In a substudy of the Valsartan in Acute MyocardialInfarction Trial VALIANT reported in this issue ofthe Journal, Solomon and colleagues3 extend andreinforce our understanding of factors
Trang 1T h e ne w e ngl a nd jou r na l o f m e dicine
report on a study assessing the efficacy of 10 mg
of rosuvastatin daily in patients with heart fail
ure and left ventricular systolic dysfunction attri
buted to coronary artery disease The study, called the Controlled Rosuvastatin Multinational Trial
in Heart Failure (CORONA), was a randomized, placebocontrolled trial involving patients who were at least 60 years of age (mean, 73 years) who were receiving high rates of evidencebased therapy for left ventricular systolic dysfunction, including angiotensinconverting–enzyme inhibi
tors or angiotensinreceptor blockers and beta
blockers As compared with placebo, treatment with rosuvastatin resulted in no significant dif
ference in the primary composite outcome of death from cardiovascular causes, nonfatal myo
cardial infarction, or nonfatal stroke, even though the drug was associated with substantial reduc
tions in levels of lowdensity lipoprotein (LDL) cholesterol and highsensitivity Creactive protein
Patients in the rosuvastatin group had signifi
cantly fewer hospitalizations for cardiovascular causes, including heart failure; rates of adverse drug events did not differ between the two study groups Rosuvastatin therapy had no effect on the health status of patients, as assessed on the basis
of New York Heart Association class and the McMaster Overall Treatment Evaluation question
naire, which were designated as tertiary outcomes
Results aside, one might ask whether a study
of a statin for secondary prevention in this pop
ulation was warranted Although the numbers of patients with systolic heart failure who have been enrolled in previous secondaryprevention trials have been inadequate to generate robust evidence, observational studies have suggested benefits of statin therapy on morbidity and mortality in this population.5 Statins also have a favorable effect on surrogate end points (e.g., endothelial function), which in theory would be beneficial for patients with heart failure
Given these facts, it might be tempting to as
sume that patients with ischemic left ventricular systolic dysfunction would accrue benefits from statins similar to those identified in previous tri
als However, there are several reasons to resist this temptation First, the limitations of assumptions based on observational data6 and surrogates7 are well documented Furthermore, the need to under
stand specifically the balance of risks and bene
fits of drug therapy in patients with heart failure
is magnified by particular characteristics of this
population Although patients with ischemic left ventricular systolic dysfunction have high rates of adverse outcomes, their risk of ischemic cardiovascular events — outcomes that statins seem most likely to prevent — may occur less frequently than
in other patients with coronary disease Moreover, heart failure disproportionately affects older persons, who often have a substantial risk of coexisting illnesses, a factor that raises questions about the applicability of evidence from clinical trials involving younger patients with a single, dominant clinical problem.8 Finally, typical regimens for this population involve multiple drugs, both because of the burden of coexisting illness
es and the number of drugs used to treat heart failure.9 The addition of a new drug to an already complex regimen increases not only the cost but also the risk of adverse drug interactions When coupled with a theoretical concern about possible adverse drug effects from statins specific to patients with heart failure,10 such factors amplify the need to understand the safety and efficacy of this therapy
How, then, can the clinical findings of the CORONA study be reconciled with the existing randomized trials of statins in patients with established coronary artery disease? First, statins as
a class may not be efficacious in patients with ischemic left ventricular systolic dysfunction who are already receiving evidencebased therapy for heart failure An attenuated effect of statins could reflect the distribution of the causes of outcomes
in this population For example, among patients
in the CORONA study, rates of nonfatal myocardi
al infarction were about one quarter of the rates reported in patients in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) study,11 a statin trial that enrolled patients whose mean age was about 75 years and who had a mean followup of about 38 months (as compared with 32.8 months in the CORONA study) It is also important to point out that the confidence intervals around the primary end point in the CORONA study are consistent with as much as a 17% relative reduction in risk or an absolute risk reduction
of approximately 2% An absolute benefit of this magnitude would be clinically significant and is similar to that identified in PROSPER Second, it
is possible that even though rosuvastatin lowered levels of LDL cholesterol and highsensitivity Creactive protein, the drug does not share the same benefits regarding important health out
Trang 2comes with other statins Although several stat
ins have proven clinical efficacy, supporting the
assumption of a class effect, experience with
cerivastatin has shown that such assumptions
can lead us astray It is reassuring that in the
CORONA study, patients in the rosuvastatin
group had fewer hospitalizations for cardiovascu
lar causes and no greater risk of adverse events
than did those in the placebo group Finally, stat
ins may have less incremental benefit in a popu
lation of older patients who are at higher risk
for competing events, which could reduce the
likelihood of ascertaining a benefit for specific
cardiovascular outcomes Although only a minor
ity of deaths in the CORONA study were desig
nated as having noncardiovascular causes, deaths
that did not have a clear cause were presumed
to be cardiovascular in nature, potentially lim
iting the quantification of the magnitude of com
peting risks
Future trials may shed light on some of these
unresolved questions The Justification for the
Use of Statins in Primary Prevention: An Inter
vention Trial Evaluating Rosuvastatin (JUPITER)
(ClinicalTrials.gov number, NCT00239681) trial12
should provide additional perspective on the
general effect of rosuvastatin on important
health outcomes in patients without estab
lished cardiovascular disease The results of
the Gruppo Italiano per lo Studio della Soprav
vivenza nell’Insufficienza Cardiaca Heart Fail
ure Study (GISSIHF) (ClinicalTrials.gov number,
NCT00336336),13 a randomized trial in which
patients with heart failure are receiving either
rosuvastatin or placebo, will complement the
findings of the CORONA study The GISSIHF
study is also enrolling patients with nonischemic
cardiomyopathies and those with preserved left
ventricular systolic function, both important sub
groups of the population with heart failure who
were not evaluated in the CORONA study
The results of the CORONA study highlight
issues that are central to the conduct of trials
involving patients with heart failure When im
portant questions are raised about the benefits
and risks of a therapy that is well established in
other populations, it may still be essential to es
tablish treatment effects in the population with
heart failure Admittedly, enrolling subjects in
trials that challenge wellestablished treatment
paradigms may be difficult despite equipoise on
an intellectual level Second, trials simply must
focus more attention on including patients who are representative of those seen in clinical prac
tice In enrolling older patients, the CORONA study made important strides, although the pro
portion of women who were enrolled (less than 25%) was no higher than that in previous heart failure trials Finally, because health status (in
cluding symptom burden and quality of life) pro
vides a patientcentered understanding of the ef
fect of any treatment, it should be included as an outcome in all studies of heart failure Ideally, health status outcomes would not be consigned
to tertiary status and would be assessed with valid, reliable, and clinically sensitive instruments designed specifically for use in populations with heart failure.14 Trials enrolling more representa
tive populations and assessing a broader range
of outcomes are instrumental to informed deci
sion making.15Meanwhile, enough uncertainty exists about the mechanisms underlying the primary results of the CORONA study that clinicians should con
tinue to prescribe statins for patients with is
chemic heart failure and left ventricular systolic dysfunction Until further evidence accumulates,
we cannot tell to what extent the CORONA study reflects the limitations of the use of statins for patients with heart failure, the problems associ
ated with a particular drug, or the intrinsic chal
lenges of treating older patients with complex coexisting illnesses
Dr Masoudi reports receiving consulting fees from Amgen, UnitedHealthcare, and Takeda and grant support from Amgen
No other potential conflict of interest relevant to this article was reported.
From the Department of Medicine, Division of Cardiology, ver Health Medical Center, Denver, and the Department of Med- icine, Division of Cardiology, University of Colorado at Denver and Health Sciences Center, Aurora, CO.
Den-This article (10.1056/NEJMe0707221) was published at www.
nejm.org on November 5, 2007.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Sur
vival Study (4S) Lancet 1994;344:13839.
Smith SC Jr, Allen J, Blair SN, et al AHA/ACC guidelines for secondary prevention for patients with coronary and other ath
erosclerotic vascular disease: 2006 update: endorsed by the Na
tional Heart, Lung, and Blood Institute Circulation 2006;113:
236372 [Erratum, Circulation 2006;113:e847.]
Krumholz HM, Anderson JL, Brooks NH, et al ACC/AHA clinical performance measures for adults with STelevation and nonSTelevation myocardial infarction: a report of the Ameri
can College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures on STElevation and NonSTElevation Myocardial Infarction) Circulation 2006;113:73261.
1.
2.
3.
Trang 3Rossouw JE, Anderson GL, Prentice RL, et al Risks and ben
efits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial JAMA 2002;288:32133.
Nissen SE, Tardif JC, Nicholls SJ, et al Effect of torcetrapib
on the progression of coronary atherosclerosis N Engl J Med 2007;356:130416 [Erratum, N Engl J Med 2007;357:835.]
Masoudi FA, Havranek EP, Wolfe P, et al Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure Am Heart J 2003;146:2507.
Masoudi FA, Baillie CA, Wang Y, et al The complexity and cost of drug regimens of older patients hospitalized with heart failure in the United States, 19982001 Arch Intern Med 2005;
Ridker PM Rosuvastatin in the primary prevention of cardio vascular disease among patients with low levels of lowdensity lipoprotein cholesterol and elevated highsensitivity Creactive protein: rationale and design of the JUPITER trial Circulation 2003;108:22927.
Tavazzi L, Tognoni G, Franzosi MG, et al Rationale and de sign of the GISSI heart failure trial: a large trial to assess the ef fects of n3 polyunsaturated fatty acids and rosuvastatin in symp tomatic congestive heart failure Eur J Heart Fail 2004;6:63541 Green CP, Porter CB, Bresnahan DR, Spertus JA Develop ment and evaluation of the Kansas City Cardiomyopathy Ques tionnaire: a new health status measure for heart failure J Am Coll Cardiol 2000;35:124555.
Tunis SR, Stryer DB, Clancy CM Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy JAMA 2003;290:162432.
Copyright © 2007 Massachusetts Medical Society.
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Trang 4The n e w e n g l a n d j o u r n a l of m e d i c i n e
e d i t o r i a l s
Sudden Death after Myocardial Infarction — Who Needs
Prophylaxis, and When?
Sudden death is the end result of multiple
process-es, usually manifested electrocardiographically asventricular fibrillation or ventricular tachycardia
The type of arrhythmia observed depends on thetemporal relation to myocardial infarction In theacute phase of myocardial infarction, the metabolicconsequences of severe ischemia may trigger ven-tricular fibrillation, even though ventricular func-tion was often normal before the event Such casesmay account for half of sudden deaths.2
Scar mation after myocardial infarction may lead to thedevelopment of the substrate for intramyocardialreentry, resulting in ventricular tachycardia, which,
for-in turn, may precipitate cardiac arrest for-in the absence
of active ischemia This type of ventricular cardia (usually monomorphic) may develop days oryears after the index infarction Finally, some pa-tients have gradual, extensive ventricular remodel-ing after myocardial infarction, and the remodelingleads to the syndrome of heart failure The devel-opment of heart failure, with its attendant neuro-hormonal abnormalities, sets the stage for othermechanisms that may cause ventricular tachycardia(usually the polymorphic type) Thus, the mecha-nisms responsible for sudden death vary according
tachy-to their temporal relation tachy-to myocardial infarctionand multiple other factors, including the presence
or severity of left ventricular dysfunction
In the prethrombolytic era, multiple variableswere shown to influence the risk of both suddenand nonsudden death after myocardial infarction
In a substudy of the Valsartan in Acute MyocardialInfarction Trial (VALIANT) reported in this issue ofthe Journal, Solomon and colleagues3
extend andreinforce our understanding of factors influencingthe risk of death after acute myocardial infarction.VALIANT compared the effect of valsartan, capto-pril, or both on the risk of death in more than14,000 patients with acute myocardial infarctioncomplicated by left ventricular dysfunction (de-fined as a left ventricular ejection fraction of 40 per-cent or less), heart failure, or both between 1998
Several characteristics of the patientsenrolled in the trial are noteworthy The mean leftventricular ejection fraction was 35 percent, 28 per-cent had had a prior myocardial infarction, and ap-proximately three fourths were in Killip class II, III,
or IV at the time of enrollment.4 During a medianfollow-up of 24.7 months, 7.3 percent of the pa-tients died suddenly or were resuscitated after car-diac arrest.3 Solomon et al emphasize two majorpoints: the temporal occurrence of sudden deathafter myocardial infarction and the importance andlimitations of the left ventricular ejection fraction
as a risk factor for sudden death
Clustering of sudden deaths in the early periodafter myocardial infarction was noted in the pre-thrombolytic era.5
The time course of sudden death
in the modern era has been explored less
extensive-ly, but some work in unselected populations of vivors of acute myocardial infarction suggests a de-lay in sudden death to 18 months after the acuteevent.6
This issue is clarified in the current study.Solomon et al clearly demonstrate the period of
Trang 5e d i t o r i a l s
highest risk to be the first month after myocardial
infarction (event rate, 1.4 percent), with a dramatic
drop to a fairly constant rate of 0.14 to 0.18 percent
per month thereafter
The association between a reduced left
ventricu-lar ejection fraction and an increased risk of death
after myocardial infarction has been recognized
for years In both the prethrombolytic era and the
post-thrombolytic era, the risk of death increases
markedly if the left ventricular ejection fraction is
40 percent or less.7
At first glance, it may seem prising that Solomon et al found the risk of sud-
sur-den death to be similar among patients with a left
ventricular ejection fraction of more than 40
per-cent and those with an ejection fraction of 30 to 40
percent This finding is most likely explained by
the fact that in order to enter VALIANT, any patient
with a left ventricular ejection fraction of more than
40 percent would have had to have heart failure,
re-affirming the importance of heart failure as a risk
factor for sudden death
Although Solomon et al note a number of
sig-nificant differences between survivors and patients
who died, there were no clinically useful factors
distinguishing those who died suddenly from
those who had a nonsudden death In other words,
a reduced left ventricular ejection fraction and
evi-dence of advanced heart failure carried an equally
increased risk of sudden and of nonsudden death
and did not have a cause-and-effect relation to
ar-rhythmic events The importance of this limitation
has implications for preventive therapy If we are to
use efficacious treatments, such as implantable
car-dioverter–defibrillators (ICDs), in a cost-effective
manner, we need risk-stratification tests that
iden-tify patients whose risk of sudden death
significant-ly exceeds their risk of nonsudden death To date,
there is only one such test — the
electrophysiolog-ical test.8
What is the importance of the current study? It
reinforces findings in earlier studies that the risk of
sudden death is greatest in the early period after
in-farction among patients with clinically significant
ventricular dysfunction or heart failure This point
raises several questions Should patients with
high-risk characteristics undergo prolonged
hospitaliza-tion after myocardial infarchospitaliza-tion? An alternative
so-lution, given the observation of Solomon et al that
risk drops dramatically within six months after
acute myocardial infarction, might be to provide
noninvasive vest defibrillators or automatic
exter-nal defibrillators to high-risk patients for limited
periods The latter approach is the subject of an going trial sponsored by the National Heart, Lung,and Blood Institute in selected patients with a re-cent anterior myocardial infarction These nonin-vasive approaches to prophylactic defibrillation areattractive in light of the results of the Defibrillator
on-in Acute Myocardial Infarction Trial (DINAMIT),which demonstrated the failure of ICDs to reducethe risk of death among high-risk patients with clin-ically significant left ventricular dysfunction after arecent myocardial infarction.9
How do the results of this large, multicenter trial
by Solomon et al relate to studies demonstratingthe ability of ICDs to prevent sudden death in pa-tients with chronic coronary heart disease?10-12
These trials — the Multicenter Automatic lator Implantation Trial (MADIT), the Multicen-ter Unsustained Tachycardia Trial (MUSTT), andMADIT-II — were predicated on earlier observa-tions, similar to those of Solomon et al., that pa-tients with spontaneous ventricular arrhythmiasand clinically significant ventricular dysfunctionafter a recent myocardial infarction have a substan-tial risk of death However, a minority of patients
Defibril-in these trials had a myocardial Defibril-infarction withDefibril-in
2 years before enrollment: the average times frommyocardial infarction to enrollment were 39 months
in MUSTT and 81 months in MADIT-II The totalmortality rate in VALIANT after the first year wasapproximately 5 percent per year The rate of sud-den death or resuscitation after cardiac arrest wasapproximately 2.5 percent per year among patientswith a left ventricular ejection fraction of 30 per-cent or less After the first year, the total mortalityrates and the rate of sudden death were fairly con-stant and low These figures contrast with the totalmortality rates of 11 percent per year in the controlpatients with a left ventricular ejection fraction ofless than 30 percent in both MUSTT and MADIT-II
Thus, event rates in the ICD trials were doublethose in VALIANT
What is the explanation for this difference? Inpart, it may be due to the fact that two thirds of thepatients enrolled in MADIT and MUSTT had symp-tomatic heart failure, as reflected by a New YorkHeart Association class of at least II, in addition to
a reduced left ventricular ejection fraction I suspectthat another reason for the higher rates of events inthe ICD trials is enrollment bias, resulting in the re-cruitment of patients at very high risk Why is thisimportant? Because it suggests that the results ofthe ICD trials may not be generalizable to all pa-
Trang 6The n e w e n g l a n d j o u r n a l of m e d i c i n e
tients meeting the entry criteria for those studies
The mortality risks observed in the ICD trials mayhave been exaggerated because of the manner inwhich patients were recruited Thus, when perform-ing such studies, we must strive to enroll broad-based, representative populations, unencumbered
by referral bias
In summary, the analysis by Solomon et al is auseful reality check on the problem of sudden deathamong survivors of acute myocardial infarction
This study documents the natural history of den death and some of the risk factors for it withcontemporary treatment of myocardial infarction
sud-The challenge going forward is to translate theseobservations into cost-effective preventive therapy
From the Cardiology Division, Department of Medicine, Brown Medical School, Lifespan Academic Medical Center, Providence, R.I.
1. Zheng Z-J, Croft JB, Giles WH, Mensah GA Sudden cardiac death in the United States, 1989 to 1998 Circulation 2001;104:
2158-63.
2. Gorgels APM, Gijsbers C, de Vreede-Swagemakers J, Lousberg
A, Wellens HJJ Out-of-hospital cardiac arrest — the relevance of heart failure: the Maastricht Circulatory Arrest Registry Eur Heart J 2003;24:1204-9.
3. Solomon SD, Zelenkofske S, McMurray JJV, et al Sudden death
in patients with myocardial infarction and left ventricular tion, heart failure, or both N Engl J Med 2005;352:2581-8.
dysfunc-4. Pfeffer MA, McMurray JJV, Velazquez EJ, et al Valsartan, pril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both N Engl J Med 2003;349:1893-
capto-906 [Erratum, N Engl J Med 2004;350:203.]
5. Daly LE, Hickey N, Graham IM, Mulcahy R Predictors of den death up to 18 years after a first attack of unstable angina or myocardial infarction Br Heart J 1987;58:567-71.
sud-6. Huikuri HV, Tapanainen JM, Lindgren K, et al Prediction of sudden cardiac death after myocardial infarction in the beta-block- ing era J Am Coll Cardiol 2003;42:652-8.
7. Rouleau JL, Talajic M, Sussex B, et al Myocardial infarction patients in the 1990s — their risk factors, stratification and survival
in Canada: the Canadian Assessment of Myocardial Infarction (CAMI) Study J Am Coll Cardiol 1996;27:1119-27.
8. Buxton A, Hafley G, Lee K, et al Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the Multi- center Unsustained Tachycardia Trial Circulation 2002;106:2466- 72.
9. Hohnloser SH, Kuck KH, Dorian P, et al Prophylactic use of an implantable cardioverter–defibrillator after acute myocardial infarc- tion N Engl J Med 2004;351:2481-8.
10.Moss AJ, Hall WJ, Cannom DS, et al Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia N Engl J Med 1996;335:1933-40.
11.Buxton AE, Lee KL, Fisher JD, et al A randomized study of the prevention of sudden death in patients with coronary artery disease.
N Engl J Med 1999;341:1882-90 [Erratum, N Engl J Med 2000;342: 1300.]
12.Moss AJ, Zareba W, Hall WJ, et al Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejec- tion fraction N Engl J Med 2002;346:877-83.
Copyright © 2005 Massachusetts Medical Society.
Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer —
The Smoke Clears
Non–small-cell lung cancer, the mostcommon form, accounts for 80 to 85 percent ofcases Given the size of the problem, the benefit
of adjuvant chemotherapy for non–small-cell lungcancer, reported by Winton et al in this issue ofthe Journal, has tremendous implications.2
Complete surgical resection is the best hope forcure in patients with operable non–small-cell lungcancer, yet the five-year overall survival rate is only
23 to 67 percent, depending on the size of the mary tumor and the presence or absence of inva-
After surgery,relapse at distant sites occurs two to three times asfrequently as local recurrence and is most often fa-tal Postoperative radiotherapy decreases the rate oflocal recurrence in stage IIIA disease but has a det-
rimental effect on survival in patients with stage I
or stage II disease.4
Adjuvant systemic
chemothera-py directed at micrometastatic disease has an tablished role in the treatment of breast and coloncancer; however, its use in non–small-cell lung can-cer has, until now, been controversial
es-Decades ago, initial forays into adjuvant therapyfor non–small-cell lung cancer failed — the trialswere poorly designed and used relatively inactivechemotherapy The next generation of studies in-corporated cisplatin (an agent still considered a cor-nerstone of treatment), but the studies were toosmall to detect a benefit
A 1995 meta-analysis of results from ized trials of adjuvant therapy conducted between
random-1965 and 1991 showed that treatment with ing agents alone or in combination with radiationreduced overall survival (an absolute decrease inthe rate of survival of 5 to 7 percent at five years,and an increase in the risk of death of 15 to 35 per-
Trang 7alkylat-The ne w engl and
a b s t r a c t
From the Cardiovascular Division, Brigham and Women’s Hospital, Boston (S.D.S., P.V.F., M.A.P.); Novartis Pharmaceuticals, East Hanover, N.J (S.Z.); the Department
of Cardiology, Western Infirmary, Glasgow, Scotland (J.J.V.M.); Duke University Medi- cal Center, Durham, N.C (E.V., K.P., R.M.C.); University of Wurzburg, Wurzburg, Germa-
ny (G.E.); the National Center for Health Services, Budapest, Hungary (A.H.); the University of Montreal, Montreal Heart In- stitute, Montreal (J.L.R.); Associazione Na- zionale Medici Cardiologi Ospedalieri Re- search Center, Florence, Italy (A.M.); the Department of Cardiology, Rigshospitalet, Copenhagen (L.K.); the Department of Car- diology, Green Lane Hospital, Auckland, New Zealand (H.W.); and Leuven Coordi- nating Center, Leuven, Belgium (F.V.W.) Address reprint requests to Dr Solomon
at the Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St., Bos- ton, MA 02115, or at ssolomon@rics.bwh harvard.edu.
myocar-a 21 percent myocar-adjusted incremyocar-ase in the risk of sudden demyocar-ath or cmyocar-ardimyocar-ac myocar-arrest with tation in the first 30 days
resusci-c o n resusci-c l u s i o n s
The risk of sudden death is highest in the first 30 days after myocardial infarctionamong patients with left ventricular dysfunction, heart failure, or both Thus, earlier im-plementation of strategies for preventing sudden death may be warranted in selectedpatients
Trang 8The n e w e n g l a n d j o u r n a l of m e d i c i n e
udden death is a catastrophic plication of acute myocardial infarction.1
though many patients who die from an acutemyocardial infarction do so before reaching thehospital, those admitted remain at substantial riskfor ventricular arrhythmias That risk is greatest inthe first few hours, declines rapidly thereafter, and
Al-is influenced by the extent of myocardial injury, current ischemia, electrolyte abnormalities, andother factors.2,3
The success of coronary care units
in the 1960s was, in part, related to the early fication and treatment of life-threatening arrhyth-mias that occurred in the setting of an acute myo-cardial infarction Though the risk of sudden death
identi-is believed to decrease rapidly after infarction, theextent and time course of this change in risk havenot been well studied, especially since the use ofcoronary reperfusion, beta-blockers, and angio-tensin-converting–enzyme inhibitors has becomewidespread
Reduced left ventricular function is a major riskfactor for death, including sudden death, after myo-cardial infarction.4,5
This observation has led totrials of implantable cardioverter–defibrillators(ICDs) in patients with a low left ventricular ejec-tion fraction after infarction.6
The Multicenter sustained Tachycardia Trial (MUSTT) demonstrat-
Un-ed the benefit of an ICD in patients with coronaryartery disease, a left ventricular ejection fraction of
40 percent or less, and inducible sustained ular tachycardia.7
The Multicenter Automatic brillator Implantation Trial II (MADIT-II)8
furthershowed a benefit of empirical ICD therapy in pa-tients with a left ventricular ejection fraction of 30percent or less one month or more after myocardialinfarction Although these studies enrolled few pa-tients within six months after they had had a myo-cardial infarction, the results are reflected in thecurrent American College of Cardiology–AmericanHeart Association guidelines for the management
of acute myocardial infarction,9
which recommendthe implantation of an ICD one month or more aftermyocardial infarction in patients with a left ventric-ular ejection fraction of 30 percent or less and inthose with a left ventricular ejection fraction of 40percent or less and additional evidence of electri-cal instability In contrast, the recently reportedDefibrillator in Acute Myocardial Infarction Trial
did not show that the implantation
of an ICD 6 to 40 days after myocardial infarctionreduced the risk of death in patients with a left ven-tricular ejection fraction of 35 percent or less andreduced heart-rate variability Nevertheless, the risk
of sudden death in the early period after myocardialinfarction remains high and has not been wellstudied in the modern era.11
To better delineate theearly and later risk of sudden death after myocar-dial infarction and the association of these risks withthe left ventricular ejection fraction, we studied pa-tients enrolled in the Valsartan in Acute MyocardialInfarction Trial (VALIANT)
VALIANT was a randomized, controlled trial oftreatment with valsartan, captopril, or both in14,703 patients with a first or subsequent acutemyocardial infarction complicated by heart failure,left ventricular systolic dysfunction, or both.12
tients were enrolled between December 1998 andJune 2001 All patients had an ejection fraction of
Pa-no more than 40 percent or clinical or radiologicevidence of heart failure complicating their myo-cardial infarction For this analysis, we excluded 94patients because they had already received an ICDbefore randomization All patients gave written in-formed consent, and the research protocol was ap-proved by the appropriate review boards The de-tails of the patient population and the protocol,including inclusion and exclusion criteria, havebeen reported previously.12
A central adjudication committee reviewed alldeaths and episodes of cardiac arrest with resusci-tation in a blinded fashion, using source documen-tation provided by the site investigators Deathswere classified as having cardiovascular or noncar-diovascular causes, and deaths from cardiovascularcauses were further classified as sudden or due tomyocardial infarction, heart failure, stroke, or an-other cardiovascular cause Sudden death was ex-plicitly defined as death that occurred “suddenly andunexpectedly” in a patient in otherwise stable con-dition and included witnessed deaths (with or with-out documentation of arrhythmia) and unwitnesseddeaths if the patient had been seen within 24 hoursbefore death but had not had premonitory heartfailure, myocardial infarction, or another clear cause
of death Cardiac arrest with resuscitation was fined as cardiac arrest from which a patient re-gained consciousness and subsequent cognitivefunction, even briefly
de-The median duration of follow-up was 24.7months Sudden deaths and episodes of cardiacarrest with resuscitation were combined for thisanalysis The left ventricular ejection fraction wasdetermined before randomization (a median of five
s
m e t h o d s
Trang 9s u d d e n d e a t h a f t e r m y o c a r d i a l i n f a r c t i o n
days after myocardial infarction) at the clinical site
in 11,256 patients: echocardiography was used in
9095, radionuclide ventriculography in 272, and
contrast ventriculography in 1889 The analysis of
the incidence and timing of sudden death included
all patients and was related to the left ventricular
ejection fraction in the subgroup of patients for
whom information on the ejection fraction was
available: 3852 with an ejection fraction of 30
per-cent or less, 4998 with an ejection fraction of 31 to
40 percent, and 2406 with an ejection fraction of
more than 40 percent
The rates of sudden death were assessed by
di-viding the events in each period by the number of
person-days of exposure and are expressed as the
percentage per month Baseline clinical
character-istics were compared with the use of Student’s t-test
for continuous variables and the chi-square test for
categorical variables The risk of sudden death
as-sociated with each decrease of 5 percentage points
in the left ventricular ejection fraction was assessed
in a Cox proportional-hazards model, with
adjust-ment for all known baseline covariates
Of 14,609 patients, 1067 (7 percent) had an event:
903 patients died suddenly, and 164 were
resusci-tated after cardiac arrest For 643 of the 1067
pa-tients (60 percent), this was the first cardiovascular
event after enrollment Five patients who were
re-suscitated after cardiac arrest died on the day of
resuscitation The median time to sudden death
or cardiac arrest with resuscitation was 180 days
after myocardial infarction (interquartile range,
50 to 428) Of the 164 patients who were
resusci-tated, 108 (66 percent) were alive at six months and
93 (57 percent) were alive at the end of the trial As
compared with surviving patients without events,
patients who died suddenly or had cardiac arrest
with resuscitation were significantly older; had
higher baseline systolic and diastolic blood
pres-sures, baseline heart rate, and Killip class; had a
lower left ventricular ejection fraction; were more
likely to have a history of diabetes or hypertension;
and were less likely to have been treated with
reper-fusion therapy, amiodarone, or beta-blockers
(Ta-ble 1) The differences between patients who died
suddenly or were resuscitated after cardiac arrest
and those who died of other causes were much less
clinically apparent
During the first 30 days after myocardial
infarc-tion, 126 patients died suddenly and 72 patients
were resuscitated after cardiac arrest (representing
19 percent of all patients with such events duringthe trial), for an event rate of 1.4 percent per month(95 percent confidence interval, 1.2 to 1.6 percent)
Eighty-three percent of sudden-death events fromwhich the patients were not resuscitated occurredafter hospital discharge Of the patients who wereresuscitated during the first 30 days after myocar-dial infarction, 74 percent were alive at 1 year Eventrates and the cumulative incidence of events duringvarious periods in the study are shown in Table 2
The rate of sudden death or cardiac arrest with suscitation decreased precipitously during the firstyear, declining to 0.14 percent per month (95 per-cent confidence interval, 0.11 to 0.18 percent) afteryear 2
re-Figure 1 shows the Kaplan–Meier estimates ofthe rate of sudden death or cardiac arrest with re-suscitation according to the left ventricular ejectionfraction in patients in whom the ejection fractionwas measured The increased early incidence ofthese events was most apparent among patientswith an ejection fraction of 30 percent or less: theincidence rate during the first 30 days was 2.3 per-cent per month (95 percent confidence interval, 1.8
to 2.8 percent) (Fig 1 and 2) Of the 156 suddendeaths or episodes of cardiac arrest with resuscita-tion that occurred during the first 30 days, 85 oc-curred among the 3852 patients with an ejectionfraction of 30 percent or less (54 percent; 1 percent
of all patients with a known left ventricular ejectionfraction) Of the 3852 patients with an ejection frac-tion of 30 percent or less, 399 (10 percent) died sud-denly or had cardiac arrest with resuscitation dur-ing the trial, as compared with 295 of the 4998patients with an ejection fraction of 31 to 40 per-cent (6 percent) and 119 of the 2406 patients with
an ejection fraction of more than 40 percent (5 cent) Among the patients with a known left ven-tricular ejection fraction, 49 percent of all suddendeaths or cardiac arrests with resuscitation occurred
per-in patients with an ejection fraction of 30 percent orless, and this proportion remained relatively con-stant throughout follow-up
Among the 399 patients with an ejection fraction
of 30 percent or less who died suddenly or had diac arrest with resuscitation, 85 (21 percent) did
car-so during the first 30 days after myocardial tion, as compared with 50 of 295 such patients with
infarc-an ejection fraction of 31 to 40 percent (17 percent)and 21 of 119 such patients with an ejection frac-tion of more than 40 percent (18 percent) Never-theless, even among patients with an ejection frac-
r e s u l t s
Trang 10The n e w e n g l a n d j o u r n a l of m e d i c i n e
tion of more than 40 percent, the rate of suddendeath or cardiac arrest with resuscitation was morethan six times as high in the first month as afterone year Although the incidence of sudden death orcardiac arrest with resuscitation declined markedlyover time in all groups, the relative risk of theseevents remained two to three times as high asamong patients with a left ventricular ejection frac-tion of 30 percent or less as among patients with anejection fraction of more than 40 percent, althoughoverall, the absolute rate after two years was sub-stantially lower than during the early period Whenthe left ventricular ejection fraction was considered
as a continuous variable, each decrease of 5 age points in the ejection fraction was associatedwith a 21 percent increase in the risk of sudden
percent-death or cardiac arrest with resuscitation during thefirst 30 days after myocardial infarction (hazardratio, 1.21; 95 percent confidence interval, 1.10 to1.30), after adjustment for all known baseline co-variates
The results of our analysis confirm that patientswith left ventricular dysfunction, heart failure, orboth after myocardial infarction are at high risk forsudden death or cardiac arrest with resuscitation.The absolute risk is greatest in the early period aftermyocardial infarction and among patients with thelowest ejection fraction and declines significantlyover time, reaching a steady state at approximately
d i s c u s s i o n
* Plus–minus values are means ±SD The body-mass index is the weight in kilograms divided by the square of the height
in meters Percentages may not sum to 100 because of rounding CHF denotes congestive heart failure, PCI ous coronary intervention, and LVEF left ventricular ejection fraction.
percutane-† P values are for the comparison with sudden death or cardiac arrest with resuscitation.
Table 1 Baseline Characteristics of the Patients, According to the Outcome.*
Characteristic
Sudden Death
or Cardiac Arrest with Resuscitation (N=1067)
Death from Cause Other Than Sudden Death (N=1905)
P Value
Survival Free
of Sudden Death
or Cardiac Arrest with Resuscitation (N=11,637)
P Value†
Trang 11s u d d e n d e a t h a f t e r m y o c a r d i a l i n f a r c t i o n
one year The risk was increased despite the fact that
all patients, according to the study design, were
re-ceiving inhibitors of the renin–angiotensin system
and the majority were receiving beta-blockers and
aspirin
Several measures may identify patients at
high-est risk for sudden death in the first year after
myo-cardial infarction.3,13,14
These are an assessment ofthe frequency or severity of arrhythmia, including
the incidence of premature ventricular contractions,
nonsustained ventricular tachycardia, dispersion of
the QT interval, and late potentials on
signal-aver-aged electrocardiograms; measures of autonomic
function; and the results of invasive
electrophysio-logical testing.15-17 The left ventricular ejection
frac-tion, an independent risk factor for sudden death,
is currently the most widely used and robust
clini-cal determinant of risk after infarction and has
be-come the basis for determining a patient’s eligibility
for ICD therapy.9
However, it is poor at
distinguish-ing between patients who will die from arrhythmia
and those who will die of other cardiovascular
causes.18
In VALIANT, patients who died suddenly
were similar to those who died of other causes
Other causes of death included pump failure,
recur-rent myocardial infarction, procedure-related
caus-es, other cardiac causcaus-es, and noncardiac causcaus-es,
which were relatively rare in this population
Base-line characteristics that were associated with an
in-creased risk of death from other causes were also
associated with an increased risk of sudden death
Our inability to distinguish patients who died
sud-denly from those who died of other causes may
re-flect our lack of more sophisticated measures of
the risk of arrhythmia in this study
The other key determinant of the risk of sudden
death is the time after myocardial infarction Theabsolute risk of sudden death is highest in the firstyear after myocardial infarction Our data suggestthat this risk is greatest within the first week aftermyocardial infarction and falls rapidly within thefirst month The increased early rate of suddendeath was highest among patients with the lowestleft ventricular ejection fraction, but the high inci-dence was not restricted to patients with the lowestleft ventricular ejection fraction Indeed, the inci-dence of sudden death in the group with the high-est ejection fraction was greater in the first 30 daysthan was the incidence of sudden death in the groupwith the lowest ejection fraction after 90 days More-over, patients who died suddenly or had cardiac ar-rest with resuscitation were in clinically stable con-
* CI denotes confidence interval.
Table 2 Event Rate and Cumulative Incidence of Events during Follow-up.*
No of Patients Event Rate Cumulative Incidence
The analysis was restricted to patients for whom data on LVEF were available.
0.20
0.15
0.05 0.10
Trang 12The n e w e n g l a n d j o u r n a l of m e d i c i n e
dition and many had recently been discharged fromthe hospital Thus, to prevent sudden death after in-farction, the ideal strategy must also take into ac-count patients with a better-preserved left ventricu-lar ejection fraction (more than 40 percent)
The discriminatory effect of the left ventricularejection fraction appears to be greatest in the firstsix months after myocardial infarction Among pa-tients who survived beyond one year, the annualizedrate of sudden death was still highest in the groupwith the lowest left ventricular ejection fraction butwas fairly similar among the three ejection-fractiongroups, although the relative risk remained higher
in the groups with a lower ejection fraction This servation, however, should be tempered by the factthat patients who survive are already at lower risk
ob-Also, ventricular function was measured relativelyearly after infarction, and in some patients, substan-tial recovery of ventricular function may have oc-curred with a concomitant decrease in the risk ofsudden death An additional decline in the left ven-tricular ejection fraction may occur over time, andthe risk of sudden death at a particular time aftermyocardial infarction is more likely to be related to
the ejection fraction at that time than to the ejectionfraction in the periinfarction period
Although our findings suggest that a strategy oftreating a greater proportion of patients early andfocusing on those with a low left ventricular ejectionfraction later might be the most efficient approach
to minimizing the risk of sudden death after cardial infarction, the recently reported DINAMITshowed no benefit of implanting an ICD 6 to 40days after myocardial infarction in patients with anejection fraction of 35 percent or less and evidence
myo-of reduced heart-rate variability.10
Indeed, in thattrial, a decrease in the rate of death from arrhythmiawas offset by an increase in the rate of death fromother causes.19
The DINAMIT findings thus did notprovide support for the use of early ICD therapy in ahigh-risk population after myocardial infarctionand underscore the fact that patients at increasedrisk for sudden death from arrhythmia are also atincreased risk for death from other causes.Although it is difficult to reconcile the absence
of a benefit in DINAMIT with the substantially creased risk of sudden death we observed in theearly post-infarction period, there were a number
in-of important differences between the two studies.Although DINAMIT enrolled patients with a loweroverall left ventricular ejection fraction than didVALIANT, the average time to enrollment was 18days after myocardial infarction — 13 days laterthan the average enrollment date in VALIANT —and thus, DINAMIT may have selected for patientsalready at lower risk for sudden death Moreover, at7.2 percent per year, the overall mortality rate waslower in DINAMIT than in VALIANT Although therate of death from arrhythmia in the DINAMIT con-trol group was similar to the rate of sudden death
in VALIANT (3.5 percent and 3.7 percent per year,respectively), the true rate of death from arrhyth-mia in our study may have been much higher, sinceonly unexpected deaths were categorized as sudden,thereby excluding patients with fatal arrhythmia inthe setting of myocardial infarction or pump failure.Alternatively, DINAMIT, with only 120 deaths, mayhave been statistically underpowered to demon-strate a clinically important difference betweengroups, an interpretation that would suggest theneed for additional studies of ways to prevent sud-den death from arrhythmia in the early period afterinfarction
It remains unclear whether therapies targeted at
a high-risk population soon after infarction wouldreduce the risk of sudden unexpected death, but
Figure 2 Rate of Sudden Death or Cardiac Arrest with Resuscitation
over the Course of the Trial in the Three Categories of Left Ventricular
Ejection Fraction (LVEF).
The analysis was restricted to patients for whom data on LVEF were available
The average rate (percentage per month) is shown at the midpoint of each
period.
LVEF ≤30% (n=3852) LVEF, 31– 40% (n=4998) LVEF >40% (n=2406)
Rate of Sudden Death or Cardiac Arrest with Resuscitation (%/mo)
Trang 13s u d d e n d e a t h a f t e r m y o c a r d i a l i n f a r c t i o n
our data provide a rationale for considering
early-intervention strategies, including short-term
ther-apies, in selected patients at risk This is supported
by the fact that the majority of our patients (74
per-cent) who were resuscitated during the first 30 days
were alive at 1 year In addition, although our data
suggest that the overall risk of sudden death or
car-diac arrest with resuscitation increases with a
de-creasing left ventricular ejection fraction, even in
patients with an ejection fraction of more than 40
percent, the risk of sudden death or cardiac arrest
with resuscitation was six times as high in the first
30 days as at 1 year, suggesting a potential role for
early short-term intervention, even in lower-risk
pa-tients For example, if all sudden deaths could be
prevented, a strategy of treating everyone for 30
days and only those with a left ventricular ejection
fraction of 30 percent or less beyond 30 days in the
VALIANT study would potentially have prevented
or postponed 507 deaths, as compared with 317
deaths with the use of the currently recommended
strategy of treating only those with an ejection
frac-tion of 30 percent or less beyond 30 days This
ap-proach may not be practical on the basis of current
ICD technology, but such an approach might be
practical and cost-effective in the future, although
it must be noted that current Medicare regulations
do not allow for payment for ICD therapy before 40
days after myocardial infarction.6
A number of limitations of this analysis should
be noted First, the left ventricular ejection fraction
was measured locally, not centrally, although local
estimation of the ejection fraction is used to makeclinical decisions Second, some patients identified
as having died suddenly may have died from causessuch as aortic dissection, pulmonary embolism,stroke, and especially, reinfarction; in the case ofreinfarction, sudden death may still be due to ar-rhythmia.20
Also, since our definition of suddendeath specified prior stability, we may have exclud-
ed many deaths from arrhythmia that occurred inthe setting of myocardial infarction or heart failure
Finally, although our data may help guide tional strategies that reduce risk, we did not assessthe efficacy of such strategies
interven-In summary, we demonstrated that the risk ofsudden death is highest soon after myocardial in-farction — particularly during the first 30 days
This risk is greatest among patients with the est left ventricular ejection fraction (30 percent orless), but even patients with a high ejection frac-tion (more than 40 percent) are at substantiallyincreased risk in the early post-infarction period,
low-as compared with the subsequent risk, and thediscriminatory effect of the left ventricular ejec-tion fraction declines over time Although it is notknown whether early ICD therapy would reducethese risks, taken in the context of recent data dem-onstrating the benefits of ICD therapy in high-riskpatients,21 our data suggest the need to considerimplementing strategies to prevent sudden death
in selected patients before the time recommended
by current guidelines
Supported by a grant from Novartis Pharmaceuticals.
r e f e r e n c e s
1. Huikuri HV, Castellanos A, Myerburg RJ.
Sudden death due to cardiac arrhythmias.
N Engl J Med 2001;345:1473-82.
2. Savard P, Rouleau JL, Ferguson J, et al.
Risk stratification after myocardial infarction
using signal-averaged electrocardiographic
criteria adjusted for sex, age, and
myocar-dial infarction location Circulation 1997;
96:202-13.
3. Zipes DP, Wellens HJ Sudden cardiac
death Circulation 1998;98:2334-51.
4. The Multicenter Postinfarction Research
Group Risk stratification and survival after
myocardial infarction N Engl J Med 1983;
309:331-6.
5. Mukharji RJ, Rude RE, Poole WK, et al.
Risk factors for sudden death after acute
myocardial infarction: two year follow-up.
Am J Cardiol 1984;54:31-6.
6. Al-Khatib SM, Sanders GD, Mark DB,
et al Implantable cardioverter defibrillators
and cardiac resynchronization therapy in
patients with left ventricular dysfunction:
randomized trial evidence through 2004.
Am Heart J (in press).
7. Buxton AE, Lee KL, Fisher JD, son ME, Prystowsky EN, Hafley G A ran- domized study of the prevention of sudden death in patients with coronary artery dis- ease N Engl J Med 1999;341:1882-90 [Erra- tum, N Engl J Med 2000;342:1300.]
Joseph-8. Moss AJ, Zareba W, Hall WJ, et al phylactic implantation of a defibrillator in patients with myocardial infarction and re- duced ejection fraction N Engl J Med 2002;
Pro-346:877-83.
9. Antman EM, Anbe DT, Armstrong PW,
et al ACC/AHA guidelines for the ment of patients with ST-elevation myo- cardial infarction: a report of the American College of Cardiology/American Heart As- sociation Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction) Circulation 2004;
manage-110:e82-e292.
10.Hohnloser SH, Kuck KH, Dorian P, et
al Prophylactic use of an implantable dioverter–defibrillator after acute myocar- dial infarction N Engl J Med 2004;351:
car-2481-8.
11.Huikuri HV, Tapanainen JM, Lindgren K,
et al Prediction of sudden cardiac death after myocardial infarction in the beta-blocking era J Am Coll Cardiol 2003;42:652-8.
12.Pfeffer MA, McMurray JJ, Velazquez EJ,
et al Valsartan, captopril, or both in cardial infarction complicated by heart fail- ure, left ventricular dysfunction, or both.
myo-N Engl J Med 2003;349:1893-906 [Erratum,
N Engl J Med 2004;350:203.]
13.Califf RM, McKinnis RA, Burks J, et al.
Prognostic implications of ventricular rhythmias during 24 hour ambulatory mon- itoring in patients undergoing cardiac cath- eterization for coronary artery disease Am J Cardiol 1982;50:23-31.
ar-14.Myerburg RJ, Kessler KM, Castellanos
A Sudden cardiac death: epidemiology,
Trang 14tran-s u d d e n d e a t h a f t e r m y o c a r d i a l i n f a r c t i o n
sient risk, and intervention assessment.
Ann Intern Med 1993;119:1187-97.
15.Naccarella F, Lepera G, Rolli A mic risk stratification of post-myocardial in- farction patients Curr Opin Cardiol 2000;
Arrhyth-15:1-6.
16.Steinberg JS, Regan A, Sciacca RR, ger JT Jr, Fleiss JL Predicting arrhythmic events after acute myocardial infarction us- ing the signal-averaged electrocardiogram.
Big-Am J Cardiol 1992;69:13-21.
17.Kleiger RE, Miller JP, Bigger JT Jr, Moss
AJ Decreased heart rate variability and its association with increased mortality after acute myocardial infarction Am J Cardiol 1987;59:256-62.
18.Every N, Hallstrom A, McDonald KM, et
al Risk of sudden versus nonsudden cardiac death in patients with coronary artery dis- ease Am Heart J 2002;144:390-6.
19.Hohnloser SH, Connolly SJ, Kuck KH,
et al The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT): study protocol.
Am Heart J 2000;140:735-9.
20.Uretsky BF, Thygesen K, Armstrong
PW, et al Acute coronary findings at topsy in heart failure patients with sudden death: results from the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial Circulation 2000;102:611- 6.
au-21.Bardy GH, Lee KL, Mark DB, et al Amiodarone or an implantable cardiover- ter-defibrillator for congestive heart failure.
N Engl J Med 2005;352:225-37.
Copyright © 2005 Massachusetts Medical Society.
Trang 15Sudden Death in Patients with Myocardial Infarction
and Left Ventricular Dysfunction, Heart Failure, or
Both
Sudden Death in Patients with Myocardial Infarction and Left
Ventric-ular Dysfunction, Heart Failure, or Both On page 2581, lines 9 and
10 in the Results section of the Abstract should have stated that ``83
percent of all patients who died suddenly in the first 30 days did so
after hospital discharge,´´ rather than ``83 percent of all patients who
died suddenly did so in the first 30 days after hospital discharge,´´ as
printed We regret the error.
Trang 16though the Office for Civil Rights
issued guidelines in 2003 that
seem to allow health care
facili-ties to opt out of providing
lan-guage services if their costs are
too burdensome, Title VI provides
no such exemption
Ad hoc interpreters, including
family members, friends,
un-trained members of the support
staff, and strangers found in
wait-ing rooms or on the street, are
commonly used in clinical
en-counters But such interpreters
are considerably more likely than
professional interpreters to
com-mit errors that may have adverse
clinical consequences.1,5 Ad hoc
interpreters are also unlikely to
have had training in medical
ter-minology and confidentiality;
their priorities sometimes
con-flict with those of patients; and
their presence may inhibit
dis-cussions regarding sensitive issues
such as domestic violence,
sub-stance abuse, psychiatric illness,
and sexually transmitted
diseas-es.5 It is especially risky to have
children interpret, since they are
unlikely to have a full command
of two languages or of medical
terminology; they frequently make
errors of clinical consequence; and
they are particularly likely to avoid
sensitive issues.1,5 Given the umented risks associated with the use of ad hoc interpreters, it is of concern that the 2003 guidance from the Office for Civil Rights states that such use “may be ap-propriate.”
doc-Later this year, the California legislature will consider a bill pro-hibiting state-funded organiza-tions from using children young-
er than 15 years of age as medical interpreters Leland Yee, the Cali-fornia speaker pro tempore, pro-posed the bill, prompted by his experiences interpreting for his mother and, later, as a child psy-chologist The bill requires orga-nizations receiving state funding
to establish a procedure for viding competent interpretation services that does not involve the use of children.”
“pro-Although this legislation may emerge as a state model, as an un-funded mandate, it will have lim-ited power to improve care Per-haps the time has come for payers
to be required to reimburse viders for interpreter services The provision of adequate language services results in optimal com-munication, patient satisfaction, outcomes, resource use, and pa-tient safety.1,5 A 2002 report from
pro-the Office of Management and Budget estimated that it would cost, on average, only $4.04 (0.5 percent) more per physician visit
to provide all U.S patients who have limited English proficiency with appropriate language services for emergency-department, inpa-tient, outpatient, and dental visits This seems like a small price to pay to ensure safe, high-quality health care for 49.6 million Amer-icans
Dr Flores is director of the Center for the Advancement of Underserved Children and
a professor of pediatrics, epidemiology, and health policy at the Medical College of Wisconsin and the Children’s Research In- stitute of the Children’s Hospital of Wiscon- sin, Milwaukee.
Flores G, Laws MB, Mayo SJ, et al Errors
in medical interpretation and their potential clinical consequences in pediatric encoun- ters Pediatrics 2003;111:6-14.
Flores G, Abreu M, Schwartz I, Hill M The importance of language and culture in pediatric care: case studies from the Latino community J Pediatr 2000;137:842-8 Baker DW, Parker RM, Williams MV, Coates WC, Pitkin K Use and effectiveness
of interpreters in an emergency department JAMA 1996;275:783-8.
Youdelman M, Hitov S Racial, ethnic and primary language data collection: an assess- ment of federal policies, practices and per- ceptions Vol 2 Washington, D.C.: National Health Law Program, October 2001 Flores G The impact of medical interpret-
er services on the quality of health care: a systematic review Med Care Res Rev 2005; 62:255-99.
language barriers to health care in the united states
Taking Heart — Cardiac Transplantation
Past, Present, and Future
Sharon A Hunt, M.D
Heart transplantation hit the
international news with a
splash in December 1967, when
the first human-to-human
trans-plantation was performed in South
Africa by Christiaan Barnard, and
the first transplantation in the
United States, performed by
Nor-man Shumway at Stanford
Uni-versity, followed a month later
Initial enthusiasm for the dure was quickly curbed, however, when it became evident that sur-vival rates were usually measured
proce-in days or weeks This poor vival was due not to poor surgi-cal technique, but to an inade-quate understanding of the type
sur-of postoperative complications one should anticipate and a lack of tools for addressing these com-plications when they were rec-ognized
A 1971 cover story in Life
mag-azine, entitled “A New and quieting Look at Transplants,”1reflected the public perception of
Trang 17the field, though the article
fo-cused specifically on the psychosis
the patients experienced in the
in-tensive care unit as a result of sleep
deprivation caused by intense,
round-the-clock surveillance by
anxious clinicians Problems that
were less easily solved included
the occurrence of allograft
rejec-tion and opportunistic infecrejec-tions
After the early enthusiasm for
the procedure subsided, a decade
of slow, steady clinical research
ultimately led to some viable
so-lutions for these clinical obstacles,
as well as to the recognition of an
unanticipated hurdle that today
remains the most important
fac-tor limiting long-term survival
after heart transplantation:
pre-mature development of transplant
coronary vasculopathy Little has
changed in surgical technique
since the 1960s except for the
introduction of the bicaval
anasta-mosis (see figure), which better
preserves the integrity of the
si-nus node and the architecture of
the right atrium In the 1970s, a
number of developments helped
to make the field ripe for
resur-gence First, the use of
endomyo-cardial biopsy to confirm a
clin-ical diagnosis of acute allograft
rejection and to document the
adequacy of therapy was
validat-ed.2 After the introduction of
cyclosporine-based
immunosup-pression in 1980, the clinical
di-agnosis of rejection became much
more problematic, so routine
sur-veillance biopsies of the heart
were introduced; this approach
remains the mainstay of
diagno-sis of rejection for the first one to
three years after transplantation
A second major advance during
the 1970s was the development of
safe methods for the cold
preser-vation of donor hearts, with ischemia times of up to three hours This development opened the way to the procurement of hearts from distant donors, a sys-tem that is universally used to-day In the early days, the donor had to be transferred to the trans-plantation center so that the heart could be harvested in an operat-ing room adjoining that of the recipient — a cumbersome and expensive requirement to which many families of potential donors objected
cold-Subsequent legal recognition
of the concept of brain death led
to the founding of local and then national organ-procurement sys-tems with uniformly applied cri-teria for the allocation of donated organs For the past two decades, the national organ-allocation sys-tem has been run by the private United Network for Organ Shar-ing under contract to the federal government
During the same period, ognition of which opportunistic infections were to be expected and their most common presenta-tions in transplant recipients led
rec-to a highly aggressive approach
to infectious complications and the institution of effective prophy-laxis against some of the more prevalent ones — for example, the use of trimethoprim–sulfa-methoxazole against Pneumocystis carinii infection.
The undisputed leader of the field during the 1970s was Stan-ford’s Shumway Dr Shumway died
in February of this year, but not before seeing his vision of the wider application of heart trans-plantation become a reality.3
It had initially been anticipated that young, healthy donor hearts
would live out their biologic tiny in a new location and not de-velop coronary artery disease for many decades This supposition was proved invalid in the early 1970s, when a number of early re-cipients of heart transplants died from ischemic heart disease Pathologically, this disease was
des-a form of intimdes-al thickening thdes-at was characteristically diffuse, con-centric, and longitudinal Since it was entirely limited to vessels of the allograft, the intuitive conclu-sion was that it was immuno-logically mediated Subsequent re-search has suggested that the process involves an initial immu-nologic insult to the coronary vas-culature that can be exacerbated
by nonimmunologic factors, such
as dyslipidemia, diabetes, and viral infection The model of graft vasculopathy has contributed greatly to an understanding of the biology of vascular injury and its sequelae
Investigations into therapies for graft vasculopathy have cen-tered on palliation and preven-tion Standard palliative percu-taneous interventions, including angioplasty and coronary stent-ing, have been shown to be safe and to have some short-term ef-fectiveness in the occasional pa-tient with one or more focal cor-onary narrowings.4 However, the technology is not applicable in the majority of patients with dif-fuse, distal disease Pharmacolog-
ic interventions have thus far been validated mainly for the preven-tion of this disease Such inter-ventions have included statins and the newer immunosuppressive agents mycophenolate mofetil and the mammalian target of rapamy-cin (mTOR) inhibitors everolimus taking heart — cardiac transplantation past, present, and future
Trang 18PERSPECTIVE taking heart — cardiac transplantation past, present, and future
A Standard (Biatrial) Heart Transplantation
B Orthotopic Cardiac Transplantation with Bicaval Technique
Left common carotid artery
Brachiocephalic trunk
Inferior vena cava
Left atrium
Pulmonary artey trunk
Arch of aorta
Right superior pulmonary vein
Right inferior pulmonary vein
Superior vena cava Superior vena cava
Left subclavian artery
Left common carotid artery Brachiocephalictrunk
Inferior vena cava
Inferior vena cava
Right atrium Left atrium
Left atrium
Standard (Panel A) and New Bicaval (Panel B) Surgical Anastamoses