Volume 125
`
`Number 1
`
`1 July 1996
`ML 1st &
`nd f lO Ol'~
`1
`N675
`. 125
`o. 1
`
`.
`
`1Twice Monthly by the American College of Physicians
`
`•
`
`-
`
`-
`
`•
`
`J
`
`I
`
`I
`I
`
`Ad Libitum
`Letters
`
`77
`
`7
`
`Three· Year Follow-up on Effects
`of Transdermal Estrogen
`
`Medical Heuristics
`
`The Literature
`of Medicine
`79
`
`ART ICLES
`
`The Long-Term Clinical Course of Acute Deep Venous
`Thrombosis
`
`The Appropriateness of Coronary Artery Bypass Graft
`Surgery in Academic Medical Centers
`
`Deletion Polymorphism of the Angiotensin I(cid:173)
`Converting Enzyme Gene Is Associated with
`Increased Plasma Angiotensin-Converting Enzyme
`Activity but Not with Increased Risk for Myocardial
`Infarction and Coronary Artery Disease
`
`Somatostatin Receptor Scintigraphy: Its Sensitivity
`Compared with That of Other Imaging Methods in
`Detecting Primary and Metastatic Gastrinomas.
`A Prospective Study
`
`BRIEF COMMUNICATION
`
`Nonsustained Ventricular Tachycardia in Coronary
`Artery Disease: Relation to Inducible Sustained
`Ventricular Tachycardia
`
`Update in Cardiology
`
`UPDATE
`
`REVIEW
`
`1
`
`8
`
`19
`
`26
`
`35
`
`Prandoni, Lensing,
`Cogo, and others
`
`Leape, Hilborne,
`Schwartz, and others
`
`Winkelmann, Nauck,
`Klein, Russ, Bohm,
`Siekmeier, lhnken,
`Verho, GroB, and Marz
`
`Gibril, Reynolds,
`Doppman, Chen,
`Venzon, Termanini,
`Weber, and others
`
`Buxton, Lee, DiCarlo,
`Echt, Fisher, Greer,
`Josephson, and others
`
`40
`
`Alpert and Cheitlin
`
`Anthracycline-Induced Cardiotoxicity
`
`47
`
`Shan and others
`
`Physician-Run Health Plans and Antitrust
`
`MEDICINE AND PUBLIC ISSUES
`59
`
`American College of
`Physicians
`
`Mandated Choice for Organ Donation: Time To Give
`It a Try
`
`66
`
`Spital
`
`IN THE BALANCE
`
`Who Are the Donors in Organ Donation?
`The Family's Perspective in Mandated Choice
`
`70
`
`Klassen and Klassen
`
`Farewell to the "Shy-Drager Syndrome"
`
`74
`
`Schatz
`
`EDITORIALS
`
`~-O(l)CO*
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`.. · «~s and Progress
`Davidoff
`76
`of inte r nal medicin e
`nn al
`·:...-~~~~~~~~~~~~~~~~~~~~~~~~~~
`ML 1 s t &. 2nd Fl 0 0 r ~
`!ptete contents, see pages 1-3 and I-4. For subscription information, see page 1-7. Canadian GST
`UC San Di eg o
`1s121s9·AIMEAS 125(1)1-80(1996) · US ISSN 0003-4819
`I
`Rec e i ved on: 06 - 28-96
`I
`I
`
`HOSPIRA EX. 1142
`Page 1
`
`

`

`1 July 1996
`
`Volume 125
`
`I Number 1
`
`Annals of Internal Medicine
`Contents
`
`Volume 125 Number 1 AIMEAS 125(1)1-80(1996) US ISSN 0003-4819
`
`ARTICLES
`
`The Long-Term Clinical Course of Acute
`Deep Venous Thrombosis
`
`1
`
`P. Prandoni, A . WA. Lensing, A. Cogo,
`S. Cuppini, S. Villalta, M. Carta, A.M. Cattelan,
`P. Polistena, E. Bernardi, and M.H. Prins
`Patients w ith symptomatic deep venous thrombosis, especially those
`without transient risk factors for deep venous thrombosis, have a high
`risk for recurrent venous thromboembolism that persists for years. The
`post-thrombotic syndrome occurs in almost one third of these patients
`and is strongly related to ipsilateral recurrent deep venous throm bosis.
`These findings challenge the w idespread use of short-course anticoag(cid:173)
`ulation therapy in patients with symptomatic deep venous thrombosis.
`
`8
`
`The Appropriateness of Coronary Artery
`Bypass Graft Surgery in Academic Medical
`Centers
`L.L. Leape, L.H. Hilbome, JS. Schwartz,
`D. W Bates, H.R. Rubin, P. Slavin, R.E. Park,
`D.M. Witter Jr. , R.J. Panzer, R.H. Brook, and the
`Working Group of the Appropriateness Project of
`the Academic Medical Center Consortium
`The use of coronary artery bypass graft surgery in Academic Medical
`Center Consortium hospitals was judged to be inappropriate or of
`uncertain appropriateness in only a few cases. The overall evaluation of
`appropriateness remained the same regardless of the criteria used for
`assessment.
`
`19
`
`Deletion Polymorphism of the Angiotensin 1-
`Converting Enzyme Gene Is Associated with
`Increased Plasma Angiotensin-Converting
`Enzyme Activity but Not with Increased Risk
`for Myocardial Infarction and Coronary
`Artery Disease
`B.R. Winkelmann, M. Nauck, B. Klein, A.P. Russ,
`B.O. Bohm, R. Siekmeier, K. Ihnken, M. Verho,
`W Groj3, and W Marz
`In an angiographically defined study sample, angiotensin I-converting
`enzyme insertion/deletion gene polymorphism was not associated with
`increased risk for coronary artery disease or myocardial infarction.
`
`26
`
`Somatostatin Receptor Scintigraphy: Its
`Sensitivity Compared with That of Other
`Imaging Methods in Detecting Primary and
`Metastatic Gastrinomas. A Prospective Study
`F. Gibril, JC. Reynolds, J.L. Doppman,
`C. C. Chen, D.J. Venzon, B. Termanini,
`H. C. Weber, C.A. Stewart, and R. T. Jensen
`Somatostatin receptor scintigraphy is the single most sensitive method
`for imaging either primary or metastatic liver lesions in patients with
`the Zollinger-Ellison syn drome.
`
`BRIEF COMMUNICATION
`
`35
`
`Nonsustained Ventricular Tachycardia in
`Coronary Artery Disease: Relation to
`Inducible Sustained Ventricular Tachycardia
`A .E. Buxton, K.L. Lee, L. DiCarlo, D.S. Echt,
`J.D. Fisher, G.S. Greer, M.E. Josephson,
`D. Packer, E.N. Prystowsky, and M. Talajic, with
`G.E. Hafley and P.M. Smith, for the MUSTT
`Investigators
`Electrocardiographic characteristics of spontaneous nonsustained ven(cid:173)
`tricular tachycardia do not predict which patients with coronary artery
`disease wi ll have inducible sustained ventricular tachycardia .
`
`UPDATE
`
`40
`
`Update in Cardiology
`JS. Alpert and M.D. Cheitlin
`This review, the first in the new Updates series, examines the latest
`research in cardiology. Much of this research has focused on the
`pathophysiology of coronary artery disease and its clinical implications.
`Recent studies have also shown the effectiveness of afterload reduction
`in patients with asymptomatic aortic regurgitation and of carefully
`monitored anticoagulation in patients with atrial fibrillation. lmmuno(cid:173)
`suppressive therapy has been shown to have no effect on outcome in
`patients with myocarditis.
`
`(Continued on page I-4)
`
`Postmaster: Send changes of address to Customer Service, Annals of Internal Medicine, Independence Mall West, Sixth Street at Race,
`Philadelphia, PA 19106-1572.
`·
`Annals of Internal Medicine is published twice monthly and copyrighted <Cl 1996 by the American College of Physicians, Independence Mall West,
`Sixth Street at Race, Philadelphia, PA 19106-1572, USA. Basic USA subscription price is $103.00 per year. Periodicals po.stage paid at Philadelphia,
`Pennsylvania, and at additional mailing offices. Canada Post International Publications Mail Sales Agreement #546186. GST ID#l28512159._
`
`1 July 1996 • Annals of Internal Medicine • Volume 125 • Number 1
`
`1-3
`
`HOSPIRA EX. 1142
`Page 2
`
`

`

`(Table of Contents, continued)
`
`REVIEW
`Anthracycline-Induced Cardiotoxicity
`K. Shan, A.M. Lincojf, and J.B. Young
`A rapidly growing number of persons will have substantial morbidity
`and mortality because of anthracycline-related cardiac disease. The de(cid:173)
`velopment of effective protection against anthracycline-induced cardio(cid:173)
`toxicity will probably have a significant effect on the overall survival of
`these patients.
`
`47
`
`EDITORIALS
`Farewell to the "Shy-Drager Syndrome"
`J.J. Schatz
`A recent statement from the American Autonomic Society and the
`American Academy of Neurology defines the various primary neuro(cid:173)
`genic causes of autonomic dysfunction. Implicit in this document is the
`need to bid goodbye to the term " Shy-Drager syndrome," which has
`served since the condition was first described in 1962.
`
`74
`
`MEDICINE AND PUBLIC ISSUES
`
`59
`
`Physician-Run Health Plans and Antitrust
`American College of Physicians
`Under current antitrust law, physicians have the authority to form their
`own health plans and networks. An examination of federal enforce(cid:173)
`ment agency actions since the mid-1970s shows that physician-run
`networks have rarely been challenged. Because of market develop(cid:173)
`ments, however, the American College of Physicians has urged federal
`antitrust agencies to analyze the effect of their current enforcement
`policies on physician activities. Further monitoring and analysis of the
`changing health care marketplace are needed to ensure that physicians
`are treated fairly and to determine which factors spur or inhibit the
`development of physician-run health plans and networks.
`
`66
`
`IN THE BALANCE
`Mandated Choice for Organ Donation:
`Time To Give It a Try
`A. Spital
`The miracle of transplantation is limited by a severe shortage of avail(cid:173)
`able organs, caused in part by a high rate of refusal among families
`who are asked to allow the removal of organs from a recently de(cid:173)
`ceased relative . Mandated choice would eliminate the need for family
`consent and return control to the individual. Preliminary research sug(cid:173)
`gests that public commitment to organ donation wou ld increase under
`mandated choice.
`
`Who Are the Donors in Organ Donation?
`The Family's Perspective in Mandated Choice
`A. C. Klassen and D.K. Klassen
`Mandated choice has been proposed as a way to increase rates of
`organ donation, but this plan has serious ethical and logistic problems.
`Public education and voluntary donor identification are better solu(cid:173)
`tions.
`
`70
`
`Updates and Progress
`F. Davidoff
`This issue contains the first of a special series that will be published in
`the new Updates format over the coming months.
`
`76
`
`ADUBITUM
`Autosomal/Recessive (Familial Hypocalciuric
`Hypercalcemia)
`H.J. Van Peenen
`
`Three-Year Follow-up on Effects of
`Transdermal Estrogen
`E.G. Lufkin and B.L. Riggs
`
`Medical Heuristics
`W.J. Oetgen; DA. Gerber; C.J. McDonald
`
`THE LITERATURE OF MEDICINE
`
`Reviews and Notes
`
`Information for Authors
`
`Copyright Form
`
`Abstracts of Articles
`
`Book Listings
`
`Medical Notices
`
`7
`
`77
`
`77
`
`79
`
`1-13
`
`1-19
`
`Begin on 1-20
`
`Begin onl-28
`
`Begin on 1-41
`
`Business and Subscription Information
`
`1-79
`
`Classified Services
`
`Index to Advertisers
`
`Begin on 1-107
`
`1-122
`
`1-4
`
`1 July 1996 • Annals of Internal Medicine • Volume 125 • Number 1
`
`HOSPIRA EX. 1142
`Page 3
`
`

`

`Anthracycline-Induced Cardiotoxicity
`
`Kesavan Shan, MD; A. Michael Lincoff, MD; and James B. Young, MD
`
`Purpose: To review the current understanding of the
`clinical significance, detection, pathogenesis, and preven(cid:173)
`tion of anthracycline-induced cardiotoxicity.
`Data Sources: A MEDLINE search of the English-lan(cid:173)
`guage medical literature and a manual search of the bib(cid:173)
`liographies of relevant articles, including abstracts from
`national cardiology meetings.
`Study Selection: Pertinent clinical and experimental
`studies addressing the clinical relevance, pathogenesis,
`detection, and prevention of anthracycline cardiotoxicity
`were selected from peer-reviewed journals without judg(cid:173)
`ments about study design. A total of 137 original studies
`and 9 other articles were chosen.
`Data Extraction: Data quality and validity were assessed
`by each author independently. Statistical analysis of com(cid:173)
`bined data was inappropriate given the differences in
`patient selection, testing, and follow-up in the available
`studies.
`Data Synthesis: Anthracyline-induced cardiotoxicity lim(cid:173)
`its effective cancer chemotherapy by causing early cardio(cid:173)
`myopathy, and it can produce late-onset ventricular dys(cid:173)
`function years after treatment has ceased. Detection of
`subclinical anthracyline-induced cardiomyopathy through
`resting left ventricular ejection fraction or echocardio(cid:173)
`graphic fractional shortening is suboptimal. Conventional
`doses of anthracycline often lead to permanent myocar(cid:173)
`dial damage and reduced functic:rnal reserve. Underlying
`pathogenetic mechanisms may include free-radical(cid:173)
`mediated myocyte damage, adrenergic dysfunction, in(cid:173)
`tracellular calcium overload, and the release of cardiotoxic
`cytokines. Dexrazoxane is the only cardioprotectant clini(cid:173)
`cally approved for use against anthracyclines, and it was
`only recently introduced for selected patients with breast
`cancer who are receiving anthracycline therapy.
`Conclusions: A rapidly growing number of persons, in(cid:173)
`cluding an alarming fraction of the 150 000 or more adults
`in the United.States who have survived childhood cancer,
`w ill have substantial morbidity and mortality because of
`anthracycline-related cardiac disease. The development of
`effective protection against anthracycline-induced cardio(cid:173)
`toxicity will probably have a significant effect on the over(cid:173)
`all survival of these patients.
`
`A nn Intern Med. 1996;125:47-58.
`
`From The Cleveland Clinic Foundation, Cleveland, Ohio. For
`current author addresses, see end of text.
`
`A nthracyclines are well established as highly ef(cid:173)
`
`ficacious antineoplastic agents for various he(cid:173)
`mopoietic (1) and solid tumors (2-4). A clear dose(cid:173)
`response relation for anthracyclines in several curative
`chemotherapeutic regimens has been shown; de(cid:173)
`creased doses result in inferior survival and remis(cid:173)
`sion rates (1, 4). However, the cardiotoxicity of
`these agents ( 4-6), which has been recognized for
`more than 20 years (7), continues to limit their
`therapeutic potential arl.d threaten the cardiac func(cid:173)
`tion of many patients with cancer.
`Three distinct types of anthracycline-induced car(cid:173)
`diotoxicity have been described. First, acute or sub(cid:173)
`acute injury can occur immediately after treatment.
`This rare form of cardiotoxicity may cause transient
`arrhythmias (8, 9), a pericarditis-myocarditis syn(cid:173)
`drome, or acute failure of the left ventricle (10).
`Second, anthracyclines can induce chronic cardio(cid:173)
`toxicity resulting in cardiomyopathy. This a more
`common form of damage and is clinically the most
`important (11-13). Finally, late-onset anthracycline
`cardiotoxicity causing late-onset ventricular dysfunc(cid:173)
`tion (14-16) and arrhythmias (17-19), which mani(cid:173)
`fest years to decades after anthracycline treatment
`, has been completed, is increasingly recognized.
`Chronic anthracycline-induced cardiomyopathy
`characteristically presents within 1 year of treatment.
`In a series of more than 3900 patients treated with
`anthracycline, Von Hoff and associates ( 6) noted
`that congestive heart failure secondary to anthracy(cid:173)
`cline-induced chronic cardiomyopathy occurred 0 to
`231 days after the completion of anthracycline ther(cid:173)
`apy. In contrast, late-onset anthracycline-induced
`cardiac abnormalities have been reported to occur
`much later, after a prolonged asyniptomatic period
`(14-16). Other cardiovascular risk factors predis(cid:173)
`posing to heart failure, such as occult hypertension
`and subclinical coronary artery disease, may have
`confounded interpretation of the exact contribution
`made by anthracyclines in these studies. However,
`anthracyclines are clearly an important independent
`risk factor leading to both early and delayed con(cid:173)
`gestive heart failure in survivors of cancer. There is
`no universally defined point after the onset of
`chronic cardiomyopathy at which late-onset cardiac
`abnormalities appear. For the purposes of this re(cid:173)
`view, we broadly define "chronic cardiotoxicity" as
`cardiotoxicity occurring within 1 year of treatment
`
`© 1996 American College of Physicians
`
`47
`
`HOSPIRA EX. 1142
`Page 4
`
`

`

`and "late-onset cardiotoxicity" as cardiotoxicity oc(cid:173)
`currin_g more than 1 year after the completion of
`anthracycline therapy.
`
`Clinical Significance
`
`Acute and Subacute Cardiotoxicity
`Acute and subacute cardiac toxicity, which occur
`immediately after a single dose of an anthracycline
`or a course of anthracycline therapy, are uncommon
`under current treatment protocols. Several distinct,
`early cardiotoxic effects of anthracyclines have been
`described. First, electrophysiologic abnormalities
`may result in nonspecific ST and T-wave changes,
`decreased QRS voltage, and prolongation of the QT
`interval. Sinus tachycardia is the most common
`rhythm disturbance, but arrhythmias, including ven(cid:173)
`tricular, supraventricular, and junctional tachycar(cid:173)
`dias, have been reported (8-11). Atrioventricular
`and bundle-branch block have also been seen (8).
`These electrophysiologic changes are seldom a seri(cid:173)
`ous clinical problem (11). Rare cases of subacute
`cardiotoxicity resulting in acute failure of the left
`ventricle, pericarditis, or a fatal pericarditis-myocar(cid:173)
`ditis syndrome have been reported (12).
`
`Chronic Cardiotoxicity
`The incidence of congestive heart failure second(cid:173)
`ary to doxorubicin-induced cardiomyopathy depends
`on the cumulative dose of the drug. At total doses
`of less than 400 mg/m2 body surface area, the inci(cid:173)
`dence of congestive heart failure is 0.14%; this in(cid:173)
`cidence increases to 7% at a dose of 550 mg/m 2
`body surface area and to 18% at a dose of 700
`mg/m2 body surface area (6) (Figure 1). The rapid
`increase in clinical toxicity at doses greater than 550
`mg/m2 body surface area has made the 550-mg dose
`
`1.00
`
`0.90
`u. 0.80
`:c
`u 0.70
`..,
`>.
`0.60
`:.0 0.50
`~ .c
`0.40
`0 .....
`0. 0.30
`0.20
`
`0.10
`
`0
`0
`
`100 200 300 400 500 600 700 800 900 k)()()
`Total Dose (mg/m2)
`Figure ~. Cumulative probability of developing doxorubicin-induced
`congestive heart failure (CHF) plotted against total cumulative dose
`of doxorubicin in all patients receiving the drug (3941 patients· 88
`cases of congestive heart failure}. Reproduced from Von Hoff and ' col(cid:173)
`leagues (6) with permission of Annals of Internal Medicine.
`
`the popular empiric limiting dose for doxorubicin(cid:173)
`induced cardiotoxicity. Mortality directly related to
`doxorubicin-induced cardiac failure is substantial·
`large series have reported rates of more than 20%
`(5, 6). However, recent reports have suggested a
`better prognosis (20-24), with up to 59% clinical
`recovery in patients with anthracycline-induced con(cid:173)
`gestive heart failure who are treated with digoxin
`and diuretics (14). Complete recovery of echocar(cid:173)
`diographic shortening fraction may also occur if an(cid:173)
`thracycline therapy is discontinued at an early stage
`(24), but this does not exclude long-term reductions
`in functional reserve (23).
`Although reports conflict, proposed risk factors
`for chronic anthracycline cardiotoxicity
`include
`higher rates of drug administration (25), mediastinal
`radiation (10, 26), advanced age (3, 6), younger age
`(27, 28), female sex (29), pre-existing heart disease,
`and hypertension (6). Multivariate analysis of these
`factors by Torti and colleagues (30), based on his(cid:173)
`tologic evidence of anthracycline cardiotoxicity,
`showed that only higher rates of anthracycline ad(cid:173)
`ministration and previous cardiac irradiation were
`independent risk factors. An additional confounding
`factor in the identification of patients at highest risk
`for cardiotoxicity is the wide variation in individual
`sensitivity to anthracyclines (31-33). Doses in excess
`of 1000 mg/m2 body surface area can be well toler(cid:173)
`ated by some patients (31, 33). In contrast, appre(cid:173)
`ciable decreases in left ventricular ejection fraction
`have been documented by multigated nuclear scans
`at doses as low as 300 mg/m2 body surface area (26,
`27). Furthermore, endomyocardial biopsy specimens
`may show histopathologic changes characteristic of
`doxorubicin-induced cardiotoxicity (Figure 2) at
`doses as low as 183 mg/m2 body surface area (13)(cid:173)
`less than one third of the conventional limiting
`dose. Thus, a substantial proportion of patients have
`anthracycline-induced cardiac damage while receiv(cid:173)
`ing standard treatment regimens, whereas others
`can tolerate cumulative doses twice as large as the
`conventional limiting dose.
`
`Late-Onset Cardiotoxicity
`Several . recent studies have noted occult ventric(cid:173)
`ular dysfunction, heart failure, and arrhythmias oc(cid:173)
`curring in asymptomatic patients more than 1 year
`after anthracycline treatment (16-21, 34-36). These
`initial findings suggest that survivors of cancer may
`have a previously unacknowledged increase in car(cid:173)
`diac morbidity and mortality due to anthracycline
`therapy. Steinherz and associates (16), who studied
`201 patients with solid tumors or leukemia, found
`an 18% incidence of reduced fractional shortening
`on resting echocardiograms in patients followed for
`4 to 10 years after completion of anthracycline ther(cid:173)
`apy. Even more troubling are the findings of Lip-
`
`48
`
`1 July 1996 • Annals of Internal Medicine • Volume 125 • Number 1
`
`HOSPIRA EX. 1142
`Page 5
`
`

`

`shultz and coworkers (17), who noted that cumula(cid:173)
`tive doses of doxorubicin as low as 228 mg/m2 body
`surface area increased afterload or decreased con(cid:173)
`tractility or both in 65 % of patients with leukemia
`up to 15 years after treatment with anthracyclines.
`These abnormalities appear to be progressive and
`reflect future clinical decompensation.
`Lipshultz and coworkers (17) noted both early
`and late congestive heart failure in 5 of 115 patients
`within 11 years of the completion of anthracycline
`therapy. A similar incidence of late-onset heart fail(cid:173)
`ure, occurring in 9 of 201 patients, was reported by
`Steinherz and associates ( 16). However, most pa(cid:173)
`tients in the study by Steinherz and associates were
`followed for fewer than 10 years after completion of
`therapy, and new-onset symptomatic ventricular dys(cid:173)
`function was not seen until 12 to 14 years after
`treatment in the study by Lipshultz and coworkers
`(17). Additionally, the incidence of severe echocar(cid:173)
`diographic abnormalities increased with the dura(cid:173)
`tion of follow-up (Figure 3). These findings indicate
`that the full extent of the problem has yet to unfold
`in many asymptomatic patients after remote anthra(cid:173)
`cycline treatment. In addition, late-onset arrhyth(cid:173)
`mias and sudden death have been reported to have
`occurred in patients more than 15 years after an(cid:173)
`thracycline treatment (19-21). Incidences of non(cid:173)
`sustained ventricular tachycardia ranging between
`3% and 5%
`in anthracycline-treated patients at
`long-term follow-up have been reported ( 17, 19).
`The natural history of
`these arrhythmias and
`whether they occur independently of ventricular
`dysfunction (19) are issues that remain to be clari(cid:173)
`fied.
`As with the form of anthracycline cardiotoxicity
`that manifests earlier, the incidence of late-onset
`cardiac decompensation increases with larger cumu(cid:173)
`lative doses (16, 17), higher rates of anthracycline
`administration (37), and mediastinal radiotherapy
`(16). Young age (16) at the time of treatment and
`female sex (38) may be risk factors for late-onset
`anthracycline cardiotoxicity, but this is still contro(cid:173)
`versial (17, 39). However, recent evidence appears
`to support both characteristics as independent risk
`factors for late-onset ventricular dysfunction (37).
`
`Figure 2. Changes characteristic of adriamycin-induced cardiotox(cid:173)
`icity. Top. Light microscopy. Section of left ventricle from a 57-year-old
`woman with adriamycin-induced cardiomyopa thy showing marked myofibril
`loss and vacuolar degeneration (arrow). (Hematoxyli n and eosin stain. Orig(cid:173)
`inal magnification. X400). Bottom. Electron microscopy. Cardiac myocyte
`showing adriamycin-induced cardiotoxicity with extensive loss of myofila(cid:173)
`ments (large arrows). Unaffected myocytes are shown in lower left. Small
`arrow denotes normal myocyte. (Original magnification, x 2800).
`
`at the cellular level include free-radical-mediated
`myocardial injury ( 41-48), myocyte damage from
`calcium overload ( 49-53), disturbances in myocar(cid:173)
`dial adrenergic function (54-56), release of vasoac(cid:173)
`tive amines (57, 58), and cellular toxicity from metab(cid:173)
`olites of doxorubicin (59, 60). Finally, elaboration of
`
`40
`
`""'
`
`S0.65%
`(n.56)
`
`·- -- -- -- -· ··---- ·- --------1\'!!o .• ... .. ...... •
`SD·55%
`(n•58)
`
`Pathogenesis
`
`""
`so.JS%
`(n-87)
`-- p:::z:z:l===:t-
`
`10
`
`Chronic Cardiomyopathy
`Anthracyclines cause the selective inhibition of
`cardiac muscle gene expression for a-actin, tropo(cid:173)
`nin, myosin light-chain 2, and the M isoform of
`creatine kinase in vivo ( 40), which may explain the
`myofibrillar loss (Figure 2, bottom) associated with
`anthracycline-induced cardiomyopathy. Hypotheses
`
`4-6
`
`2' 10
`
`7-9
`Follow-up, y
`Figure 3. Late-onset ventricular dysfunction over time. Percent(cid:173)
`age of patients w ith abnormal fractional shortening at long-term follow-up
`over time alter completion of therapy. Adapted from Steinherz and col(cid:173)
`leag ues ( 16) with permission of The Journal of the American Medical Asso(cid:173)
`ciation . White bars = mild reduction in fractional shortening (25% to 28%);
`striped bars = moderate reduction in fractional shortening (21 % to 24%);
`black bars = severe reduction in fractional shortening (s20%).
`
`l July 1996 • Annals of Internal Medicine • Volume 125 • Number 1
`
`49
`
`HOSPIRA EX. 1142
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`
`

`

`Table 1. Abnormalities in Diastolic and Systolic Ventricular Function for the Early Detection of Anthracycline(cid:173)
`lnduced Cardiotoxicity*
`
`Study (Reference)
`
`Patients
`
`Age
`
`Anthracycline Dose
`
`Mediastinal Radiotherapy
`
`Follow-up Period after
`Anthracycline Treatment
`
`Cottin et al. (107)
`
`Ewer et al. (106)
`
`Marchandise et al. (101)
`
`Stoddard et al. (103)
`
`Schmitt et al. (108)
`
`Lee et al. (102)
`
`n
`
`60
`
`41
`
`45
`
`26
`
`14
`
`12
`
`y
`
`mg/m2
`
`Mean, 50
`Range, 23 to 72
`Range, 7 to 15.5
`
`Mean, 45
`
`Mean, 251
`Range, 75 to 550
`Mean, 119
`Range, 50 to 475
`Range, 200 to 450
`
`No
`
`No
`
`NS
`
`Mean, 48
`
`Range, ;;;:200
`
`Range, 3 to 12
`
`Mean, 53
`Range, 16 to 69
`
`Mean, 240
`Range, 200 to 300
`Mean, 193
`Range, 80 to 448
`
`None within 3 weeks of
`anthracycline
`treatment
`NS
`
`No
`
`Measurements during therapy
`
`Within 2 months
`
`3 to 9 months
`
`3 months (22 patients) and 3
`weeks (4 patients)
`
`Within 2 years
`
`7 to 43 weeks
`
`•NE = atria Vearly mitral flow velocities; NS = not stated .
`
`pro-inflammatory cytokines, which have been con(cid:173)
`sistently identified in other forms of ventricular dys(cid:173)
`function (61-64), may be directly relevant to an(cid:173)
`thracycline-induced cardiac injury.
`Although the cause of anthracycline-induced car(cid:173)
`diotoxicity is probably multifactorial, a large body of
`evidence points to free-radical-mediated myocyte
`damage (41-44). Increased oxygen radical activity
`generated through the semiquinone moiety of the
`doxorubicin molecule can cause lipid peroxidation
`and cell injury ( 41, 42). Anthracycline-induced
`intracellular calcium overload may also lead to
`myocyte death ( 49-53). Doxorubicin activates the
`calcium-release channel across the sarcoplasmic
`reticulum (52) and causes calcium influx into the
`myocyte (50, 51, 53). Free-radical-induced cell
`membrane damage has also been seen with cal(cid:173)
`cium influx (65, 66), suggesting that these two
`putative anthracycline-induced cardiotoxic path(cid:173)
`ways may be linked. Adrenergic dysfunction, in(cid:173)
`cluding downregulation of myocardial {3-adrener(cid:173)
`gic receptors (67, 68), may be present in evolving
`(69, 70) as well as established anthracycline-induced
`ventricular dysfunction (71, 72).
`Recent reports (61-64) that circulating pro-inflam(cid:173)
`matory cytokines may be intimately linked to the
`evolution of ventricular dysfunction and dilated car(cid:173)
`diomyopathies may provide further insight into the
`process by which anthracyclines produce cardiac in(cid:173)
`jury. Doxorubicin induces the release of tumor ne(cid:173)
`crosis factor-a from macrophages and of interleu(cid:173)
`kin-2 from monocytes (73-75). Interleukin-2 and
`tumor necrosis factor-a, which has functional
`myocardial receptors (76), have documented car(cid:173)
`diotoxicity that . can result . in dilated cardiomyopathy
`(77, 78). Varying degrees of cytokine liberation from
`different tumors (79-81) during anthracycline treat(cid:173)
`ment may provide another explanation for the dis-
`
`crepancy in the incidence of cardiotoxicity in differ(cid:173)
`ent populations with cancer (82, 83).
`
`Late-Onset Cardiotoxicity
`Progressive ventricular dysfunction after an initial
`myocardial insult probably underlies late-onset de(cid:173)
`compensation. Reductions in left ventricular mass,
`mass index, and compliance have been reported in
`anthracycline-treated survivors of childhood cancer
`followed for more than 7 years after completion of
`chemotherapy (34, 84). These patients appear to
`have a thin-walled left ventricle working against
`high systolic wall stress (34). Such a pattern of
`cardiac injury is concordant with the theory that
`occult late-onset anthracycline cardiac dysfunction
`manifests clinically in patients who remain in a com(cid:173)
`pensated state for many years. Acute viral infection
`(85) and cardiovascular stressors, such as weight
`lifting (20), pregnancy, and surgery, are possible
`triggers of late-onset anthracycline-induced cardiac
`dysfunction.
`
`Monitoring
`
`The lifelong cardiotoxic effects of conventional
`anthracycline therapy highlight the need for moni(cid:173)
`toring methods that are highly sensitive and capable
`of predicting cardiac dysfunction. In addition, the
`specificity of any test should allow for an accurate
`risk- benefit analysis in balancing the likelihood of
`cardiac dysfunction with greater drug doses against
`the harm that may result from withholding antitu(cid:173)
`mor therapy.
`
`Detection of Chronic Anthracycline-lnduced
`Cardiomyopathy
`Billingham and colleagues (86) have developed a
`semiquantitative histologic scoring system for endo-
`
`50
`
`1 July 1996 • Annals of Internal Medicine • Volume 125 • Number 1
`
`HOSPIRA EX. 1142
`Page 7
`
`

`

`Table 1. Continued
`
`Method of Evaluation
`
`Major Abnormality in Diastolic
`Function
`
`Major Abnormality in Systolic
`Function
`
`Relation of Systolic to Diastolic
`Abnormalities
`
`Radionuclide angiocardiography
`
`Decreased peak filling rate
`
`Resting echocardiography
`
`Decreased peak A wave
`
`Resting echocardiography
`
`Resting echocardiography
`
`Increased isovolumic relaxation period;
`reduced early peak flow velocity and
`deceleration rate
`Increased isovolumic relaxation period
`
`Resting echocardiography
`
`Increased A/E velocity
`
`Radionuclide angiography
`
`Decreased rapid ventricular fill ing rate
`
`Decreased left ventricular ejection
`fraction
`Decreased fractional shortening
`
`No significant decrease in fractional
`shortening
`
`Simultaneous diastolic and systolic
`dysfunction
`Systolic dysfunction precedes
`diastolic dysfunction
`Diastolic dysfunction precedes
`systolic dysfunction
`
`Decreased left ventricular ejection
`fraction
`
`Diastolic dysfunction precedes and
`predicts systolic dysfunction
`
`Inconsistent decrease in fractional
`shortening
`No significant decrease in left ventricular
`ejection fraction
`
`Diastolic dysfunction; no significant
`systolic dysfunction
`Diastolic dysfunction; no significant
`systolic dysfunction
`
`myocardial biopsy specimens that correlates well
`with cumulative anthracycline dose. Biopsy grade is
`predictive of the rate of early progression around
`the time of therapy and is currently considered the
`most sensitive indicator of chronic anthracycline(cid:173)
`induced cardiotoxicity (87). Underestimation of car(cid:173)
`diac damage with right ventricular biopsy may occur
`because of scattered cardiomyopathic changes (88)
`or the predominance of left ventricular injury (89).
`Also, expertise in obtaining and interpreting biopsy
`specimens is not widely available, and concerns re(cid:173)
`main about the safety of repeated testing, particu(cid:173)
`larly in children (90). Thus, the use of endomyocar(cid:173)
`dial biopsy for the routine monitoring of early
`anthracycline-induced cardiotoxicity has been limited.
`is extensively
`Radionuclide angiocardiography
`used in monitoring for early anthracycline-induced
`cardiotoxicity on the basis of its proven value in
`reducing the incidence of cardiac failure from early
`anthracycline cardiotoxicity (91-93). Having used
`data on serial left ventricular ejection fraction in