immunization will prevent condyloma and anal cancer.

CHICKENPOX AND SHINGLES VACCINES

Varicella vaccine (Varivax) contains a live-attenuated virus to protect against chickenpox. It is recommended for all adults who have no evidence of immunity. Immunity is assumed with a history of chickenpox, being born before 1980, or having positive titers. Vaccination should be emphasized for those who come in contact with patients at high risk of severe disease (eg, health care workers, family contacts of immunocompromised patients) and in individuals with a high risk of personal exposure (eg, teachers, day care workers).

The vaccine is given in two doses, 4 to 8 weeks apart. Women who are pregnant or who may get pregnant within 4 weeks should not be vaccinated.

The shingles vaccine (Zostavax) is a larger dose of the varicella vaccine and reduces the incidence of shingles by 50% and postherpetic neuralgia by 66%.⁴ It was approved by the US Food and Drug Administration in May 2006 for people starting at age 50, but was recommended by ACIP in October 2006 for people age 60 and older; as a result, some insurance companies deny coverage for patients ages 50 through 59.

The shingles vaccine can be given to patients who have already had shingles. Pregnancy and severe immunodeficiency are contraindications.

Our patient, 58 years old, could be considered for shingles vaccine if covered by his insurance company or if he wishes to pay for it.

MENINGOCOCCUS VACCINE

Meningococcal immunization is recommended for people at high risk: college students who plan to live in dormitories, adults without a spleen or with complement deficiencies or HIV infection, or travelers to the “meningitis belt” of sub-Saharan Africa.

Two types of meningococcal vaccine are available: the conjugate quadrivalent vaccine (MCV4) for people age 55 and younger, and the polysaccharide quadrivalent vaccine (MPSV4) for people over age 56.

References

US Centers for Disease Control and Prevention (CDC). Adult immunization schedules. www.cdc.gov/vaccines/schedules/hcp/adult.html. Accessed August 21, 2014.
US Centers for Disease Control and Prevention (CDC). Pertussis epidemic—Washington, 2012. MMWR Morb Mortal Wkly Rep 2012; 61:517–522.
US Centers for Disease Control and Prevention (CDC). Measles cases and outbreaks, January 1 to August 15, 2014. www.cdc.gov/measles/cases-outbreaks.html. Accessed August 21, 2014.
Oxman MN, Levin MJ, Johnson MS, et al; for the Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352:2271–2284.

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Medical Grand Rounds articles are based on edited transcripts from Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

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Medical Grand Rounds articles are based on edited transcripts from Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

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Which immunizations, if any, would be most appropriate for this patient?

TETANUS, DIPHTHERIA, PERTUSSIS EVERY 10 YEARS

The patient described above is due for his tetanus-diphtheria booster and so should be given Tdap.

MEASLES, MUMPS, RUBELLA FOR THOSE BORN AFTER 1957

The clinical syndrome consists of fever, conjunctivitis, cough, rash, and the characteristic Koplik spots—small white spots occurring on the inside of cheeks early in the disease course.

Women of childbearing age should be screened for immunity to rubella. Susceptible women should receive MMR, although not during pregnancy and not if they may get pregnant within 4 weeks.

The patient described above was born before 1957, and so he is probably immune to measles and mumps.

HEPATITIS B FOR THOSE AT RISK

The patient described above has diabetes and so is a candidate for vaccination.

HEPATITIS A: A SLIGHTLY DIFFERENT RISK GROUP

A hepatitis A and hepatitis B combination vaccine (Twinrix) is also available. It is given in three doses, at 0, 1, and 6 months.

ANNUAL INFLUENZA VACCINE FOR ALL

An intranasal live-attenuated influenza vaccine is also available and may be used for people ages 2 through 49. It should not be given to immunosuppressed people or to pregnant women.

Our patient should get a flu shot.

PNEUMOCOCCAL VACCINE FOR THOSE AGE 65 AND OLDER OR AT RISK

Two formulations are now available for pneumococcal immunization. The standard is a 23-valent polysaccharide vaccine (PPSV23; Pneumovax) indicated for people age 65 and older.

Our patient is a candidate for PPSV23 since he smokes and has diabetes.

The current revaccination schedule for PPSV23 is as follows:

One-time revaccination 5 years after the first dose in patients with chronic renal failure, nephrotic syndrome, asplenia, or an immunosuppressive condition
One-time revaccination for patients age 65 or older if they were younger than 65 when first immunized (with one or two doses of PPSV23) and 5 years have passed
No revaccination is needed for people vaccinated with PPSV23 after age 65.

HUMAN PAPILLOMAVIRUS VACCINE

CHICKENPOX AND SHINGLES VACCINES

The vaccine is given in two doses, 4 to 8 weeks apart. Women who are pregnant or who may get pregnant within 4 weeks should not be vaccinated.

The shingles vaccine can be given to patients who have already had shingles. Pregnancy and severe immunodeficiency are contraindications.

Our patient, 58 years old, could be considered for shingles vaccine if covered by his insurance company or if he wishes to pay for it.

MENINGOCOCCUS VACCINE

Two types of meningococcal vaccine are available: the conjugate quadrivalent vaccine (MCV4) for people age 55 and younger, and the polysaccharide quadrivalent vaccine (MPSV4) for people over age 56.

Which immunizations, if any, would be most appropriate for this patient?

TETANUS, DIPHTHERIA, PERTUSSIS EVERY 10 YEARS

The patient described above is due for his tetanus-diphtheria booster and so should be given Tdap.

MEASLES, MUMPS, RUBELLA FOR THOSE BORN AFTER 1957

The clinical syndrome consists of fever, conjunctivitis, cough, rash, and the characteristic Koplik spots—small white spots occurring on the inside of cheeks early in the disease course.

Women of childbearing age should be screened for immunity to rubella. Susceptible women should receive MMR, although not during pregnancy and not if they may get pregnant within 4 weeks.

The patient described above was born before 1957, and so he is probably immune to measles and mumps.

HEPATITIS B FOR THOSE AT RISK

The patient described above has diabetes and so is a candidate for vaccination.

HEPATITIS A: A SLIGHTLY DIFFERENT RISK GROUP

A hepatitis A and hepatitis B combination vaccine (Twinrix) is also available. It is given in three doses, at 0, 1, and 6 months.

ANNUAL INFLUENZA VACCINE FOR ALL

An intranasal live-attenuated influenza vaccine is also available and may be used for people ages 2 through 49. It should not be given to immunosuppressed people or to pregnant women.

Our patient should get a flu shot.

PNEUMOCOCCAL VACCINE FOR THOSE AGE 65 AND OLDER OR AT RISK

Two formulations are now available for pneumococcal immunization. The standard is a 23-valent polysaccharide vaccine (PPSV23; Pneumovax) indicated for people age 65 and older.

Our patient is a candidate for PPSV23 since he smokes and has diabetes.

The current revaccination schedule for PPSV23 is as follows:

One-time revaccination 5 years after the first dose in patients with chronic renal failure, nephrotic syndrome, asplenia, or an immunosuppressive condition
One-time revaccination for patients age 65 or older if they were younger than 65 when first immunized (with one or two doses of PPSV23) and 5 years have passed
No revaccination is needed for people vaccinated with PPSV23 after age 65.

HUMAN PAPILLOMAVIRUS VACCINE

CHICKENPOX AND SHINGLES VACCINES

The vaccine is given in two doses, 4 to 8 weeks apart. Women who are pregnant or who may get pregnant within 4 weeks should not be vaccinated.

The shingles vaccine can be given to patients who have already had shingles. Pregnancy and severe immunodeficiency are contraindications.

Our patient, 58 years old, could be considered for shingles vaccine if covered by his insurance company or if he wishes to pay for it.

MENINGOCOCCUS VACCINE

Two types of meningococcal vaccine are available: the conjugate quadrivalent vaccine (MCV4) for people age 55 and younger, and the polysaccharide quadrivalent vaccine (MPSV4) for people over age 56.

References

US Centers for Disease Control and Prevention (CDC). Adult immunization schedules. www.cdc.gov/vaccines/schedules/hcp/adult.html. Accessed August 21, 2014.
US Centers for Disease Control and Prevention (CDC). Pertussis epidemic—Washington, 2012. MMWR Morb Mortal Wkly Rep 2012; 61:517–522.
US Centers for Disease Control and Prevention (CDC). Measles cases and outbreaks, January 1 to August 15, 2014. www.cdc.gov/measles/cases-outbreaks.html. Accessed August 21, 2014.
Oxman MN, Levin MJ, Johnson MS, et al; for the Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352:2271–2284.

References

US Centers for Disease Control and Prevention (CDC). Adult immunization schedules. www.cdc.gov/vaccines/schedules/hcp/adult.html. Accessed August 21, 2014.
US Centers for Disease Control and Prevention (CDC). Pertussis epidemic—Washington, 2012. MMWR Morb Mortal Wkly Rep 2012; 61:517–522.
US Centers for Disease Control and Prevention (CDC). Measles cases and outbreaks, January 1 to August 15, 2014. www.cdc.gov/measles/cases-outbreaks.html. Accessed August 21, 2014.
Oxman MN, Levin MJ, Johnson MS, et al; for the Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352:2271–2284.

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KEY POINTS

Information on immunization schedules, including an app for mobile devices, is available at www.cdc.gov/vaccines/schedules/hcp/adult.html.
Vaccination rates in adults are low, and appropriate vaccinations should be encouraged. The electronic medical record can help remind us when vaccinations are due.
The live-attenuated vaccines, ie, zoster, varicella, and combined measles, mumps, and rubella, are contraindicated during pregnancy and in immunocompromised patients.

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Terry nails in a patient with chronic alcoholic liver disease

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A 45-year-old man with chronic alcoholism for the past 20 years and chronic liver disease for the past 2 years was admitted to the hospital with abdominal distention, yellowish discoloration of the eyes, itching all over the body, decreased appetite, and fresh rectal bleeding.

He had the classic signs of chronic liver disease, including icterus, pallor, parotid swelling, gynecomastia, spider angiomata, sparse axillary and pubic hair, transverse stretched umbilicus, divarication of the rectus abdominis muscles, caput medusae, small testes, and bilateral pedal edema.

Figure 1. The nail bed was white, with only a narrow zone of pink at the distal end.

Examination of the fingernails revealed a distal thin pink-to-brown transverse band 0.5 to 2.0 mm in width, a white nail bed, and no lunula (Figure 1)—the characteristic findings of Terry nails.

Systemic examination revealed moderate ascites (shifting dullness present), splenomegaly, and external hemorrhoids suggestive of portal hypertension.

TERRY NAILS

In 1954, Dr. Richard Terry first reported the finding of a white nail bed with ground-glass opacity in patients who had hepatic cirrhosis.¹ The condition is bilaterally symmetrical, with a tendency to be more marked in the thumb and forefinger.¹

In 1984, Holzberg and Walker² consecutively studied 512 hospitalized patients and observed Terry nails in 25.2% of them. Based on their findings, they redefined the criteria for Terry nail as follows:

Distal thin pink-to-brown transverse band, 0.5 to 3.0 mm in width
Decreased venous return not obscuring the distal band
White or light pink proximal nail
Lunula possibly absent
At least 4 of 10 nails with the above criteria.

Patients who do not have the findings on all fingernails commonly have involvement of the thumb and forefinger. Holzberg and Walker confirmed a statistically significant association of Terry nails with cirrhosis, chronic heart failure, and adult-onset diabetes, especially in younger patients.² Terry nails have also been observed in thyrotoxicosis, pulmonary eosinophilia, malnutrition, actinic keratosis, and advanced age.^1–4

Using the updated diagnostic criteria, Park et al⁵ studied fingernails in 444 medical inpatients with chronic systemic disease, and only 30.6% had Terry nails. There were statistically significant associations with cirrhosis (57%), congestive heart failure (51.5%), and diabetes mellitus (49%); the associations with chronic renal failure (19%) and cancer (18%) were not statistically significant.⁵ They were more common in older patients. The average number of nails affected per patient tended to be higher in frequency close to the thumb; 28.7% patients had all nails affected.⁵

Terry nails should alert the clinician to the possibility of an underlying systemic disease, especially advanced liver disease. Possible explanations for the clinical changes observed in Terry nails include abnormal steroid metabolism, abnormal estrogen-androgen ratio, alteration of nail bed-to-nail plate attachment, hypoalbuminemia, increased digital blood flow, and overgrowth of the connective tissue between nail bed and the growth plate. The pathologic study of longitudinal nail biopsy specimens shows telangiectasia in the upper dermis of the distal nail band.³

Important differential diagnoses are Lindsay (half-and-half) nails, associated with chronic renal failure, and Neapolitan nails, associated with aging.³

References

Terry R. White nails in hepatic cirrhosis. Lancet 1954; 266:757–759.
Holzberg M, Walker HK. Terry’s nails: revised definition and new correlations. Lancet 1984; 1:896–899.
Holzberg M. The nail in systemic disease. In:Baran R, de Berker DAR, Holzberg M, Thomas L, editors. Baran & Dawber’s Diseases of the Nails and Their Management, 4th ed. Oxford, UK: Blackwell Publishing Ltd.; 2012.
Nia AM, Ederer S, Dahlem KM, Gassanov N, Er F. Terry’s nails: a window to systemic diseases. Am J Med 2011; 124:602–604.
Park KY, Kim SW, Cho JS. Research on the frequency of Terry’s nail in the medical inpatients with chronic illnesses. Korean J Dermatol 1992; 30:864–870.

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Sardar Patel Medical College, Rajasthan, India

Address: Satyendra Khichar, MBBS, Department of Medicine, Sardar Patel Medical College and PBM Hospitals, Bikaner, Rajasthan, India; e-mail: [email protected]

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Shyama Choudhary, MBBS, MD
Sardar Patel Medical College, Rajasthan, India

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Systemic examination revealed moderate ascites (shifting dullness present), splenomegaly, and external hemorrhoids suggestive of portal hypertension.

TERRY NAILS

Distal thin pink-to-brown transverse band, 0.5 to 3.0 mm in width
Decreased venous return not obscuring the distal band
White or light pink proximal nail
Lunula possibly absent
At least 4 of 10 nails with the above criteria.

Important differential diagnoses are Lindsay (half-and-half) nails, associated with chronic renal failure, and Neapolitan nails, associated with aging.³

Systemic examination revealed moderate ascites (shifting dullness present), splenomegaly, and external hemorrhoids suggestive of portal hypertension.

TERRY NAILS

Distal thin pink-to-brown transverse band, 0.5 to 3.0 mm in width
Decreased venous return not obscuring the distal band
White or light pink proximal nail
Lunula possibly absent
At least 4 of 10 nails with the above criteria.

Important differential diagnoses are Lindsay (half-and-half) nails, associated with chronic renal failure, and Neapolitan nails, associated with aging.³

References

Terry R. White nails in hepatic cirrhosis. Lancet 1954; 266:757–759.
Holzberg M, Walker HK. Terry’s nails: revised definition and new correlations. Lancet 1984; 1:896–899.
Holzberg M. The nail in systemic disease. In:Baran R, de Berker DAR, Holzberg M, Thomas L, editors. Baran & Dawber’s Diseases of the Nails and Their Management, 4th ed. Oxford, UK: Blackwell Publishing Ltd.; 2012.
Nia AM, Ederer S, Dahlem KM, Gassanov N, Er F. Terry’s nails: a window to systemic diseases. Am J Med 2011; 124:602–604.
Park KY, Kim SW, Cho JS. Research on the frequency of Terry’s nail in the medical inpatients with chronic illnesses. Korean J Dermatol 1992; 30:864–870.

References

Terry R. White nails in hepatic cirrhosis. Lancet 1954; 266:757–759.
Holzberg M, Walker HK. Terry’s nails: revised definition and new correlations. Lancet 1984; 1:896–899.
Holzberg M. The nail in systemic disease. In:Baran R, de Berker DAR, Holzberg M, Thomas L, editors. Baran & Dawber’s Diseases of the Nails and Their Management, 4th ed. Oxford, UK: Blackwell Publishing Ltd.; 2012.
Nia AM, Ederer S, Dahlem KM, Gassanov N, Er F. Terry’s nails: a window to systemic diseases. Am J Med 2011; 124:602–604.
Park KY, Kim SW, Cho JS. Research on the frequency of Terry’s nail in the medical inpatients with chronic illnesses. Korean J Dermatol 1992; 30:864–870.

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Should all patients have a resting 12-lead ECG before elective noncardiac surgery?

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Prashant Sharma, MD, FACP

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Should all patients have a resting 12-lead ECG before elective noncardiac surgery?

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Sourab Dhungel, MD, FACP

Anbazhagan Prabhakaran, MD, MRCP (Edin), FACP

A 55-year-old lawyer with hypertension well controlled on lisinopril and amlodipine is scheduled for elective hernia repair under general anesthesia. His surgeon has referred him for a preoperative evaluation. He has never smoked, runs 4 miles on days off from work, and enjoys long hiking trips. On examination, his body mass index is 26 kg/m² and his blood pressure is 130/78 mm Hg; his cardiac examination and the rest of the clinical examination are unremarkable. He asks if he should have an electrocardiogram (ECG) as a part of his workup.

A preoperative ECG is not routinely recommended in all asymptomatic patients undergoing noncardiac surgery.

Consider obtaining an ECG in patients planning to undergo a high-risk surgical procedure, especially if they have one or more clinical risk factors for coronary artery disease, and in patients undergoing elevated-cardiac-risk surgery who are known to have coronary artery disease, chronic heart failure, peripheral arterial disease, or cerebrovascular disease. However, a preoperative ECG is not routinely recommended for patients perceived to be at low cardiac risk who are planning to undergo low-risk surgery. In those patients it could delay surgery unnecessarily, cause further unnecessary testing, drive up costs, and increase patient anxiety.

Here we discuss the perioperative cardiac risk based on type of surgery and patient characteristics and summarize the current guidelines and recommendations on obtaining a preoperative 12-lead ECG in patients undergoing noncardiac surgery.

RISK DEPENDS ON TYPE OF SURGERY AND PATIENT FACTORS

Physicians, including primary care physicians, hospitalists, cardiologists, and anesthesiologists, are routinely asked to evaluate patients before surgical procedures. The purpose of the preoperative evaluation is to optimize existing medical conditions, to identify undiagnosed conditions that can increase risk of perioperative morbidity and death, and to suggest strategies to mitigate risk.^1,2

Cardiac risk is multifactorial, and risk factors for postoperative adverse cardiac events include the type of surgery and patient factors.^1,3

Cardiac risk based on type of surgery

Low-risk procedures are those in which the risk of a perioperative major adverse cardiac event is less than 1%.^1,4 Examples:

Ambulatory surgery
Breast or plastic surgery
Cataract surgery
Endoscopic procedures.

Elevated-risk procedures are those in which the risk is 1% or higher. Examples:

Intraperitoneal surgery
Intrathoracic surgery
Carotid endarterectomy
Head and neck surgery
Orthopedic surgery
Prostate surgery
Aortic surgery
Major vascular surgery
Peripheral arterial surgery.

Cardiac risk based on patient factors

The 2014 American College of Cardiology and American Heart Association (ACC/AHA) perioperative guidelines list a number of clinical risk factors for perioperative cardiac morbidity and death.¹ These include coronary artery disease, chronic heart failure, clinically suspected moderate or greater degrees of valvular heart disease, arrhythmias, conduction disorders, pulmonary vascular disease, and adult congenital heart disease.

Patients with these conditions and patients with unstable coronary syndromes warrant preoperative ECGs and sometimes even urgent interventions before any nonemergency surgery, provided such interventions would affect decision-making and perioperative care.¹

The risk of perioperative cardiac morbidity and death can be calculated using either the Revised Cardiac Risk Index scoring system or the American College of Surgeons National Surgical Quality Improvement Program calculator.¹⁵⁷ The former is fairly simple, validated, and accepted, while the latter requires use of online calculators (eg, www.surgicalriskcalculator.com/miorcardiacarrest, www.riskcalculator.facs.org).

The Revised Cardiac Risk Index has six clinical predictors of major perioperative cardiac events:

History of cerebrovascular disease
Prior or current compensated congestive heart failure
History of coronary artery disease
Insulin-dependent diabetes mellitus
Renal insufficiency, defined as a serum creatinine level of 2 mg/dL or higher
Patient undergoing suprainguinal vascular, intraperitoneal, or intrathoracic surgery.

A patient who has 0 or 1 of these predictors would have a low risk of a major adverse cardiac event, whereas a patient with 2 or more would have elevated risk. These risk factors must be taken into consideration to determine the need, if any, for a preoperative ECG.

What an ECG can tell us

Abnormalities such as left ventricular hypertrophy, ST-segment depression, and pathologic Q waves on a preoperative ECG in a patient undergoing an elevated-risk surgical procedure may predict adverse perioperative cardiac events.^3,6

In a retrospective study of 23,036 patients, Noordzij et al⁷ found that in patients undergoing elevated-risk surgery, those with an abnormal preoperative ECG had a higher incidence of cardiovascular death than those with a normal ECG. However, a preoperative ECG was obtained only in patients with established coronary artery disease or risk factors for cardiovascular disease. Hence, although an abnormal ECG in such patients undergoing elevated-risk surgery was predictive of adverse postoperative cardiac outcomes, we cannot say that the same would apply to patients without these characteristics undergoing elevated-risk surgery.

In a prospective observational study of patients with known coronary artery disease undergoing major noncardiac surgery, a preoperative ECG was found to contain prognostic information and was predictive of long-term outcome independent of clinical findings and perioperative ischemia.⁸

CURRENT GUIDELINES AND RECOMMENDATIONS

Several guidelines address whether to order a preoperative ECG but are mostly based on low-level evidence and expert opinion.^1,2,6,9

Current guidelines recommend obtaining a preoperative ECG in patients with known coronary, peripheral arterial, or cerebrovascular disease.^1,6,9

Obesity and associated comorbidities such as coronary artery disease, heart failure, systemic hypertension, and sleep apnea can predispose to increased perioperative complications. A preoperative 12-lead ECG is reasonable in morbidly obese patients (body mass index ≥ 40 kg/m²) and in obese patients (body mass index ≥ 30 kg/m²) with at least one risk factor for coronary artery disease or poor exercise tolerance, or both.¹⁰

Liu et al¹¹ looked at the predictive value of a preoperative 12-lead ECG in 513 elderly patients (age ≥ 70) undergoing noncardiac surgery and found that electrocardiographic abnormalities were not predictive of adverse cardiac outcomes. In this study, although electrocardiographic abnormalities were common (noted in 75% of the patients), they were nonspecific and less useful in predicting postoperative cardiac complications than was the presence of comorbidities.¹¹ Age alone as a cutoff for obtaining a preoperative ECG is not predictive of postoperative outcomes and a preoperative ECG is not warranted in all elderly patients. This is also reflected in current ACC/AHA guidelines on perioperative cardiovascular evaluation¹ and is a change from prior ACC/AHA guidelines when age was used as a criterion for preoperative ECGs.¹²

Current guidelines do not recommend getting a preoperative ECG in asymptomatic patients undergoing low-cardiac-risk surgery.^1,4,9

Although the ideal time for ordering an ECG before a planned surgery is unknown, obtaining one within 90 days before the surgery is considered adequate in stable patients in whom an ECG is indicated.¹

BACK TO OUR PATIENT

On the basis of current evidence, our patient does not need a preoperative ECG, as it is unlikely to alter his perioperative management and instead may delay his surgery unnecessarily if any nonspecific changes prompt further cardiac workup.

CLINICAL BOTTOM LINE

Although frequently ordered in clinical practice, preoperative electrocardiography has a limited role in predicting postoperative outcome and should be ordered only in the appropriate clinical setting.¹ Moreover, there is little evidence that outcomes are better if we obtain an ECG before surgery. The clinician should consider patient factors and the type of surgery before ordering diagnostic tests, including electrocardiography.

In asymptomatic patients undergoing nonemergent surgery:

It is reasonable to obtain a preoperative ECG in patients with known coronary artery disease, significant arrhythmia, peripheral arterial disease, cerebrovascular disease, chronic heart failure, or other significant structural heart disease undergoing elevated-cardiac-risk surgery.
Do not order a preoperative ECG in asymptomatic patients undergoing low-risk surgery.
Obtaining a preoperative ECG is reasonable in morbidly obese patients and in obese patients with one or more risk factors for coronary artery disease, or poor exercise tolerance, undergoing high-risk surgery.

References

Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. J Am Coll Cardiol 2014; Jul 29. 10.1016/j.jacc.2014.07.944. [Epub ahead of print]
Feely MA, Collins CS, Daniels PR, Kebede EB, Jatoi A, Mauck KF. Preoperative testing before noncardiac surgery: guidelines and recommendations. Am Fam Physician 2013; 87:414–418.
Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999; 100:1043–1049.
Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery; European Society of Cardiology (ESC); Poldermans D, Bax JJ, Boersma E, et al. Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery. Eur Heart J 2009; 30:2769–2812.
Bilimoria KY, Liu Y, Paruch JL, Zhou L, Kmiecik TE, Ko CY, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg 2013; 217:833–842.
Landesberg G, Einav S, Christopherson R, et al. Perioperative ischemia and cardiac complications in major vascular surgery: importance of the preoperative twelve-lead electrocardiogram. J Vasc Surg 1997; 26:570–578.
Noordzij PG, Boersma E, Bax JJ, et al. Prognostic value of routine preoperative electrocardiography in patients undergoing noncardiac surgery. Am J Cardiol 2006; 97:1103–1106.
Jeger RV, Probst C, Arsenic R, et al. Long-term prognostic value of the preoperative 12-lead electrocardiogram before major noncardiac surgery in coronary artery disease. Am Heart J 2006; 151:508–513.
Committee on Standards and Practice Parameters; Apfelbaum JL, Connis RT, Nickinovich DG, Pasternak LR, Arens JF, Caplan RA, et al. Practice advisory for preanesthesia evaluation: an updated report by the American Society of Anesthesiologists Task Force on Preanesthesia Evaluation. Anesthesiology 2012; 116:522–538.
Poirier P, Alpert MA, Fleisher LA, et al. Cardiovascular evaluation and management of severely obese patients undergoing surgery: a science advisory from the American Heart Association. Circulation 2009; 120:86–95.
Liu LL, Dzankic S, Leung JM. Preoperative electrocardiogram abnormalities do not predict postoperative cardiac complications in geriatric surgical patients. J Am Geriatr Soc 2002; 50:1186–1191.
Eagle KA, Berger PB, Calkins H, et al; American College of Cardiology; American Heart Association. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—executive summary. J Am Coll Cardiol 2002; 39:542–553.

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Sourab Dhungel, MD, FACP
Assistant Professor of Clinical Medicine, Section of Hospital Medicine, Temple University Hospital, Philadelphia, PA

Anbazhagan Prabhakaran, MD, MRCP (Edin), FACP
Assistant Clinical Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Medical Director, IMPACT Center, Cleveland Clinic

Address: Prashant Sharma, MD, FACP, Department of Hospital Internal Medicine, Mayo Clinic, 200 1st Street SW, OL-4, Rochester, MN 55905; e-mail: [email protected]

Smart Testing is a joint project of the Cleveland Clinic Journal of Medicine and the American College of Physicians (ACP). The series, an extension of the ACP High Value Care initiative (hvc.acponline.org/index.html), provides recommendations for improving patient outcomes while reducing unnecessary testing and treatment.

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Anbazhagan Prabhakaran, MD, MRCP (Edin), FACP

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Address: Prashant Sharma, MD, FACP, Department of Hospital Internal Medicine, Mayo Clinic, 200 1st Street SW, OL-4, Rochester, MN 55905; e-mail: [email protected]

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Address: Prashant Sharma, MD, FACP, Department of Hospital Internal Medicine, Mayo Clinic, 200 1st Street SW, OL-4, Rochester, MN 55905; e-mail: [email protected]

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A preoperative ECG is not routinely recommended in all asymptomatic patients undergoing noncardiac surgery.

RISK DEPENDS ON TYPE OF SURGERY AND PATIENT FACTORS

Cardiac risk is multifactorial, and risk factors for postoperative adverse cardiac events include the type of surgery and patient factors.^1,3

Cardiac risk based on type of surgery

Low-risk procedures are those in which the risk of a perioperative major adverse cardiac event is less than 1%.^1,4 Examples:

Ambulatory surgery
Breast or plastic surgery
Cataract surgery
Endoscopic procedures.

Elevated-risk procedures are those in which the risk is 1% or higher. Examples:

Intraperitoneal surgery
Intrathoracic surgery
Carotid endarterectomy
Head and neck surgery
Orthopedic surgery
Prostate surgery
Aortic surgery
Major vascular surgery
Peripheral arterial surgery.

Cardiac risk based on patient factors

The Revised Cardiac Risk Index has six clinical predictors of major perioperative cardiac events:

History of cerebrovascular disease
Prior or current compensated congestive heart failure
History of coronary artery disease
Insulin-dependent diabetes mellitus
Renal insufficiency, defined as a serum creatinine level of 2 mg/dL or higher
Patient undergoing suprainguinal vascular, intraperitoneal, or intrathoracic surgery.

What an ECG can tell us

CURRENT GUIDELINES AND RECOMMENDATIONS

Several guidelines address whether to order a preoperative ECG but are mostly based on low-level evidence and expert opinion.^1,2,6,9

Current guidelines recommend obtaining a preoperative ECG in patients with known coronary, peripheral arterial, or cerebrovascular disease.^1,6,9

Current guidelines do not recommend getting a preoperative ECG in asymptomatic patients undergoing low-cardiac-risk surgery.^1,4,9

BACK TO OUR PATIENT

CLINICAL BOTTOM LINE

In asymptomatic patients undergoing nonemergent surgery:

It is reasonable to obtain a preoperative ECG in patients with known coronary artery disease, significant arrhythmia, peripheral arterial disease, cerebrovascular disease, chronic heart failure, or other significant structural heart disease undergoing elevated-cardiac-risk surgery.
Do not order a preoperative ECG in asymptomatic patients undergoing low-risk surgery.
Obtaining a preoperative ECG is reasonable in morbidly obese patients and in obese patients with one or more risk factors for coronary artery disease, or poor exercise tolerance, undergoing high-risk surgery.

A preoperative ECG is not routinely recommended in all asymptomatic patients undergoing noncardiac surgery.

RISK DEPENDS ON TYPE OF SURGERY AND PATIENT FACTORS

Cardiac risk is multifactorial, and risk factors for postoperative adverse cardiac events include the type of surgery and patient factors.^1,3

Cardiac risk based on type of surgery

Low-risk procedures are those in which the risk of a perioperative major adverse cardiac event is less than 1%.^1,4 Examples:

Ambulatory surgery
Breast or plastic surgery
Cataract surgery
Endoscopic procedures.

Elevated-risk procedures are those in which the risk is 1% or higher. Examples:

Intraperitoneal surgery
Intrathoracic surgery
Carotid endarterectomy
Head and neck surgery
Orthopedic surgery
Prostate surgery
Aortic surgery
Major vascular surgery
Peripheral arterial surgery.

Cardiac risk based on patient factors

The Revised Cardiac Risk Index has six clinical predictors of major perioperative cardiac events:

History of cerebrovascular disease
Prior or current compensated congestive heart failure
History of coronary artery disease
Insulin-dependent diabetes mellitus
Renal insufficiency, defined as a serum creatinine level of 2 mg/dL or higher
Patient undergoing suprainguinal vascular, intraperitoneal, or intrathoracic surgery.

What an ECG can tell us

CURRENT GUIDELINES AND RECOMMENDATIONS

Several guidelines address whether to order a preoperative ECG but are mostly based on low-level evidence and expert opinion.^1,2,6,9

Current guidelines recommend obtaining a preoperative ECG in patients with known coronary, peripheral arterial, or cerebrovascular disease.^1,6,9

Current guidelines do not recommend getting a preoperative ECG in asymptomatic patients undergoing low-cardiac-risk surgery.^1,4,9

BACK TO OUR PATIENT

CLINICAL BOTTOM LINE

In asymptomatic patients undergoing nonemergent surgery:

It is reasonable to obtain a preoperative ECG in patients with known coronary artery disease, significant arrhythmia, peripheral arterial disease, cerebrovascular disease, chronic heart failure, or other significant structural heart disease undergoing elevated-cardiac-risk surgery.
Do not order a preoperative ECG in asymptomatic patients undergoing low-risk surgery.
Obtaining a preoperative ECG is reasonable in morbidly obese patients and in obese patients with one or more risk factors for coronary artery disease, or poor exercise tolerance, undergoing high-risk surgery.

References

Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. J Am Coll Cardiol 2014; Jul 29. 10.1016/j.jacc.2014.07.944. [Epub ahead of print]
Feely MA, Collins CS, Daniels PR, Kebede EB, Jatoi A, Mauck KF. Preoperative testing before noncardiac surgery: guidelines and recommendations. Am Fam Physician 2013; 87:414–418.
Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999; 100:1043–1049.
Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery; European Society of Cardiology (ESC); Poldermans D, Bax JJ, Boersma E, et al. Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery. Eur Heart J 2009; 30:2769–2812.
Bilimoria KY, Liu Y, Paruch JL, Zhou L, Kmiecik TE, Ko CY, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg 2013; 217:833–842.
Landesberg G, Einav S, Christopherson R, et al. Perioperative ischemia and cardiac complications in major vascular surgery: importance of the preoperative twelve-lead electrocardiogram. J Vasc Surg 1997; 26:570–578.
Noordzij PG, Boersma E, Bax JJ, et al. Prognostic value of routine preoperative electrocardiography in patients undergoing noncardiac surgery. Am J Cardiol 2006; 97:1103–1106.
Jeger RV, Probst C, Arsenic R, et al. Long-term prognostic value of the preoperative 12-lead electrocardiogram before major noncardiac surgery in coronary artery disease. Am Heart J 2006; 151:508–513.
Committee on Standards and Practice Parameters; Apfelbaum JL, Connis RT, Nickinovich DG, Pasternak LR, Arens JF, Caplan RA, et al. Practice advisory for preanesthesia evaluation: an updated report by the American Society of Anesthesiologists Task Force on Preanesthesia Evaluation. Anesthesiology 2012; 116:522–538.
Poirier P, Alpert MA, Fleisher LA, et al. Cardiovascular evaluation and management of severely obese patients undergoing surgery: a science advisory from the American Heart Association. Circulation 2009; 120:86–95.
Liu LL, Dzankic S, Leung JM. Preoperative electrocardiogram abnormalities do not predict postoperative cardiac complications in geriatric surgical patients. J Am Geriatr Soc 2002; 50:1186–1191.
Eagle KA, Berger PB, Calkins H, et al; American College of Cardiology; American Heart Association. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—executive summary. J Am Coll Cardiol 2002; 39:542–553.

References

Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. J Am Coll Cardiol 2014; Jul 29. 10.1016/j.jacc.2014.07.944. [Epub ahead of print]
Feely MA, Collins CS, Daniels PR, Kebede EB, Jatoi A, Mauck KF. Preoperative testing before noncardiac surgery: guidelines and recommendations. Am Fam Physician 2013; 87:414–418.
Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999; 100:1043–1049.
Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery; European Society of Cardiology (ESC); Poldermans D, Bax JJ, Boersma E, et al. Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery. Eur Heart J 2009; 30:2769–2812.
Bilimoria KY, Liu Y, Paruch JL, Zhou L, Kmiecik TE, Ko CY, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg 2013; 217:833–842.
Landesberg G, Einav S, Christopherson R, et al. Perioperative ischemia and cardiac complications in major vascular surgery: importance of the preoperative twelve-lead electrocardiogram. J Vasc Surg 1997; 26:570–578.
Noordzij PG, Boersma E, Bax JJ, et al. Prognostic value of routine preoperative electrocardiography in patients undergoing noncardiac surgery. Am J Cardiol 2006; 97:1103–1106.
Jeger RV, Probst C, Arsenic R, et al. Long-term prognostic value of the preoperative 12-lead electrocardiogram before major noncardiac surgery in coronary artery disease. Am Heart J 2006; 151:508–513.
Committee on Standards and Practice Parameters; Apfelbaum JL, Connis RT, Nickinovich DG, Pasternak LR, Arens JF, Caplan RA, et al. Practice advisory for preanesthesia evaluation: an updated report by the American Society of Anesthesiologists Task Force on Preanesthesia Evaluation. Anesthesiology 2012; 116:522–538.
Poirier P, Alpert MA, Fleisher LA, et al. Cardiovascular evaluation and management of severely obese patients undergoing surgery: a science advisory from the American Heart Association. Circulation 2009; 120:86–95.
Liu LL, Dzankic S, Leung JM. Preoperative electrocardiogram abnormalities do not predict postoperative cardiac complications in geriatric surgical patients. J Am Geriatr Soc 2002; 50:1186–1191.
Eagle KA, Berger PB, Calkins H, et al; American College of Cardiology; American Heart Association. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—executive summary. J Am Coll Cardiol 2002; 39:542–553.

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To dream the maybe possible dream: A breast cancer vaccine

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Brian F. Mandell, MD, PhD

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To dream the maybe possible dream: A breast cancer vaccine

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The Journal generally does not publish articles on topics not yet clinically relevant. But since the topic of immunization is so often in the news, and since immunotherapeutic strategies against cancer continue to be tested in clinical trials, we decided to include in this issue an edited transcript of a Medicine Grand Rounds presentation at Cleveland Clinic by Dr. Vincent Tuohy on a novel strategy to develop a vaccine against a particularly virulent form of breast cancer.

The immune system’s response to cancer is complex. Melanoma and renal cell carcinoma seem particularly susceptible to suppression by the native or augmented immune response. But most cancers seem to grow—and many metastasize—seemingly unaffected by our immune system, and sometimes even in the presence of detectable antitumor cell-directed lymphocytes and antibodies. Many attempts at devising human antitumor vaccines and immunotherapies have failed. On the other hand, we have seen the successful development of effective monoclonal antibody therapies (eg, rituximab for B cell lymphoma), immunomodulatory treatments for patients with advanced disease, and vaccines against viruses that cause cancer, ie, human papillomavirus and hepatitis B.

To fully appreciate the nuances of Dr. Tuohy’s proposed strategy, which has not yet been tested in clinical trials, and the complexities of tumor immunology, a very brief primer on the challenges is in order.

CHALLENGES TO DEVELOPING CANCER IMMUNOTHERAPY

Solid tumors can be triggered by multiple mechanisms, alone or in combination, including viruses, spontaneous mutations, overexpression of tumor promoters, and underexpression of tumor suppressors. Once growing, the solid tumor establishes its own rogue growth community, complete with a new infrastructure to supply nutrition and oxygen, potential means for expansion locally and distally, and a system to defend itself from the body’s immune system. The last of these poses specific challenges to successful spontaneous immune surveillance and to immunotherapy designed to kill cancer cells.

Microbial pathogens trigger both a nonspecific (innate) and a specific immune response in the human body. Initially, the immune system is nonspecifically “revved up,” triggered by shared “danger signals” associated with the perceived pathogen and its specific antigens. Then, specialized cells including dendritic cells locally and in proximate lymph nodes are primed to present the de novo antigens in a way that generates a specific and maturing immune response capable of getting rid of the pathogen. Tumors are also pathogenic and in some ways “foreign.” However, they are also similar to normal tissue and interact quite differently with the immune response in ways that enhance their likelihood of growth and survival. Tumor cells often do not send a danger signal to the immune system akin to what is generated by a staphylococcal or mycobacterial invader.

Tumor cells express specific antigens on their surface, such as viral proteins, cancer-associated mutated proteins, and overexpressed differentiated or undifferentiated antigens, including in some cases what Dr. Tuohy discusses as “retired proteins.” But some of these antigens may also be expressed in normal tissues, especially in an environment of resolving inflammation. Some signal the immune system to down-regulate what could otherwise be a vigorous self-destructive response every time there was inflammation.

The dendritic cell activation of the potential antitumor T-cell response and the antitumor T-cell response itself seem to be systematically blunted by many tumors. Reversal of this blunting represents one strategy currently used with very modest clinical success in treating advanced melanoma. Some newly generated tumor-antigen–recognizing T cells may in fact exert suppressor (or regulator) and not cytotoxic activity. Some tumors exhibit systemic immunosuppressive activity; this can be manifested not only by unchecked tumor growth, but also by an increased susceptibility to certain infections.

PITFALLS OF MESSING WITH THE IMMUNE SYSTEM

Messing with the immune system is not without pitfalls. Not all toxicities will be predicted by preclinical animal studies, and human immunity is not a mirror image of rodents’ or even other primates’ immune systems. Augmentation of an antitumor response, in part from the interplay of the complexities noted above, may lead to destruction of normal tissue elsewhere, or even to disruption of tolerance with the expression of autoimmunity. The toxicities will be different than the somewhat predictable toxicities from traditional antiproliferative chemotherapies—witness the striking systemic toxicity from interleukin 2-based therapies.

Whether Dr. Tuohy’s approach to developing a tumor vaccine will ultimately reach our formularies remains to be seen. The work is in an extremely preliminary phase. But the concept of immunotherapy for cancer remains an active area of research that is worth keeping an eye on.

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CHALLENGES TO DEVELOPING CANCER IMMUNOTHERAPY

PITFALLS OF MESSING WITH THE IMMUNE SYSTEM

CHALLENGES TO DEVELOPING CANCER IMMUNOTHERAPY

PITFALLS OF MESSING WITH THE IMMUNE SYSTEM

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The most proven, effective way to control disease is through prophylactic vaccination. The childhood vaccination program is a testament to this disease prevention approach, and in its current form protects us from diseases caused by 16 different pathogens.¹

Childhood immunization ends in the teen years with recommended vaccination against multiple strains of human papillomavirus that are associated with several cancers, most notably cervical carcinoma.² However, even though we have known for over 30 years that the immune system can provide considerable vaccine-induced protection against the development of cancer,³ we have not produced any vaccines that prevent cancers that commonly occur with age, such as breast and prostate cancer, which afflict 1 of 8 women and 1 of 6 men, respectively.^4,5

The lack of an adult vaccine program that provides protection against such commonly occurring adult-onset cancers represents a glaring health care deficiency and a challenge for this current generation to protect coming generations.

THE ‘RETIRED’ PROTEIN HYPOTHESIS

Given that most cancers are not associated with any disease-inducing pathogens, at what targets can we aim our immune system to induce safe and effective protection against these commonly occurring adult-onset cancers?

Perhaps an understanding of the natural aging process may provide us with insights regarding possible vaccine targets. As we age, there is a decline in expression of many tissue-specific proteins, often to the point where they may be considered “retired” and no longer found at detectable or immunogenic levels in normal cells. Examples of this natural aging process include the pigment proteins as our hair whitens, certain lactation proteins when breastfeeding ceases, and some ovarian proteins as menopause begins and production of mature egg follicles ceases. If these retired proteins are expressed in invigorated emerging tumors, then preemptive immunity directed against these retired proteins would attack and destroy the emerging tumors and ignore normal tissues, thereby avoiding any complicating collateral autoimmune damage.

Thus, we propose that retired tissue-specific self-proteins may substitute for unavailable pathogens as targets for mediating safe and effective immune protection against adult-onset cancers such as breast cancer.

SAFE AND EFFECTIVE PREVENTION OF BREAST CANCER IN MICE

To test this retired-protein hypothesis for immunoprevention of breast cancer, we selected alpha-lactalbumin as our vaccine target, for two reasons:

Alpha-lactalbumin is a protein expressed exclusively in lactating breast tissue and is not expressed at immunogenic levels in either normal nonlactating breast tissues or in any of 78 other normal human tissues examined.^6–8
Alpha-lactalbumin is expressed in most human triple-negative breast cancers (TNBC),^9,10 the most aggressive and lethal form of breast cancer, and the predominant form that occurs in women with mutations in the breast cancer 1, early-onset gene (BRCA1).^11,12

We found that alpha-lactalbumin vaccination consistently inhibited the formation and growth of breast tumors in three different mouse models commonly used in breast cancer research.¹³ More importantly, the observed immune protection against the development of breast cancer in mice occurred in the absence of any detectable autoimmune inflammatory damage in any normal tissues examined. Thus, we concluded that alpha-lactalbumin vaccination could provide healthy women with safe and effective immune protection against the more malignant forms of breast cancer.

FROM BENCH TO BEDSIDE

How then do we determine whether alpha-lactalbumin vaccination prevents the development of TNBC in otherwise healthy cancer-free women, and whether it prevents recurrence of TNBC in women already diagnosed with TNBC? Our initial approach will involve two phase 1 clinical trials designed to determine the safety of the vaccine as well as the dose and number of vaccinations needed to induce optimum tumor immunity.

The first (phase 1a) trial will involve vaccination of women recently diagnosed with TNBC who have recovered with the current standard of care. These women will be vaccinated in groups receiving various doses of both recombinant human alpha-lactalbumin and an appropriate immune adjuvant that activates the immune system so it responds aggressively to the alpha-lactalbumin and creates the proinflammatory T-cell response needed for effective tumor immunity. This trial will simply provide dosage and safety profiles of the vaccine and will thereby lay the groundwork for subsequent (phase 2 and 3) trials designed to determine whether alpha-lactalbumin vaccination is effective in preventing recurrence of TNBC in women already diagnosed with this disease.

The dosage and number of immunizations shown to provide optimum immunity in the phase 1a trial will be used in a second (phase 1b) trial designed primarily to determine the safety of alpha-lactalbumin vaccination in healthy cancer-free women who have elected to undergo voluntary prophylactic mastectomy to reduce their breast cancer risk. Most of the women who elect to have this surgery have an established family history of breast cancer or a known BRCA1 mutation associated with high breast cancer risk, or both.^11,12 Consenting women will be vaccinated against alpha-lactalbumin several months before their mastectomy, and their surgically removed breast tissues will be examined extensively for signs of vaccine-induced autoimmune damage. Thus, this trial will determine the safety of alpha-lactalbumin vaccination in healthy cancer-free women and will lay the groundwork for subsequent phase 2 and 3 trials designed to determine whether alpha-lactalbumin vaccination is effective in preventing TNBC in women at high risk of developing this form of breast cancer.

We estimate that completing our preclinical studies, obtaining permission from the US Food and Drug Administration to test our investigational new drug, and completing both phase 1 clinical trials will require about 5 years. Thereafter, completion of phase 2 and 3 trials designed to prevent both recurrence of TNBC in women already diagnosed with this disease and occurrence of TNBC in otherwise healthy, cancer-free women will likely take at least another 5 years, so that this vaccine will likely not be available to the general public before 2024.

TO SUM UP

Although our immune system is potentially capable of protecting us from some cancers, we currently have no immune protection against cancers we commonly confront as we age. We propose that tissue-specific self proteins that are retired from expression with age in normal tissues but are expressed at immunogenic levels in emerging tumors may substitute for unavailable pathogens as targets for immunoprevention of adult-onset cancers that commonly occur with age. We know that the retired breast-specific protein, alpha-lactalbumin, is overexpressed in TNBC and that vaccination with alpha-lactalbumin provides safe and effective protection from breast cancer in preclinical mouse studies. Clinical trials are planned to ultimately determine whether alpha-lactalbumin vaccination can prevent recurrence of TNBC in women already diagnosed with this disease and prevent the initiation of TNBC in women at high risk of developing this most aggressive and lethal form of breast cancer.

Acknowledgment: This work was supported by a grant from Shield Biotech, Inc., Cleveland, OH. In addition, the author wishes to recognize and express his sincere gratitude for the support and encouragement received from numerous organizations that have been instrumental in making this work possible, including November Philanthropy, Brakes for Breasts, the Breast Health and Healing Foundation, the Toni Turchi Foundation, the Coalition of Women Who Care About Breast Cancer, the Sisters for Prevention, the Previvors and Survivors, the Champions of the Pink Vaccine, the Race at Legacy Village, the National Greek Orthodox Ladies Philopto-chos Society, the Daughters of Penelope Icarus Chapter 321, Can’t Stop Won’t Stop, the Babylon Breast Cancer Coalition, and Walk With A Doc.

References

Centers for Disease Control and Prevention. Immunization schedules. www.cdc.gov/vaccines/schedules/. Accessed September 4, 2014.
Schiller JT, Lowy DR. Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol 2012; 10:681–692.
Van Pel A, Boon T. Protection against a nonimmunogenic mouse leukemia by an immunogenic variant obtained by mutagenesis. Proc Natl Acad Sci USA 1982; 79:4718–4722.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63:11–30.
National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. Previous version: SEER cancer statistics review 1975–2010. http://seer.cancer.gov/csr/1975_2010/. Accessed September 4, 2014.
Uhlen M, Oksvold P, Fagerberg L, et al. Towards a knowledge-based human protein atlas. Nat Biotechnol 2010; 28:1248–1250.
Pontén F, Gry M, Fagerberg L, et al. A global view of protein expression in human cells, tissues, and organs. Mol Syst Biol 2009; 5:337.
The Human Protein Atlas. www.proteinatlas.org. Accessed September 4, 2014.
Rhodes DR, Yu J, Shanker K, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 2004; 6:1–6.
ONCOMINEdatabase. www.oncomine.org/resource/login.html. Accessed September 4, 2014.
Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008; 26:4282–4288.
Comen E, Davids M, Kirchhoff T, Hudis C, Offit K, Robson M. Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in Ashkenazi women. Breast Cancer Res Treat 2011; 129:185–190.
Jaini R, Kesaraju P, Johnson JM, Altuntas CZ, Jane-Wit D, Tuohy VK. An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nat Med 2010; 16:799–803.

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Vincent K. Tuohy, PhD
Mort and Iris November Distinguished Chair in Innovative Breast Cancer Research, Cleveland Clinic; Staff, Department of Immunology, Lerner Research Institute, Cleveland Clinic; Professor, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Chief Science Officer, Shield Biotech, Inc.

Address: Vincent K. Tuohy, PhD, Department of Immunology, Lerner Research Institute, NB30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: [email protected]

Dr. Tuohy is the inventor of vaccines based on the retired self-protein strategy, and these vaccines have been licensed to Shield Biotech, Inc., a privately owned company. The author is the Chief Science Officer of Shield Biotech and may in the future receive commercialization revenues for this technology. The author acknowledges that there is a potential conflict of interest related to his relationship with Shield Biotech and asserts that to the best of his ability he has taken all measures in this report to avoid any inappropriate bias associated with the commercial goals of the company.

Medical Grand Rounds articles are based on edited transcripts from Division of Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

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Medical Grand Rounds articles are based on edited transcripts from Division of Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

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THE ‘RETIRED’ PROTEIN HYPOTHESIS

SAFE AND EFFECTIVE PREVENTION OF BREAST CANCER IN MICE

To test this retired-protein hypothesis for immunoprevention of breast cancer, we selected alpha-lactalbumin as our vaccine target, for two reasons:

Alpha-lactalbumin is a protein expressed exclusively in lactating breast tissue and is not expressed at immunogenic levels in either normal nonlactating breast tissues or in any of 78 other normal human tissues examined.^6–8
Alpha-lactalbumin is expressed in most human triple-negative breast cancers (TNBC),^9,10 the most aggressive and lethal form of breast cancer, and the predominant form that occurs in women with mutations in the breast cancer 1, early-onset gene (BRCA1).^11,12

FROM BENCH TO BEDSIDE

TO SUM UP

THE ‘RETIRED’ PROTEIN HYPOTHESIS

SAFE AND EFFECTIVE PREVENTION OF BREAST CANCER IN MICE

To test this retired-protein hypothesis for immunoprevention of breast cancer, we selected alpha-lactalbumin as our vaccine target, for two reasons:

Alpha-lactalbumin is a protein expressed exclusively in lactating breast tissue and is not expressed at immunogenic levels in either normal nonlactating breast tissues or in any of 78 other normal human tissues examined.^6–8
Alpha-lactalbumin is expressed in most human triple-negative breast cancers (TNBC),^9,10 the most aggressive and lethal form of breast cancer, and the predominant form that occurs in women with mutations in the breast cancer 1, early-onset gene (BRCA1).^11,12

FROM BENCH TO BEDSIDE

TO SUM UP

References

Centers for Disease Control and Prevention. Immunization schedules. www.cdc.gov/vaccines/schedules/. Accessed September 4, 2014.
Schiller JT, Lowy DR. Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol 2012; 10:681–692.
Van Pel A, Boon T. Protection against a nonimmunogenic mouse leukemia by an immunogenic variant obtained by mutagenesis. Proc Natl Acad Sci USA 1982; 79:4718–4722.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63:11–30.
National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. Previous version: SEER cancer statistics review 1975–2010. http://seer.cancer.gov/csr/1975_2010/. Accessed September 4, 2014.
Uhlen M, Oksvold P, Fagerberg L, et al. Towards a knowledge-based human protein atlas. Nat Biotechnol 2010; 28:1248–1250.
Pontén F, Gry M, Fagerberg L, et al. A global view of protein expression in human cells, tissues, and organs. Mol Syst Biol 2009; 5:337.
The Human Protein Atlas. www.proteinatlas.org. Accessed September 4, 2014.
Rhodes DR, Yu J, Shanker K, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 2004; 6:1–6.
ONCOMINEdatabase. www.oncomine.org/resource/login.html. Accessed September 4, 2014.
Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008; 26:4282–4288.
Comen E, Davids M, Kirchhoff T, Hudis C, Offit K, Robson M. Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in Ashkenazi women. Breast Cancer Res Treat 2011; 129:185–190.
Jaini R, Kesaraju P, Johnson JM, Altuntas CZ, Jane-Wit D, Tuohy VK. An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nat Med 2010; 16:799–803.

References

Centers for Disease Control and Prevention. Immunization schedules. www.cdc.gov/vaccines/schedules/. Accessed September 4, 2014.
Schiller JT, Lowy DR. Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol 2012; 10:681–692.
Van Pel A, Boon T. Protection against a nonimmunogenic mouse leukemia by an immunogenic variant obtained by mutagenesis. Proc Natl Acad Sci USA 1982; 79:4718–4722.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63:11–30.
National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. Previous version: SEER cancer statistics review 1975–2010. http://seer.cancer.gov/csr/1975_2010/. Accessed September 4, 2014.
Uhlen M, Oksvold P, Fagerberg L, et al. Towards a knowledge-based human protein atlas. Nat Biotechnol 2010; 28:1248–1250.
Pontén F, Gry M, Fagerberg L, et al. A global view of protein expression in human cells, tissues, and organs. Mol Syst Biol 2009; 5:337.
The Human Protein Atlas. www.proteinatlas.org. Accessed September 4, 2014.
Rhodes DR, Yu J, Shanker K, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 2004; 6:1–6.
ONCOMINEdatabase. www.oncomine.org/resource/login.html. Accessed September 4, 2014.
Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008; 26:4282–4288.
Comen E, Davids M, Kirchhoff T, Hudis C, Offit K, Robson M. Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in Ashkenazi women. Breast Cancer Res Treat 2011; 129:185–190.
Jaini R, Kesaraju P, Johnson JM, Altuntas CZ, Jane-Wit D, Tuohy VK. An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nat Med 2010; 16:799–803.

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KEY POINTS

“Retired” tissue-specific self proteins may substitute for unavailable pathogens as vaccine targets for mediating immune prevention of adult-onset cancers.
Vaccination against the retired breast-specific protein alpha-lactalbumin provides safe and effective immune protection against the development of breast tumors in several mouse models.
Alpha-lactalbumin is overexpressed in most human triple-negative breast cancers (TNBC), the most aggressive and lethal form of human breast cancer.
Forthcoming are clinical trials designed to prevent the initiation of TNBC in otherwise healthy cancer-free women, as well as trials designed to prevent recurrence of TNBC in women already diagnosed with this disease.

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Diabetes therapy and cancer risk: Where do we stand when treating patients?

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Grace E. Ching Sun, DO

Sangeeta R. Kashyap, MD

Christian Nasr, MD

In the last quarter century, many new drugs have become available for treating type 2 diabetes mellitus. The American Association of Clinical Endocrinologists incorporated these new agents in its updated glycemic control algorithm in 2013.¹ Because diabetes affects 25.8 million Americans and can lead to blindness, renal failure, cardiovascular disease, and amputation, agents that help us treat it more effectively are valuable.²

One of the barriers to effective treatment is the side effects of the agents. Because some of these drugs have been in use for only a short time, concerns of potential adverse effects have arisen. Cancer is one such concern, especially since type 2 diabetes mellitus by itself increases the risk of cancer by 20% to 50% compared with no diabetes.³

Type 2 diabetes has been linked to risk of cancers of the pancreas,⁴ colorectum,^5,6 liver,⁷ kidney,^8,9 breast,¹⁰ bladder,¹¹ and endometri-um,¹² as well as to hematologic malignancies such as non-Hodgkin lymphoma.¹³ The risk of bladder cancer appears to depend on how long the patient has had type 2 diabetes. Newton et al,¹⁴ in a prospective cohort study, found that those who had diabetes for more than 15 years and used insulin had the highest risk of bladder cancer. On the other hand, the risk of prostate cancer is actually lower in people with diabetes,¹⁵ particularly in those who have had diabetes for longer than 4 years.¹⁶

Cancer and type 2 diabetes share many risk factors and underlying pathophysiologic mechanisms. Nonmodifiable risk factors for both diseases include advanced age, male sex, ethnicity (African American men appear to be most vulnerable to both cancer and diabetes),^17,18 and family history. Modifiable risk factors include lower socioeconomic status, obesity, and alcohol consumption. These common risk factors lead to hyperinsulinemia and insulin resistance, changes in mitochondrial function, low-grade inflammation, and oxidative stress,³ which promote both diabetes and cancer. Diabetes therapy may influence several of these processes.

Several classes of diabetes drugs, including exogenous insulin,^19–22 insulin secretagogues,^23–25 and incretin-based therapies,^26–28 have been under scrutiny because of their potential influences on cancer development in a population already at risk (Table 1).

INSULIN ANALOGUES: MIXED EVIDENCE

Insulin promotes cell division by binding to insulin receptor isoform A and insulin-like growth factor 1 receptors.²⁹ Because endogenous hyperinsulinemia has been linked to cancer risk, growth, and proliferation, some speculate that exogenous insulin may also increase cancer risk.

In 2009, a retrospective study by Hemkens et al linked the long-acting insulin analogue glargine to risk of cancer.¹⁹ This finding set off a tumult of controversy within the medical community and concern among patients. Several limitations of the study were brought to light, including a short duration of follow-up, and several other studies have refuted the study’s findings.^20,21

More recently, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial²² found no higher cancer risk with glargine use than with placebo. This study enrolled 12,537 participants from 573 sites in 40 countries. Specifically, risks with glargine use were as follows:

Any cancer—hazard ratio 1.00, 95% confidence interval (CI) 0.88–1.13, P = .97
Cancer death—hazard ratio 0.94, 95% CI 0.77–1.15, P = .52.

However, the study was designed to assess cardiovascular outcomes, not cancer risk. Furthermore, the participants were not typical of patients seen in clinical practice: their insulin doses were lower (the median insulin dose was 0.4 units/kg/day by year 6, whereas in clinical practice, those with type 2 diabetes mellitus often use more than 1 unit/kg/day, depending on duration of diabetes, diet, and exercise regimen), and their baseline median hemoglobin A_1c level was only 6.4%. And one may argue that the median follow-up of 6.2 years was too short for cancer to develop.²²

In vitro studies indicate that long-acting analogue insulin therapy may promote cancer cell growth more than endogenous insulin,³⁰ but epidemiologic data have not unequivocally substantiated this.^20–22 There is no clear evidence that analogue insulin therapy raises cancer risk above that of human recombinant insulin, and starting insulin therapy should not be delayed because of concerns about cancer risk, particularly in uncontrolled diabetes.

INSULIN SECRETAGOGUES

Sulfonylureas: Higher risk

Before 1995, only two classes of diabetes drugs were approved by the US Food and Drug Administration (FDA)—insulin and sulfonylureas.

Sulfonylureas lower blood sugar levels by binding to sulfonylurea receptors and inhibiting adenosine triphosphate-dependent potassium channels. The resulting change in resting potential causes an influx of calcium, ultimately leading to insulin secretion.

Sulfonylureas are effective, and because of their low cost, physicians often pick them as a second-line agent after metformin.

The main disadvantage of sulfonylureas is the risk of hypoglycemia, particularly in patients with renal failure, the elderly, and diabetic patients who are unaware of when they are hypoglycemic. Other potential drawbacks are that they impair cardiac ischemic preconditioning³¹ and possibly increase cancer risk.^21,32 (Ischemic preconditioning is the process in which transient episodes of ischemia “condition” the myocardium so that it better withstands future episodes with minimal anginal pain and tissue injury.³³) Of the sulfonylureas, glyburide has been most implicated in cardiovascular risk.³²

In a retrospective cohort study of 62,809 patients from a general-practice database in the United Kingdom, Currie et al²¹ found that sulfonylurea monotherapy was associated with a 36% higher risk of cancer (95% CI 1.19–1.54, P < .001) than metformin monotherapy. Prescribing bias may have influenced the results: practitioners are more likely to prescribe sulfonylureas to leaner patients, who have a greater likelihood of occult cancer. However, other studies also found that the cancer death rate is higher in those who take a sulfonylurea alone than in those who use metformin alone.^23,24

Some evidence indicates that long-acting sulfonylurea formulations (eg, glyburide) likely hold the most danger, certainly in regard to hypoglycemia, but it is less clear if this translates to cancer concerns.³¹

Meglitinides: Limited evidence

Meglitinides, the other class of insulin secretagogues, are less commonly used but are similar to sulfonylureas in the way they increase endogenous insulin levels. The data are limited regarding cancer risk and meglitinide therapy, but the magnitude of the association is similar to that with sulfonylurea therapy.²⁵

INSULIN SENSITIZERS

There are currently two classes of insulin sensitizers: biguanides and thiazolidinediones (TZDs, also known as glitazones). These drugs show less risk of both cancer incidence and cancer death than insulin secretagogues such as sulfonylureas.^21,23,24 In fact, they may decrease cancer potential by alteration of signaling via the AKT/mTOR (v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin) pathway.³⁴

Metformin, a biguanide, is the oral drug of choice

Metformin is the only biguanide currently available in the United States. It was approved by the FDA in 1995, although it had been in clinical use since the 1950s. Inexpensive and familiar, it is the oral antihyperglycemic of choice if there are no contraindications to it, such as renal dysfunction (creatinine ≥ 1.4 mg/dL in women and ≥ 1.5 mg/dL in men), acute decompensated heart failure, or pulmonary or hepatic insufficiency, all of which may lead to an increased risk of lactic acidosis.¹

Metformin lowers blood sugar levels primarily by inhibiting hepatic glucose production (gluconeogenesis) and by improving peripheral insulin sensitivity. It directly activates AMP-activated protein kinase (AMPK), which affects insulin signaling and glucose and fat metabolism.³⁵ It may exert further beneficial effects by acutely increasing glucagon-like peptide-1 (GLP-1) levels and inducing islet incretin-receptor gene expression.³⁶ Although the exact mechanisms have not been fully elucidated, metformin’s insulin-sensitizing properties are likely from favorable effects on insulin receptor expression, tyrosine kinase activity, and influences on the incretin pathway.^36,37 These effects also mitigate carcinogenesis, both directly (via AMPK and liver kinase B1, a tumor-suppressor gene) and indirectly (via reduction of hyperinsulinemia).³⁵

Overall, biguanide therapy is associated with a lower cancer incidence or, at worst, no effect on cancer incidence. In vitro studies demonstrate that metformin both suppresses cancer cell growth and induces apoptosis, resulting in fewer live cancer cells.³⁴ Several retrospective studies found lower cancer risk in metformin users than in patients receiving antidiabetes drugs other than insulin-sensitizing agents,^{21,23,25,38–40} while others have shown no effect.⁴¹ Use of metformin was specifically associated with lower risk of cancers of the liver, colon and rectum, and lung.⁴² Further, metformin users have a lower cancer mortality rate than nonusers.^24,43

Thiazolidinediones

TZDs, such as pioglitazone, work by binding to peroxisome proliferator-activated gamma receptors in the cell nucleus, altering gene transcription.⁴⁴ They reduce insulin resistance and levels of endogenous insulin levels and free fatty acids.⁴⁴

Concern over bladder cancer risk with TZD use, particularly with pioglitazone, has increased in the last few years, as various cohort studies found a statistically significant increased risk with this agent.⁴⁴ The risk appears to rise with cumulative dose.^45,46

Randomized controlled trials also found an increased risk of bladder cancer with TZD therapy, although the difference was not statistically significant.^47–49 In a mean follow-up of 8.7 years, the Prospective Pioglitazone Clinical Trial in Macrovascular Events reported 23 cases of bladder cancer in the pioglitazone group vs 22 cases in the placebo group, for rates of 0.9% vs 0.8% (relative risk [RR] 1.06, 95% CI 0.59–1.89).⁴⁹

On the other hand, the risk of cancer of the breast, colon, and lung has been found to be lower with TZD use.⁴⁷ In vitro studies support the clinical data, showing that TZDs inhibit growth of human cancer cells derived from cancers of the lung, colon, breast, stomach, ovary, and prostate.^50–53

Home et al⁵⁴ compared rosiglitazone against a sulfonylurea in patients already taking metformin in the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial. Malignancies developed in 6.7% of the sulfonylurea group compared with 5.1% of the rosiglitazone group, for a hazard ratio of 1.33 (95% CI 0.94–1.88).

Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.⁵⁴

Colmers et al⁴⁷ pooled data from four randomized controlled trials, seven cohort studies, and nine case-control studies to assess the risk of cancer with TZD use in type 2 diabetes. Both the randomized and observational data showed neutral overall cancer risk with TZDs. However, pooled data from observational studies showed significantly lower risk with TZD use in terms of:

Colorectal cancer RR 0.93, 95% CI 0.87–1.00
Lung cancer RR 0.91, 95% CI 0.84–0.98
Breast cancer RR 0.89, 95% CI 0.81–0.98.

INCRETIN-BASED THERAPIES

Incretins are hormones released from the gut in response to food ingestion, triggering release of insulin before blood glucose levels rise. Their action explains why insulin secretion increases more after an oral glucose load than after an intravenous glucose load, a phenomenon called the incretin effect.⁵⁵

There are two incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). They have short a half-life because they are rapidly degraded by dipeptidyl peptidase-IV (DPP-IV).⁵⁵ Available incretin-based therapies are GLP-1 receptor agonists and DPP-IV inhibitors.

When used as monotherapy, incretin-based therapies do not cause hypoglycemia because their effect is glucose-dependent.⁵⁵ GLP-1 receptor antagonists have the added benefit of inducing weight loss, but DPP-IV inhibitors are considered to be weight-neutral.

GLP-1 receptor agonists

Exenatide, the first of the GLP-1 receptor agonists, was approved in 2005. The original formulation (Byetta) is taken by injection twice daily, and timing in conjunction with food intake is important: it should be taken within 60 minutes before the morning and evening meals. Extended-release exenatide (Bydureon) is a once-weekly formulation taken without regard to timing of food intake. Exenatide (either twice-daily Byetta or once-weekly Bydureon) should not be used in those with creatinine clearance less than 30 mL/min or end-stage renal disease and should be used with caution in patients with renal transplantation.

Liraglutide (Victoza), a once-daily formulation, can be injected irrespective of food intake. The dose does not have to be adjusted for renal function, although it should be used with caution in those with renal impairment, including end-stage renal disease. Approval for a 3-mg formulation is pending with the FDA as a weight-loss drug on the basis of promising results in a randomized phase 3 trial.⁵⁶

Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.

DPP-IV inhibitors

Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.

Sitagliptin (Januvia), the first DPP-IV inhibitor, became available in the United States in 2006. Since then, three more have become available: saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).

Concerns about thyroid cancer with incretin drugs

Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.

Studies in rodents have shown C-cell hyperplasia, sometimes resulting in increased incidence of thyroid carcinoma, and dose-dependent rises in serum calcitonin, particularly with liraglutide.²⁶ This has raised concern about an increased risk of medullary thyroid carcinoma in humans. However, the density of C cells in rodents is up to 45 times greater than in humans, and C cells also express functional GLP-1 receptors.²⁶

Gier et al²⁷ assessed the expression of calcitonin and human GLP-1 receptors in normal C cells, C cell hyperplasia, and medullary cancer. In this study, calcitonin and GLP-1 receptor were co-expressed in medullary thyroid cancer (10 of 12 cases) and C-cell hyperplasia (9 of 9 cases) more commonly than in normal C cells (5 of 15 cases). Further, GLP-1 receptor was expressed in 3 of 17 cases of papillary thyroid cancer.

Calcitonin, a polypeptide hormone produced by thyroid C cells and used as a medullary thyroid cancer biomarker, was increased in a slightly higher percentage of patients treated with liraglutide than in controls, without an increase above the normal range.⁵⁷

A meta-analysis by Alves et al⁵⁸ of 25 studies found that neither exenatide (no cases reported) nor liraglutide (odds ratio 1.54, 95% CI 0.40–6.02) was associated with increased thyroid cancer risk.

MacConell et al⁵⁹ pooled the results of 19 placebo-controlled trials of twice-daily exenatide and found a thyroid cancer incidence rate of 0.3 per 100 patient-years (< 0.1%) vs 0 per 100 patient-years in pooled comparators.

Concerns about pancreatic cancer with incretin drugs

Increased risk of acute pancreatitis is a potential side effect of both DPP-IV inhibitors and GLP-1 receptor agonists and has led to speculation that this translates to an increased risk of pancreatic cancer.

In a point-counterpoint debate, Butler et al²⁸ argued that incretin-based medications have questionable safety, with increased rates of pancreatitis possibly leading to pancreatic cancer. In counterpoint, Nauck⁶⁰ argued that the risk of pancreatitis or cancer is extremely low, and clinical cases are unsubstantiated.

Bailey⁶¹ outlined the complexities and difficulties in drawing firm conclusions from individual clinical trials regarding possible adverse effects of diabetes drugs. The trials are typically designed to assess hemoglobin A_1c reduction at varying doses and are typically restricted in patient selection, patient numbers, and drug-exposure duration, which may introduce allocation and ascertainment biases. The attempt to draw firm conclusions from such trials can be problematic and can lead to increased alarm, warranted or not.

Type 2 diabetes mellitus itself is associated with an increased incidence of pancreatic cancer, and whether incretin therapy enhances this risk is still controversial. Whether more episodes of acute pancreatitis without chronic pancreatitis can be extrapolated to an increased incidence of pancreatic cancer is doubtful. A normal pancreatic duct cell may take up to 12 years to become a tumor cell from which pancreatic carcinoma develops, another 7 years to develop metastatic capacity, and another 3 years before a diagnosis is made from clinical symptoms (which are usually accompanied by metastases).⁶²

The risks and benefits of incretin therapies remain a contentious issue, and there are no clear prospective data at this time on increased pancreatic cancer incidence. Long-term prospective studies designed to analyze these specific outcomes (pancreatitis, pancreatic cancer, and medullary thyroid cancer) need to be undertaken.⁶³

OTHER DIABETES THERAPIES

Alpha glucosidase inhibitors

Oral glucosidase inhibitors ameliorate hyperglycemia by inhibiting alpha glucosidase enzymes in the brush border of the small intestines, preventing conversion of polysaccharides to monosaccharides.⁶⁴ This slows digestion of carbohydrates and glucose release into the bloodstream and blunts the postprandial hyperglycemic excursion.

The two alpha glucosidase inhibitors currently available in the United States are acarbose and miglitol, and although data are limited, they do not appear to increase the risk of cancer.^65,66

Sodium-glucose-linked cotransporter 2 inhibitors

The newest class of oral diabetes agents to be approved are the sodium-glucose-linked cotransporter 2 (SGLT2) inhibitors canagliflozin (Invokana) and dapagliflozin (Farxiga).

SGLT2 is a protein in the S1 segment of the proximal renal tubules responsible for over 90% of renal glucose reabsorption. SGLT2 inhibitors lower serum glucose levels by promoting glycosuria and have also been shown to have favorable effects on blood pressure and weight.^67,68

Canagliflozin was the first of its class to gain FDA approval in the United States. It has not been found to be associated with increased cancer risk.⁶⁸

Dapagliflozin, originally approved in Europe, was approved in the United States on January 8, 2014. Because of a possible increased incidence of breast and bladder malignancies, the FDA advisory committee initially recommended against approval and required further data. In those who were treated, nine cases of bladder cancer and nine cases of breast cancer were reported, compared with one case of bladder cancer and no cases of breast cancer in the control group; however, the difference was not statistically significant.⁶⁸

Since SGLT2 inhibitors are still new, data on long-term outcomes are lacking. Early clinical data do not show a significant increase in cancer risk.

WHAT THIS MEANS IN PRACTICE

Many studies have found associations between diabetes, obesity, hyperinsulinemia, and cancer risk. In the last decade, concerns implicating antihyperglycemic agents in cancer development have arisen but have not been well substantiated. At this time, there are no definitive prospective data indicating that the currently available type 2 diabetes therapies increase the incidence of cancer beyond the inherent increased risk in this population. What, then, is one to do?

Educate. Lifestyle modification, including weight management, should continue to be emphasized in diabetes education, as no therapy is completely effective without adjunct modifications in diet and physical activity. Epidemiologic studies have shown the benefits of lifestyle modifications, which ameliorate many of the adverse metabolic conditions that coexist in type 2 diabetes and cancer.

Screen for cancer. Given the associations between diabetes and malignancy, cancer screening is especially important in this high-risk population.

Customize therapy to individual patients. Those with a personal history of bladder cancer should avoid pioglitazone, and those who have had pancreatic cancer should avoid sitagliptin until definitive clinical data become available.

Moreover, patients with a personal or family history of medullary thyroid cancer should not receive GLP-1 receptor agonists. These agents should also probably be avoided in patients with a personal history of differentiated thyroid carcinoma or a history of familial nonmedullary thyroid carcinoma. Until we have further elucidating data, it is not possible to say whether a family history of any of the other types of cancer should represent a contraindication to the use of any of these agents.

Discuss. The multitude of diabetes therapies warrants physician-patient discussions that carefully weigh the risks and benefits of additional agents to optimize glycemic control and metabolic factors in individual patients.

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Washio M, Mori M, Khan M, et al; JACC Study Group. Diabetes mellitus and kidney cancer risk: the results of Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). Int J Urol 2007; 14:393–397.
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Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009; 52:1732–1744.
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Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122:253–270.
Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice. Diabetologia 2011; 54:339–349.
Gunton JE, Delhanty PJ, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrinol Metab 2003; 88:1323–1332.
Ruiter R, Visser LE, van Herk-Sukel MP, et al. Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care 2012; 35:119–124.
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009; 32:1620–1625.
Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of metformin and the risk of ovarian cancer: a case-control analysis. Gynecol Oncol 2011; 123:200–204.
Azoulay L, Dell’Aniello S, Gagnon B, Pollak M, Suissa S. Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomarkers Prev 2011; 20:337–344.
Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One 2012; 7:e33411.
Currie CJ, Poole CD, Jenkins-Jones S, Gale EA, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care 2012; 35:299–304.
Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004; 351:1106–1118.
Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344:e3645.
Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 2011; 34:916–922.
Colmers IN, Bowker SL, Johnson JA. Thiazolidinedione use and cancer incidence in type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab 2012; 38:475–484.
Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR; PROactive investigators. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 2009; 32:187–202.
Erdmann E, Song E, Spanheimer R, van Troostenburg de Bruyn A, Perez A. Pioglitazone and bladder malignancy during observational follow-up of PROactive: 6-year update. Abstract presented at the 72nd Scientific Sessions of the American Diabetes Association; June 8–12, 2012; Philadelphia, PA.
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Ban JO, Oh JH, Son SM, et al. Troglitazone, a PPAR agonist, inhibits human prostate cancer cell growth through inactivation of NFKB via suppression of GSK-3B expression. Cancer Biol Ther 2011; 12:288–296.
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Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti GADOPT Study Group; RECORD Steering Committee. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia 2010; 53:1838–1845.
Martin JH, Deacon CF, Gorrell MD, Prins JB. Incretin-based therapies—review of the physiology, pharmacology and emerging clinical experience. Intern Med J 2011; 41:299–307.
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Grace E. Ching Sun, DO
Department of Medicine, Section of Endocrinology & Metabolism, Assistant Professor of Medicine, Louisiana State University Health Sciences Center, Shreveport

Sangeeta R. Kashyap, MD
Endocrinology and Metabolism Institute, Cleveland Clinic; Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Christian Nasr, MD
Endocrinology and Metabolism Institute, Cleveland Clinic

Address: Grace E. Ching Sun, DO, Department of Medicine, Section of Endocrinology & Metabolism, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130; e-mail: [email protected]

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Christian Nasr, MD

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INSULIN ANALOGUES: MIXED EVIDENCE

Any cancer—hazard ratio 1.00, 95% confidence interval (CI) 0.88–1.13, P = .97
Cancer death—hazard ratio 0.94, 95% CI 0.77–1.15, P = .52.

INSULIN SECRETAGOGUES

Sulfonylureas: Higher risk

Before 1995, only two classes of diabetes drugs were approved by the US Food and Drug Administration (FDA)—insulin and sulfonylureas.

Sulfonylureas are effective, and because of their low cost, physicians often pick them as a second-line agent after metformin.

Meglitinides: Limited evidence

INSULIN SENSITIZERS

Metformin, a biguanide, is the oral drug of choice

Thiazolidinediones

Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.⁵⁴

Colorectal cancer RR 0.93, 95% CI 0.87–1.00
Lung cancer RR 0.91, 95% CI 0.84–0.98
Breast cancer RR 0.89, 95% CI 0.81–0.98.

INCRETIN-BASED THERAPIES

GLP-1 receptor agonists

Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.

DPP-IV inhibitors

Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.

Concerns about thyroid cancer with incretin drugs

Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.

Concerns about pancreatic cancer with incretin drugs

OTHER DIABETES THERAPIES

Alpha glucosidase inhibitors

The two alpha glucosidase inhibitors currently available in the United States are acarbose and miglitol, and although data are limited, they do not appear to increase the risk of cancer.^65,66

Sodium-glucose-linked cotransporter 2 inhibitors

The newest class of oral diabetes agents to be approved are the sodium-glucose-linked cotransporter 2 (SGLT2) inhibitors canagliflozin (Invokana) and dapagliflozin (Farxiga).

Canagliflozin was the first of its class to gain FDA approval in the United States. It has not been found to be associated with increased cancer risk.⁶⁸

Since SGLT2 inhibitors are still new, data on long-term outcomes are lacking. Early clinical data do not show a significant increase in cancer risk.

WHAT THIS MEANS IN PRACTICE

Screen for cancer. Given the associations between diabetes and malignancy, cancer screening is especially important in this high-risk population.

INSULIN ANALOGUES: MIXED EVIDENCE

Any cancer—hazard ratio 1.00, 95% confidence interval (CI) 0.88–1.13, P = .97
Cancer death—hazard ratio 0.94, 95% CI 0.77–1.15, P = .52.

INSULIN SECRETAGOGUES

Sulfonylureas: Higher risk

Before 1995, only two classes of diabetes drugs were approved by the US Food and Drug Administration (FDA)—insulin and sulfonylureas.

Sulfonylureas are effective, and because of their low cost, physicians often pick them as a second-line agent after metformin.

Meglitinides: Limited evidence

INSULIN SENSITIZERS

Metformin, a biguanide, is the oral drug of choice

Thiazolidinediones

Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.⁵⁴

Colorectal cancer RR 0.93, 95% CI 0.87–1.00
Lung cancer RR 0.91, 95% CI 0.84–0.98
Breast cancer RR 0.89, 95% CI 0.81–0.98.

INCRETIN-BASED THERAPIES

GLP-1 receptor agonists

Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.

DPP-IV inhibitors

Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.

Concerns about thyroid cancer with incretin drugs

Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.

Concerns about pancreatic cancer with incretin drugs

OTHER DIABETES THERAPIES

Alpha glucosidase inhibitors

The two alpha glucosidase inhibitors currently available in the United States are acarbose and miglitol, and although data are limited, they do not appear to increase the risk of cancer.^65,66

Sodium-glucose-linked cotransporter 2 inhibitors

The newest class of oral diabetes agents to be approved are the sodium-glucose-linked cotransporter 2 (SGLT2) inhibitors canagliflozin (Invokana) and dapagliflozin (Farxiga).

Canagliflozin was the first of its class to gain FDA approval in the United States. It has not been found to be associated with increased cancer risk.⁶⁸

Since SGLT2 inhibitors are still new, data on long-term outcomes are lacking. Early clinical data do not show a significant increase in cancer risk.

WHAT THIS MEANS IN PRACTICE

Screen for cancer. Given the associations between diabetes and malignancy, cancer screening is especially important in this high-risk population.

References

Garber AJ, Abrahamson MJ, Barzilay JI, et al; American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013; 19:327–336.
Centers for Disease Control and Prevention (CDC). Diabetes data and trends. www.cdc.gov/diabetes/statistics/. Accessed April 8, 2014.
Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer 2009; 16:1103–1123.
Huxley R, Ansary-Moghaddam A, Berrington de González A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer 2005; 92:2076–2083.
Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 2005; 97:1679–1687.
Limburg PJ, Vierkant RA, Fredericksen ZS, et al. Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Am J Gastroenterol 2006; 101:1872–1879.
El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006; 4:369–380.
Lindblad P, Chow WH, Chan J, et al. The role of diabetes mellitus in the aetiology of renal cell cancer. Diabetologia 1999; 42:107–112.
Washio M, Mori M, Khan M, et al; JACC Study Group. Diabetes mellitus and kidney cancer risk: the results of Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). Int J Urol 2007; 14:393–397.
Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 2007; 121:856–862.
Larsson SC, Orsini N, Brismar K, Wolk A. Diabetes mellitus and risk of bladder cancer: a meta-analysis. Diabetologia 2006; 49:2819–2823.
Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 2007; 50:1365–1374.
Mitri J, Castillo J, Pittas AG. Diabetes and risk of non-Hodgkin’s lymphoma: a meta-analysis of observational studies. Diabetes Care 2008; 31:2391–2397.
Newton CC, Gapstur SM, Campbell PT, Jacobs EJ. Type 2 diabetes mellitus, insulin-use and risk of bladder cancer in a large cohort study. Int J Cancer 2013; 132:2186–2191.
Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006; 15:2056–2062.
Rodriguez C, Patel AV, Mondul AM, Jacobs EJ, Thun MJ, Calle EE. Diabetes and risk of prostate cancer in a prospective cohort of US men. Am J Epidemiol 2005; 161:147–152.
Centers for Disease Control and Prevention. Diabetes public health resource. National diabetes statistics report, 2014. Estimates of diabetes and its burden in the United States. www.cdc.gov/diabetes/pubs/estimates14.htm. Accessed August 12, 2014.
Centers for Disease Control and Prevention. Cancer prevention and control cancer rates by race and ethnicity. www.cdc.gov/cancer/dcpc/data/race.htm. Accessed August 12, 2014.
Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009; 52:1732–1744.
Colhoun HMSDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009; 52:1755–1765.
Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52:1766–1777.
ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367:319–328.
Baur DM, Klotsche J, Hamnvik OP, et al. Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort. Metabolism 2011; 60:1363–1371.
Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006; 29:254–258.
Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009; 137:482–488.
Bjerre Knudsen L, Madsen LW, Andersen S, et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 2010; 151:1473–1486.
Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM, Yeh MW. Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinol Metab 2012; 97:121–131.
Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care 2013; 36:2118–2125.
Belfiore A, Malaguarnera R. Insulin receptor and cancer. Endocr Relat Cancer 2011; 18:R125–R147.
Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev 2009; 25:41–49.
Riddle MC. Editorial: sulfonylureas differ in effects on ischemic preconditioning—is it time to retire glyburide? J Clin Endocrinol Metab 2003; 88:528–530.
Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am J Gastroenterol 2012; 107:620–626.
Deutsch E, Berger M, Kussmaul WG, Hirshfeld JW, Herrmann HC, Laskey WK. Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features. Circulation 1990; 82:2044–2051.
Feng YH, Velazquez-Torres G, Gully C, Chen J, Lee MH, Yeung SC. The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med 2011; 15:825–836.
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122:253–270.
Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice. Diabetologia 2011; 54:339–349.
Gunton JE, Delhanty PJ, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrinol Metab 2003; 88:1323–1332.
Ruiter R, Visser LE, van Herk-Sukel MP, et al. Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care 2012; 35:119–124.
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009; 32:1620–1625.
Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of metformin and the risk of ovarian cancer: a case-control analysis. Gynecol Oncol 2011; 123:200–204.
Azoulay L, Dell’Aniello S, Gagnon B, Pollak M, Suissa S. Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomarkers Prev 2011; 20:337–344.
Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One 2012; 7:e33411.
Currie CJ, Poole CD, Jenkins-Jones S, Gale EA, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care 2012; 35:299–304.
Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004; 351:1106–1118.
Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344:e3645.
Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 2011; 34:916–922.
Colmers IN, Bowker SL, Johnson JA. Thiazolidinedione use and cancer incidence in type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab 2012; 38:475–484.
Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR; PROactive investigators. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 2009; 32:187–202.
Erdmann E, Song E, Spanheimer R, van Troostenburg de Bruyn A, Perez A. Pioglitazone and bladder malignancy during observational follow-up of PROactive: 6-year update. Abstract presented at the 72nd Scientific Sessions of the American Diabetes Association; June 8–12, 2012; Philadelphia, PA.
Akinyeke TO, Stewart LV. Troglitazone suppresses c-Myc levels in human prostate cancer cells via a PPARγ-independent mechanism. Cancer Biol Ther 2011; 11:1046–1058.
Ban JO, Oh JH, Son SM, et al. Troglitazone, a PPAR agonist, inhibits human prostate cancer cell growth through inactivation of NFKB via suppression of GSK-3B expression. Cancer Biol Ther 2011; 12:288–296.
Yan KH, Yao CJ, Chang HY, Lai GM, Cheng AL, Chuang SE. The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells. Mol Carcinog 2010; 49:235–246.
Rashid-Kolvear F, Taboski MA, Nguyen J, Wang DY, Harrington LA, Done SJ. Troglitazone suppresses telomerase activity independently of PPARgamma in estrogen-receptor negative breast cancer cells. BMC Cancer 2010; 10:390.
Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti GADOPT Study Group; RECORD Steering Committee. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia 2010; 53:1838–1845.
Martin JH, Deacon CF, Gorrell MD, Prins JB. Incretin-based therapies—review of the physiology, pharmacology and emerging clinical experience. Intern Med J 2011; 41:299–307.
Wadden TA, Hollander P, Klein S, et al; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013; 37:1443–1451.
Hegedüs L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5,000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab 2011; 96:853–860.
Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract 2012; 98:271–284.
MacConell L, Brown C, Gurney K, Han J. Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5,594 patients from 19 placebo-controlled and comparator-controlled clinical trials. Diabetes Metab Syndr Obes 2012; 5:29–41.
Nauck MA. A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks. Diabetes Care 2013; 36:2126–2132.
Bailey CJ. Interpreting adverse signals in diabetes drug development programs. Diabetes Care 2013; 36:2098–2106.
Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010; 467:1114–1117.
Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N Engl J Med 2014; 370:794–797.
Bischoff H. The mechanism of alpha-glucosidase inhibition in the management of diabetes. Clin Invest Med 1995; 18:303–311.
Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E. Sulphonylureas and cancer: a case-control study. Acta Diabetol 2009; 46:279–284.
Tseng CH. Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan. Diabetologia 2011; 54:2009–2015.
Vallon V. The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol 2011; 300:R1009–R1022.
Kim Y, Babu AR. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes. Diabetes Metab Syndr Obes 2012; 5:313–527.

References

Garber AJ, Abrahamson MJ, Barzilay JI, et al; American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013; 19:327–336.
Centers for Disease Control and Prevention (CDC). Diabetes data and trends. www.cdc.gov/diabetes/statistics/. Accessed April 8, 2014.
Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer 2009; 16:1103–1123.
Huxley R, Ansary-Moghaddam A, Berrington de González A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer 2005; 92:2076–2083.
Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 2005; 97:1679–1687.
Limburg PJ, Vierkant RA, Fredericksen ZS, et al. Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Am J Gastroenterol 2006; 101:1872–1879.
El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006; 4:369–380.
Lindblad P, Chow WH, Chan J, et al. The role of diabetes mellitus in the aetiology of renal cell cancer. Diabetologia 1999; 42:107–112.
Washio M, Mori M, Khan M, et al; JACC Study Group. Diabetes mellitus and kidney cancer risk: the results of Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). Int J Urol 2007; 14:393–397.
Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 2007; 121:856–862.
Larsson SC, Orsini N, Brismar K, Wolk A. Diabetes mellitus and risk of bladder cancer: a meta-analysis. Diabetologia 2006; 49:2819–2823.
Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 2007; 50:1365–1374.
Mitri J, Castillo J, Pittas AG. Diabetes and risk of non-Hodgkin’s lymphoma: a meta-analysis of observational studies. Diabetes Care 2008; 31:2391–2397.
Newton CC, Gapstur SM, Campbell PT, Jacobs EJ. Type 2 diabetes mellitus, insulin-use and risk of bladder cancer in a large cohort study. Int J Cancer 2013; 132:2186–2191.
Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006; 15:2056–2062.
Rodriguez C, Patel AV, Mondul AM, Jacobs EJ, Thun MJ, Calle EE. Diabetes and risk of prostate cancer in a prospective cohort of US men. Am J Epidemiol 2005; 161:147–152.
Centers for Disease Control and Prevention. Diabetes public health resource. National diabetes statistics report, 2014. Estimates of diabetes and its burden in the United States. www.cdc.gov/diabetes/pubs/estimates14.htm. Accessed August 12, 2014.
Centers for Disease Control and Prevention. Cancer prevention and control cancer rates by race and ethnicity. www.cdc.gov/cancer/dcpc/data/race.htm. Accessed August 12, 2014.
Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009; 52:1732–1744.
Colhoun HMSDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009; 52:1755–1765.
Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52:1766–1777.
ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367:319–328.
Baur DM, Klotsche J, Hamnvik OP, et al. Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort. Metabolism 2011; 60:1363–1371.
Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006; 29:254–258.
Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009; 137:482–488.
Bjerre Knudsen L, Madsen LW, Andersen S, et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 2010; 151:1473–1486.
Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM, Yeh MW. Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinol Metab 2012; 97:121–131.
Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care 2013; 36:2118–2125.
Belfiore A, Malaguarnera R. Insulin receptor and cancer. Endocr Relat Cancer 2011; 18:R125–R147.
Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev 2009; 25:41–49.
Riddle MC. Editorial: sulfonylureas differ in effects on ischemic preconditioning—is it time to retire glyburide? J Clin Endocrinol Metab 2003; 88:528–530.
Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am J Gastroenterol 2012; 107:620–626.
Deutsch E, Berger M, Kussmaul WG, Hirshfeld JW, Herrmann HC, Laskey WK. Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features. Circulation 1990; 82:2044–2051.
Feng YH, Velazquez-Torres G, Gully C, Chen J, Lee MH, Yeung SC. The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med 2011; 15:825–836.
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122:253–270.
Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice. Diabetologia 2011; 54:339–349.
Gunton JE, Delhanty PJ, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrinol Metab 2003; 88:1323–1332.
Ruiter R, Visser LE, van Herk-Sukel MP, et al. Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care 2012; 35:119–124.
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009; 32:1620–1625.
Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of metformin and the risk of ovarian cancer: a case-control analysis. Gynecol Oncol 2011; 123:200–204.
Azoulay L, Dell’Aniello S, Gagnon B, Pollak M, Suissa S. Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomarkers Prev 2011; 20:337–344.
Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One 2012; 7:e33411.
Currie CJ, Poole CD, Jenkins-Jones S, Gale EA, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care 2012; 35:299–304.
Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004; 351:1106–1118.
Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344:e3645.
Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 2011; 34:916–922.
Colmers IN, Bowker SL, Johnson JA. Thiazolidinedione use and cancer incidence in type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab 2012; 38:475–484.
Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR; PROactive investigators. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 2009; 32:187–202.
Erdmann E, Song E, Spanheimer R, van Troostenburg de Bruyn A, Perez A. Pioglitazone and bladder malignancy during observational follow-up of PROactive: 6-year update. Abstract presented at the 72nd Scientific Sessions of the American Diabetes Association; June 8–12, 2012; Philadelphia, PA.
Akinyeke TO, Stewart LV. Troglitazone suppresses c-Myc levels in human prostate cancer cells via a PPARγ-independent mechanism. Cancer Biol Ther 2011; 11:1046–1058.
Ban JO, Oh JH, Son SM, et al. Troglitazone, a PPAR agonist, inhibits human prostate cancer cell growth through inactivation of NFKB via suppression of GSK-3B expression. Cancer Biol Ther 2011; 12:288–296.
Yan KH, Yao CJ, Chang HY, Lai GM, Cheng AL, Chuang SE. The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells. Mol Carcinog 2010; 49:235–246.
Rashid-Kolvear F, Taboski MA, Nguyen J, Wang DY, Harrington LA, Done SJ. Troglitazone suppresses telomerase activity independently of PPARgamma in estrogen-receptor negative breast cancer cells. BMC Cancer 2010; 10:390.
Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti GADOPT Study Group; RECORD Steering Committee. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia 2010; 53:1838–1845.
Martin JH, Deacon CF, Gorrell MD, Prins JB. Incretin-based therapies—review of the physiology, pharmacology and emerging clinical experience. Intern Med J 2011; 41:299–307.
Wadden TA, Hollander P, Klein S, et al; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013; 37:1443–1451.
Hegedüs L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5,000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab 2011; 96:853–860.
Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract 2012; 98:271–284.
MacConell L, Brown C, Gurney K, Han J. Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5,594 patients from 19 placebo-controlled and comparator-controlled clinical trials. Diabetes Metab Syndr Obes 2012; 5:29–41.
Nauck MA. A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks. Diabetes Care 2013; 36:2126–2132.
Bailey CJ. Interpreting adverse signals in diabetes drug development programs. Diabetes Care 2013; 36:2098–2106.
Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010; 467:1114–1117.
Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N Engl J Med 2014; 370:794–797.
Bischoff H. The mechanism of alpha-glucosidase inhibition in the management of diabetes. Clin Invest Med 1995; 18:303–311.
Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E. Sulphonylureas and cancer: a case-control study. Acta Diabetol 2009; 46:279–284.
Tseng CH. Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan. Diabetologia 2011; 54:2009–2015.
Vallon V. The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol 2011; 300:R1009–R1022.
Kim Y, Babu AR. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes. Diabetes Metab Syndr Obes 2012; 5:313–527.

Issue

Cleveland Clinic Journal of Medicine - 81(10)

Issue

Cleveland Clinic Journal of Medicine - 81(10)

Page Number

620-628

Page Number

620-628

Publications

Type 2 Diabetes ICYMI

Publications

Type 2 Diabetes ICYMI

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Diabetes therapy and cancer risk: Where do we stand when treating patients?

Display Headline

Diabetes therapy and cancer risk: Where do we stand when treating patients?

Sections

Inside the Article

KEY POINTS

Exogenous insulin, insulin secretagogues, and incretin-based therapies are under scrutiny because of their potential influences on cancer development in a population already at risk.
At present, we lack adequate prospective data on the cancer risk from diabetes drugs.
Patients with a personal history of bladder cancer should avoid pioglitazone, and those who have had pancreatic cancer should avoid incretin therapies until definitive clinical data become available.
Patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 should not receive glucagon-like peptide-1 receptor agonists. These agents should also probably be avoided in patients with a personal history of differentiated thyroid carcinoma or a history of familial nonmedullary thyroid carcinoma.
Given the associations between diabetes and malignancy, cancer screening is especially important.

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Article PDF Media

When patients on target-specific oral anticoagulants need surgery

Article Type

Toby C. Trujillo, PharmD, FCCP, FAHA, BCPS (AQ Cardiology)

Changed

Wed, 09/13/2017 - 15:48

Display Headline

When patients on target-specific oral anticoagulants need surgery

Author(s)

Mary Anderson, MD

Kathryn L. Hassell, MD

Brian Wolfe, MD

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

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

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

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

PHARMACOLOGY OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

Dabigatran, a factor IIa inhibitor

Figure 1. Mechanism of action of the target-specific oral anticoagulants: rivaroxaban and apixaban directly inhibit factor Xa, whereas dabigatran directly inhibits thrombin.

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

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

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

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

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

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

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

Rivaroxaban, a factor Xa inhibitor

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

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

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

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

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

Apixaban, a factor Xa inhibitor

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

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

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

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

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

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

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

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

Edoxaban, a factor Xa inhibitor in development

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

PERIOPERATIVE CONSIDERATIONS IN ANTICOAGULATION

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

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

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

Perioperative bleeding risk

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

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

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

Perioperative thrombotic risk

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

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

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

Perioperative bridging for patients taking warfarin

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

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

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

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

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

PERIOPERATIVE MANAGEMENT OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

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

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

Timing of cessation of anticoagulation

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

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

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

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

Evidence from clinical trials of perioperative TSOAC management

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

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

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

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

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

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

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

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

Perioperative bridging

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

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

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

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

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

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

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

Laboratory monitoring

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

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

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

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

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

Reversal of anticoagulation

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

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

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

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

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

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

Resumption of anticoagulation

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

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

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

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

UNTIL EVIDENCE-BASED GUIDELINES ARE DEVELOPED

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

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Healey JS, Eikelboom J, Douketis J, et al; RE-LY Investigators. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012; 126:343–348.
Sherwood MW, Douketis JD, Patel MR, et al; on behalf of the ROCKET AF Investigators. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation 2014; 129:1850–1859.
Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol 2013; 61:651–658.
Reynolds MR. Discontinuation of rivaroxaban: filling in the gaps. J Am Coll Cardiol 2013; 61:659–660.
Turpie AG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost 2012; 108:876–886.
Gallego P, Apostolakis S, Lip GY. Bridging evidence-based practice and practice-based evidence in periprocedural anticoagulation. Circulation 2012; 126:1573–1576.
Sié P, Samama CM, Godier A, et al; Working Group on Perioperative Haemostasis. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis 2011; 104:669–676.
King CS, Holley AB, Moores LK. Moving toward a more ideal anticoagulant: the oral direct thrombin and factor Xa inhibitors. Chest 2013; 143:1106–1116.
Baglin T, Hillarp A, Tripodi A, Elalamy I, Buller H, Ageno W. Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2013; 11:756–760.
Baglin T, Keeling D, Kitchen S; British Committee for Standards in Haematology. Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: guidance from the British Committee for Standards in Haematology. Br J Haematol 2012; 159:427–429.
Mani H, Kasper A, Lindhoff-Last E. Measuring the anticoagulant effects of target specific oral anticoagulants—reasons, methods and current limitations. J Thromb Thrombolysis 2013; 36:187–194.
Hawes EM, Deal AM, Funk-Adcock D, et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013; 11:1493–1502.
Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104:1263–1271.
Smythe MA, Fanikos J, Gulseth MP, et al. Rivaroxaban: practical considerations for ensuring safety and efficacy. Pharmacotherapy 2013; 33:1223–1245.
Van Ryn J, Litzenburger T, Waterman A, et al. Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro and in vivo models. J Am Coll Cardiol 2011; 57:E1130.
Sheffield W, Lambourne M, Bhakta V, Eltringham-Smith L, Arnold D, Crowther M. Active site-mutated thrombin S195A but not active site-blocked thrombin counteracts the anticoagulant activity of dabigatran in plasma. Abstract presented at the International Society of Thrombosis and Haemostasis 2013 Congress. http://onlinelibrary.wiley.com/doi/10.1111/jth.2013.11.issue-s2/issuetoc. Accessed August 6, 2014.
Lu G, Luan P, Hollenbach SJ, et al. Reconstructed recombinant factor Xa as an antidote to reverse anticoagulation by factor Xa inhibitors (abstract). J Thromb Haemost 2009; 7(suppl 2):abstract OC-TH-107.
Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49:259–268.
Singh T, Maw TT, Henry BL, et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol 2013; 8:1533–1539.
Kaatz S, Crowther M. Reversal of target-specific oral anticoagulants. J Thromb Thrombolysis 2013; 36:195–202.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124:1573–1579.
Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128:1234–1243.

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Author and Disclosure Information

Mary Anderson, MD
Assistant Professor, Hospital Medicine Section, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Kathryn L. Hassell, MD
Professor of Medicine, Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Toby C. Trujillo, PharmD, FCCP, FAHA, BCPS (AQ Cardiology)
Associate Professor, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences; Pharmacy Clinical Specialist, Cardiology/Anticoagulation, University of Colorado Hospital, Aurora

Brian Wolfe, MD
Assistant Professor, Hospital Medicine Section, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Address: Mary Anderson, MD, University of Colorado Anschutz Medical Campus, Leprino Building, 4th Floor, Mailstop F-782, 12401 E. 17th Avenue, Aurora, CO 80045; e-mail: [email protected]

Dr. Trujillo has disclosed consulting for Boehringer Ingelheim, Janssen Pharmaceuticals, and Pfizer/Bristol-Myers Squibb.

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Cleveland Clinic Journal of Medicine - 81(10)

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Hospital Medicine

Neurology

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629-639

Read more about When patients on target-specific oral anticoagulants need surgery

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Toby C. Trujillo, PharmD, FCCP, FAHA, BCPS (AQ Cardiology)

Author(s)

Mary Anderson, MD

Kathryn L. Hassell, MD

Brian Wolfe, MD

Author(s)

Mary Anderson, MD

Kathryn L. Hassell, MD

Toby C. Trujillo, PharmD, FCCP, FAHA, BCPS (AQ Cardiology)

Brian Wolfe, MD

Author and Disclosure Information

Mary Anderson, MD
Assistant Professor, Hospital Medicine Section, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Kathryn L. Hassell, MD
Professor of Medicine, Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Brian Wolfe, MD
Assistant Professor, Hospital Medicine Section, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Address: Mary Anderson, MD, University of Colorado Anschutz Medical Campus, Leprino Building, 4th Floor, Mailstop F-782, 12401 E. 17th Avenue, Aurora, CO 80045; e-mail: [email protected]

Dr. Trujillo has disclosed consulting for Boehringer Ingelheim, Janssen Pharmaceuticals, and Pfizer/Bristol-Myers Squibb.

Author and Disclosure Information

Mary Anderson, MD
Assistant Professor, Hospital Medicine Section, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Kathryn L. Hassell, MD
Professor of Medicine, Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Brian Wolfe, MD
Assistant Professor, Hospital Medicine Section, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Address: Mary Anderson, MD, University of Colorado Anschutz Medical Campus, Leprino Building, 4th Floor, Mailstop F-782, 12401 E. 17th Avenue, Aurora, CO 80045; e-mail: [email protected]

Dr. Trujillo has disclosed consulting for Boehringer Ingelheim, Janssen Pharmaceuticals, and Pfizer/Bristol-Myers Squibb.

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PHARMACOLOGY OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

Dabigatran, a factor IIa inhibitor

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

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

Rivaroxaban, a factor Xa inhibitor

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

Apixaban, a factor Xa inhibitor

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

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

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

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

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

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

Edoxaban, a factor Xa inhibitor in development

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

PERIOPERATIVE CONSIDERATIONS IN ANTICOAGULATION

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

Perioperative bleeding risk

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

Perioperative thrombotic risk

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

Perioperative bridging for patients taking warfarin

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

PERIOPERATIVE MANAGEMENT OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

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

Timing of cessation of anticoagulation

Evidence from clinical trials of perioperative TSOAC management

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

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

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

Perioperative bridging

Laboratory monitoring

Reversal of anticoagulation

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

Resumption of anticoagulation

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

UNTIL EVIDENCE-BASED GUIDELINES ARE DEVELOPED

PHARMACOLOGY OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

Dabigatran, a factor IIa inhibitor

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

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

Rivaroxaban, a factor Xa inhibitor

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

Apixaban, a factor Xa inhibitor

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

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

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

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

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

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

Edoxaban, a factor Xa inhibitor in development

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

PERIOPERATIVE CONSIDERATIONS IN ANTICOAGULATION

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

Perioperative bleeding risk

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

Perioperative thrombotic risk

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

Perioperative bridging for patients taking warfarin

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

PERIOPERATIVE MANAGEMENT OF TARGET-SPECIFIC ORAL ANTICOAGULANTS

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

Timing of cessation of anticoagulation

Evidence from clinical trials of perioperative TSOAC management

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

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

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

Perioperative bridging

Laboratory monitoring

Reversal of anticoagulation

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

Resumption of anticoagulation

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

UNTIL EVIDENCE-BASED GUIDELINES ARE DEVELOPED

References

Douketis JD, Berger PB, Dunn AS, et al; American College of Chest Physicians. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(suppl 6):299S–339S.
Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of Chest Physicians. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(suppl 2):e326S–e350S.
Boehringer Ingelheim Pharmaceuticals, Inc. PRADAXA (dabigatran) package insert. http://bidocs.boehringer-ingelheim.com/BIWebAc-cess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf. Accessed August 6, 2014.
Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology 2013; 118:1466–1474.
US Food and Drug Administration (FDA). FDA drug safety communication: update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran). www.fda.gov/drugs/drugsafety/ucm326580.htm. Accessed August 6, 2014.
Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139–1151.
Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342–2352.
Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368:709–718.
Eriksson BI, Dahl OE, Rosencher N, Büller HR, et al; RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370:949–956.
Eriksson BI, Dahl OE, Rosencher N, et al; RE-MODEL Study Group. Oral dabigatran etexilate vs subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5:2178–2185.
Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369:1206–1214.
Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G; American College of Chest Physicians. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(suppl 2):e44S–e88S.
Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36:386–399.
Janssen Pharmaceuticals, Inc. XARELTO (rivaroxaban) package insert. www.xareltohcp.com/about-xarelto/about-xarelto.html?utm_source=google&utm_medium=cpc&utm_campaign=Branded+-+Broad&utm_term=xarelto%20rivaroxaban&utm_content=Xarelto+Rivaroxaban|mkwid|sxSDxPb4m_dc|pcrid|34667840494. Accessed August 6, 2014.
Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–391.
EINSTEIN Investigators; Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499–2510.
EINSTEIN–PE Investigators; Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366:1287–1297.
Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358:2765–2775.
Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372:31–39.
Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358:2776–2786.
Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol 2010; 70:703–712.
Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981–992.
Bristol-Myers Squibb Company. ELIQUIS (apixaban) package insert. www.eliquis.com/index.aspx. Accessed August 6, 2014.
Furie KL, Goldstein LB, Albers GW, et al; American Heart Association Stroke Council. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012; 43:3442–3453.
ClinicalTrials.gov, US National Institutes of Health. PERIOP 2 - A Safety and Effectiveness Study of LMWH Bridging Therapy Versus Placebo Bridging Therapy for Patients on Long Term Warfarin and Require Temporary Interruption of Their Warfarin. http://clinicaltri-als.gov/show/NCT00432796. Accessed August 6, 2014.
ClinicalTrials.gov, US National Institutes of Health. Effectiveness of Bridging Anticoagulation for Surgery (The BRIDGE Study). http://clinicaltrials.gov/ct2/show/NCT00786474. Accessed August 6, 2014.
Birnie DH, Healey JS, Wells GA, et al; BRUISE CONTROL Investigators. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013; 368:2084–2093.
Oberweis BS, Nukala S, Rosenberg A, et al. Thrombotic and bleeding complications after orthopedic surgery. Am Heart J 2013; 165:427.e1–433.e1.
Omran H, Bauersachs R, Rübenacker S, Goss F, Hammerstingl C. The HAS-BLED score predicts bleedings during bridging of chronic oral anticoagulation. Results from the national multicentre BNK Online bRiDging REgistRy (BORDER). Thromb Haemost 2012; 108:65–73.
Pisters R, Lane DA, Nieuwlaaat R, de Vos CB, Crijns HJGM, Lip GYH. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation. The Euro Heart Survey. Chest 2010; 138:1093–1100.
Kaatz S, Douketis JD, Zhou H, Gage BF, White RH. Risk of stroke after surgery in patients with and without chronic atrial fibrillation. J Thromb Haemost 2010; 8:884–890.
van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103:1116–1127.
Connolly G, Spyropoulos AC. Practical issues, limitations, and periprocedural management of the NOAC’s. J Thromb Thrombolysis 2013; 36:212–222.
Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012; 120:2954–2962.
Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87(suppl 1):S141–S145.
Rowley CP, Bernard ML, Brabham WW, et al. Safety of continuous anticoagulation with dabigatran during implantation of cardiac rhythm devices. Am J Cardiol 2013; 111:1165–1168.
Healey JS, Eikelboom J, Douketis J, et al; RE-LY Investigators. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012; 126:343–348.
Sherwood MW, Douketis JD, Patel MR, et al; on behalf of the ROCKET AF Investigators. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation 2014; 129:1850–1859.
Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol 2013; 61:651–658.
Reynolds MR. Discontinuation of rivaroxaban: filling in the gaps. J Am Coll Cardiol 2013; 61:659–660.
Turpie AG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost 2012; 108:876–886.
Gallego P, Apostolakis S, Lip GY. Bridging evidence-based practice and practice-based evidence in periprocedural anticoagulation. Circulation 2012; 126:1573–1576.
Sié P, Samama CM, Godier A, et al; Working Group on Perioperative Haemostasis. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis 2011; 104:669–676.
King CS, Holley AB, Moores LK. Moving toward a more ideal anticoagulant: the oral direct thrombin and factor Xa inhibitors. Chest 2013; 143:1106–1116.
Baglin T, Hillarp A, Tripodi A, Elalamy I, Buller H, Ageno W. Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2013; 11:756–760.
Baglin T, Keeling D, Kitchen S; British Committee for Standards in Haematology. Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: guidance from the British Committee for Standards in Haematology. Br J Haematol 2012; 159:427–429.
Mani H, Kasper A, Lindhoff-Last E. Measuring the anticoagulant effects of target specific oral anticoagulants—reasons, methods and current limitations. J Thromb Thrombolysis 2013; 36:187–194.
Hawes EM, Deal AM, Funk-Adcock D, et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013; 11:1493–1502.
Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104:1263–1271.
Smythe MA, Fanikos J, Gulseth MP, et al. Rivaroxaban: practical considerations for ensuring safety and efficacy. Pharmacotherapy 2013; 33:1223–1245.
Van Ryn J, Litzenburger T, Waterman A, et al. Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro and in vivo models. J Am Coll Cardiol 2011; 57:E1130.
Sheffield W, Lambourne M, Bhakta V, Eltringham-Smith L, Arnold D, Crowther M. Active site-mutated thrombin S195A but not active site-blocked thrombin counteracts the anticoagulant activity of dabigatran in plasma. Abstract presented at the International Society of Thrombosis and Haemostasis 2013 Congress. http://onlinelibrary.wiley.com/doi/10.1111/jth.2013.11.issue-s2/issuetoc. Accessed August 6, 2014.
Lu G, Luan P, Hollenbach SJ, et al. Reconstructed recombinant factor Xa as an antidote to reverse anticoagulation by factor Xa inhibitors (abstract). J Thromb Haemost 2009; 7(suppl 2):abstract OC-TH-107.
Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49:259–268.
Singh T, Maw TT, Henry BL, et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol 2013; 8:1533–1539.
Kaatz S, Crowther M. Reversal of target-specific oral anticoagulants. J Thromb Thrombolysis 2013; 36:195–202.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124:1573–1579.
Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128:1234–1243.

References

Douketis JD, Berger PB, Dunn AS, et al; American College of Chest Physicians. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(suppl 6):299S–339S.
Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of Chest Physicians. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(suppl 2):e326S–e350S.
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Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128:1234–1243.

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How long before surgery to stop a TSOAC depends on the bleeding risk of the procedure and the patient’s renal function.
Perioperative bridging is generally unnecessary for patients on TSOACs.
Routine coagulation assays such as the prothrombin time and activated partial thromboplastin time do not reliably reflect the degree of anticoagulation with TSOACs.
There are no specific antidotes or standardized reversal strategies for TSOACs.
TSOACs have a rapid onset of action and should only be restarted postoperatively once hemostasis has been confirmed.

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A summary of the new ACOG report on neonatal brachial plexus palsy. Part 2: Pathophysiology and causation

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A summary of the new ACOG report on neonatal brachial plexus palsy. Part 2: Pathophysiology and causation

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Henry M. Lerner, MD

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

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

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

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

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

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

Maternal forces alone are an accepted cause of at least transient NBPP by most investigators.

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

No published clinical or experimental data exist to support the contention that the presence of persistent (as opposed to transient) NBPP implies the application of excessive force by the birth attendant. A single case report describes a case of persistent NBPP in a delivery in which no traction was applied by the delivering physician and no delay occurred in delivering the shoulders.² Therefore, there is insufficient evidence to support a clear division between the causative factors of transient NBPP versus persistent NBPP.¹

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

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

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

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

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

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

The cadaveric work to date to examine the in situ response of the brachial plexus has been quite crude by today’s standards of biomechanics … They do not provide a complete picture of how and why NBPP may occur during delivery.¹

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

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

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

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

Chapter 3 of the ACOG report closes with a statement:

In addition to research within the obstetric community, the pediatric, orthopedic, and neurologic literature now stress that the existence of NBPP following birth does not a priori indicate that exogenous forces are the cause of this injury.¹

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

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

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

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

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

The woman in labor should be instructed to refrain from pushing during an attempted maneuver. She can then be instructed to resume pushing following performance of a maneuver to allow determination of whether the shoulder dystocia has been successfully relieved.¹

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

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

resolving the shoulder dystocia
avoiding neonatal hypoxic-ischemic central nervous system injury
minimizing strain on the neonatal brachial plexus.

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

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

Can simulation training reduce the rate of neonatal brachial plexus injury after shoulder dystocia?

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

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

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

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

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

References

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

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

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

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

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

The report concludes with a glossary and three appendices:

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

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

The report:

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

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

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

References

1. American College of Obstetricians and Gynecologists. Executive summary: neonatal brachial plexus palsy. Report of the American College of Obstetricians and Gynecologists’ Task Force on neonatal brachial plexus palsy. Obstet Gynecol. 2014;123(4):902–904.
2. Lerner HM, Salamon E. Permanent brachial plexus injury following vaginal delivery without physician traction or shoulder dystocia. Am J Obstet Gynecol. 2008;198(3):e.7–e.8.
3. Allen R, Sorab J, Gonik B. Risk factors for shoulder dystocia: an engineering study of clinician-applied forces. Obstet Gynecol. 1991;77(3):352–355.
4. Poggi SH, Allen RH, Patel CR, Ghidini A, Pezzullo JC, Spong CY. Randomized trial of McRoberts versus lithotomy positioning to decrease the force that is applied to the fetus during delivery. Am J Obstet Gynecol. 2004;191(3):874–878.
5. Poggi SH, Allen RH, Patel C, et al. Effect of epidural anaesthesia on clinician-applied force during vaginal delivery. Am J Obstet Gynecol. 2004;191(3):903–906.
6. American College of Obstetricians and Gynecologists. Practice bulletin #40: shoulder dystocia. Obstet Gynecol. 2002;100(5 pt 1):1045–1050.

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Read more about A summary of the new ACOG report on neonatal brachial plexus palsy. Part 2: Pathophysiology and causation

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Henry M. Lerner, MD

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

Maternal forces alone are an accepted cause of at least transient NBPP by most investigators.

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

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

Chapter 3 of the ACOG report closes with a statement:

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

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

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

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

resolving the shoulder dystocia
avoiding neonatal hypoxic-ischemic central nervous system injury
minimizing strain on the neonatal brachial plexus.

Can simulation training reduce the rate of neonatal brachial plexus injury after shoulder dystocia?

References

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

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

The report concludes with a glossary and three appendices:

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

The report:

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

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

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

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

Maternal forces alone are an accepted cause of at least transient NBPP by most investigators.

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

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

Chapter 3 of the ACOG report closes with a statement:

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

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

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

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

resolving the shoulder dystocia
avoiding neonatal hypoxic-ischemic central nervous system injury
minimizing strain on the neonatal brachial plexus.

Can simulation training reduce the rate of neonatal brachial plexus injury after shoulder dystocia?

References

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

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

The report concludes with a glossary and three appendices:

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

The report:

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

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

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

References

Issue

OBG Management - 26(10)

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OBG Management - 26(10)

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46-48,50,51,56

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A summary of the new ACOG report on neonatal brachial plexus palsy. Part 2: Pathophysiology and causation

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