CLINICAL PRACTICE COMPANION An NEJM Special Collection
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Table of Contents
Table of Contents
CLINICAL 4 PRACTICE CLINICAL PRACTICE
5 Gout T. Neogi
51 52
February 3, 2011
and F.L. Coe
September 2, 2010
S.C. Lazarus
August 19, 2010
Iron-Chelating Therapy for Transfusional Iron Overload G.M. Brittenham
63
72
CLINICAL PRACTICE
Alzheimer’s Disease 35 Early R. Mayeux
CLINICAL THERAPEUTICS
Bisphosphonates for Osteoporosis M.J. Favus
43
Helicobacter pylori Infection K.E.L. McCol
C.L. Moore and J.A. Copel February 24, 2011
80
Coronary Intervention A. Prasad and J. Herrmann
CLINICAL THERAPEUTICS
REVIEW ARTICLE
Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration J.C. Folk and E.M. Stone
CLINICAL THERAPEUTICS
Dietary Therapy in Hypertension F.M. Sacks and H. Campos June 3, 2010
91
Infarction 110 Myocardial Due to Percutaneous February 3, 2011
October 21, 2010
April 29, 2010
CLINICAL THERAPEUTICS
Mitral-Valve Repair for Mitral-Valve Prolapse S. Verma and T.G. Mesana December 3, 2009
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101 Point-of-Care Ultrasonography
November 18, 2010
June 10, 2010 CLINICAL PRACTICE
REVIEW ARTICLE
REVIEW ARTICLE
CLINICAL PRACTICE
Treatment 25 Emergency of Asthma
CLINICAL THERAPEUTICS
100
CURRENT CONCEPTS
January 13, 2011
CLINICAL PRACTICE
Kidney Stones 15 Calcium E.M. Worcester
CLINICAL THERAPEUTICS
Tuberculosis — 122 MDR Critical Steps for
Prevention and Control E. Nathanson and others September 9, 2010
131
OTHER CLINICAL RESOURCES VIDEOS IN CLINICAL MEDICINE
Evaluation 132 Clinical of the Knee
T.L. Schraeder and others July 22, 2010 INTERACTIVE MEDICAL CASE
Low 137 Lying J.J. Ross and others February 10, 2011
Clinical Practice Clinical Practice articles begin with the presentation of a single case and continue to provide a complete description of diagnostic and treatment strategies, therapeutic options, areas of uncertainty, treatment guidelines — everything you need to know about the current state of knowledge about a common condition. These articles are also available in audio format, so you can listen at your computer or download articles for transfer to any iPod or MP3 player.
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4
The
n e w e ng l a n d j o u r na l
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Gout Tuhina Neogi, M.D., Ph.D. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.
A 54-year-old man with crystal-proven gout has a history of four attacks during the previous year. Despite receiving 300 mg of allopurinol daily, his serum urate level is 7.2 mg per deciliter (428 μmol per liter). He is moderately obese and has hypertension, for which he receives hydrochlorothiazide, and his serum creatinine level is 1.0 mg per deciliter (88 μmol per liter). How should his case be managed?
The Cl inic a l Probl em Symptoms and Prevalence
Gout is a type of inflammatory arthritis induced by the deposition of monosodium urate crystals in synovial fluid and other tissues. It is associated with hyperuricemia, which is defined as a serum urate level of 6.8 mg per deciliter (404 μmol per liter) or more, the limit of urate solubility at physiologic temperature and pH.1 Humans lack uricase and thus cannot convert urate to soluble allantoin as the end product of purine metabolism. Hyperuricemia that is caused by the overproduction of urate or, more commonly, by renal urate underexcretion is necessary but not sufficient to cause gout. In one cohort study, gout developed in only 22% of subjects with urate levels of more than 9.0 mg per deciliter (535 μmol per liter) during a 5-year period.2 Gout has two clinical phases. The first phase is characterized by intermittent acute attacks that spontaneously resolve, typically over a period of 7 to 10 days, with asymptomatic periods between attacks. With inadequately treated hyperuricemia, transition to the second phase can occur, manifested as chronic tophaceous gout, which often involves polyarticular attacks, symptoms between attacks, and crystal deposition (tophi) in soft tissues or joints. Although the prevalence of tophaceous gout varies among populations, in one study, tophi were detected in three quarters of patients who had had untreated gout for 20 years or more.3 Recurrent attacks are common. In one study, approximately two thirds of patients with at least one gout attack in the previous year had recurrent attacks.4 An estimated 6.1 million adults in the United States have had gout.5 The prevalence increases with age and is higher among men than among women, with a ratio of 3 or 4 to 1 overall.5-7 However, this sex disparity decreases at older ages, at least in part because of declining levels of estrogen, which has uricosuric effects in women. The rising incidence and prevalence of gout are probably related to the aging of the population, increasing levels of obesity, and dietary changes.6,7
From the Section of Clinical Epidemiology Research and Training Unit, Boston University School of Medicine; and the Department of Epidemiology, Boston University School of Public Health — both in Boston. Address reprint requests to Dr. Neogi at the Clinical Epidemiology Unit, Boston University School of Medicine, 650 Albany St., Suite X-200, Boston, MA 02118, or at
[email protected]. N Engl J Med 2011;364:443-52. Copyright © 2011 Massachusetts Medical Society.
An audio version Click here to of this article access audio is available at version. NEJM.org
Risk Factors
The use of thiazide diuretics, cyclosporine, and low-dose aspirin (4–32 ng/ml
Stone et al.21
Study
Table 2. Large Cohort Studies of Cardiac-Biomarker Elevation after Percutaneous Coronary Intervention (PCI), and Outcomes.*
The
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february 3, 2011
2.0 6.5 0.3
cTnI, 10–15.9 ng/ml
cTnI, ≥16.0 ng/ml
Q-wave MI
9.1
7.6
4.6
PCI
PCI
16.0
36.5
61.0
cTnI, 6–9.9 ng/m
1157
1128
cTnI, 2–5.9 ng/ml
Nallamothu et al.32
cTnI, ≥5× ULN
cTnI, 1–4× ULN
Natarajan et
6.4
CK-MB, >25 ng/ml
al.31
14.6
CK-MB, 5–25 ng/ml
Drug-eluting stenting PCI
5.1 40.9
CK-MB, >20 ng/ml 1807
4.4
Jang et al.30
19.9
CK-MB, >12–20 ng/ml
PCI
CK-MB, 4–12 ng/ml
30.4
15.2 3864
CK-MB, >20 ng/ml
Andron et al.29
32.1
Saphenous-vein graft PCI
CK-MB, 4–20 ng/ml
79.0
5
CK-MB, >88 ng/ml (CK-MB, >10× ULN) 1693
6
CK-MB, >44–88 ng/ml (CK-MB, >5–10× ULN)
Hong et al.28
6
PCI
CK-MB, >26.4–44 ng/ml (CK-MB, >3–5× ULN)
NA 21
3573
CK-MB, >8.8–26.4 ng/ml (CK-MB, >1–3× ULN)
Brener et al.27
NA
Increased risk of major cardiac events (3.8 for cTnI ≥5× ULN)
No association
NA
Increased need for balloon pump (7.8% vs. 1.1%) and repeat PCI (4.2% vs. 1.2%) for CK-MB elevation vs. no elevation
NA
11±7
12
13±7
6–42
12
36
Increased risk of death (hazard ratio, 2.4 for cTnI ≥8× ULN, 8.9 for Q-wave MI)
No association
Increased risk of death (0.5, 1.1, and 2.6% for CK-MB 5× ULN, respectively)
Increased risk of death (hazard ratio, 1.3, 1.76, and 2.26 for CK-MB 1–3, >3–5 and >5× ULN, respectively)
Increased risk of death (hazard ratio, 3.3 for CK-MB >5× ULN)
Increased risk of death (hazard ratio, 1.1 for CK-MB >10× ULN)
current concepts
457
114
458
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16.0
CK-MB, >5 ng/ml
24
8
24
12
25±8
24
26
mo
Length of Follow-up
Increased risk of death (odds ratio, 1.04 per peak CK-MB ratio unit)§
No association
No association
No association
Increased risk of death (hazard ratio, 1.6)
No association
Increased risk of death (hazard ratio, 1.2 per log2 increase in cTnT)
Multivariate Adjusted Long-Term Outcomes
* Plus–minus values are means ±SD. Only data from studies that included at least 1000 patients, long-term outcome data, and concentration-based biomarker analysis are shown. Hazard ratios were determined by means of a multivariate Cox proportional-hazards regression model, if available; otherwise, odds ratios were determined by multivariate analysis. Acute coronary syndromes (ACS) included angina at rest and urgent priority interventions. CK-MB denotes the MB fraction of creatine kinase, cTnI cardiac troponin I, cTnT cardiac troponin T, MI myocardial infarction, NA not available, and ULN upper limit of the normal range. † Outcomes other than evolving myocardial infarction are shown. P0.15 ng/ml
NA
Increased risk of major adverse cardiovascular events (odds ratio, 2.1 for cTnI >3× ULN)
NA
NA
No association
NA
Increased length of stay
In-Hospital Outcomes†
of
Cavallini et al.39
15.4 40.8
19.8
19.7
23.4
51.9
20
19.6
%
Incidence
CK-MB, >4 ng/ml PCI
PCI
PCI
PCI
PCI
PCI
PCI
Type of Intervention
cTnI, >0.45 ng/ml 50.8
70.9
45.1
0.0
43.3
31.0
47.9
%
Incidence of ACS
15.2
3494
1129
2362
3200
1601
1208
1949
No. of Patients
n e w e ng l a n d j o u r na l
cTnI, 0.15–0.45 ng/ml
Fuchs et al.38
cTnI, >0.45 ng/ml
cTnI, 0.15–0.45 ng/ml
Cavallini et al.37
cTnI, >0.30 ng/ml
De Labriolle et al.36
cTnI, ≥0.15 ng/ml
Feldman et al.35
Increase in cTnT >0.1 ng/ml
Hubacek et al.34
cTnT, ≥0.03 ng/ml
Prasad et al.
Study
Table 2. (Continued.)
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current concepts
gested that any elevation in CK-MB was associated with reduced long-term survival and that there was a direct correlation between the magnitude of myonecrosis and mortality.26,39,41,42 In contrast, other studies have shown that only large myocardial infarctions, variably defined as a CK-MB level exceeding 5 or 8 times the upper limit of normal or the presence of new Q waves, were predictive of a poor long-term outcome, especially if they were related to an unsuccessful revascularization procedure (Table 2).21,40,43,44 Studies evaluating the relationship between the postprocedural cardiac troponin level and longterm mortality, in general, have not excluded patients with acute coronary syndromes, many of whom would have had abnormal cardiac-biomarker levels at baseline.31,32,35,39,45-47 Thus, the reported frequency of postprocedural elevations in cardiac troponin has been highly variable, and although some studies showed that the serum concentration of cardiac troponin was an independent predictor of survival, others did not (Table 2). The inconsistent findings were most likely due to heterogeneity of the inclusion criteria, variations in the sensitivity and specificity of the biomarker assays, different sample sizes, and differences in the duration of follow-up. Two recent meta-analyses concluded that an elevated cardiac troponin level after PCI does provide prognostic information.48,49 Both analyses were influenced by studies from our catheterization laboratories on postprocedural cardiac troponin T elevations in which we had reached a similar conclusion.33,50 However, the studies included in the meta-analyses (including our own) had used cardiac troponin cutoff values for normal that were higher than the currently recommended 99th percentile, thereby limiting the accuracy of their conclusions.8
Focus on Pr epro cedur a l R isk To date, virtually all studies of periprocedural myocardial infarction have been limited by the lack of precision with which they determined preprocedural risk. Contemporary cardiac troponin assays have greatly enhanced our ability to detect myonecrosis before and after PCI.46,51 In a recent analysis, using the currently recommended 99th percentile value as the cutoff for a normal cardiac troponin T level, we found that approximately one third of patients who underwent nonemergency PCI had evidence of preprocedural n engl j med 364;5 BACK to TOC
myonecrosis.6 These patients had a greater atherosclerotic burden and more unstable disease than patients without evidence of preprocedural myonecrosis, a finding that is consistent with previous reports.52 Applying the universal definition of myocardial infarction to patients with normal preprocedural cardiac troponin T levels, another one third of patients sustained a periprocedural myocardial infarction after the procedure when cardiac troponin T was used to detect myonecrosis, as compared with only 1 in 15 patients when CK-MB was used.6 The preprocedural rather than postprocedural cardiac-biomarker level was a powerful independent predictor of shortterm and long-term mortality.6 Similar findings have been reported in two additional recent studies that used cardiac troponin I within the framework of the universal definition of myocardial infarction36,37 and in an analysis from the Evaluation of Drug Eluting Stents and Ischemic Events (EVENT) registry.53 These observations may seem surprising, since one might argue that the clinical effect of myocardial infarction should be the same regardless of its cause. However, most periprocedural myocardial infarcts are very small in relation to the magnitude of myonecrosis, especially in patients with stable coronary artery disease. Among patients with normal preprocedural cardiac troponin values, less than 5% have CK-MB values that are higher than 5 times the upper reference limit after PCI, and Q-wave infarctions are rare (5× upper reference limit or equivalent magnitude of troponin elevation or new Q waves Prolong in-hospital observation (by at least 1 day) Assess for left ventricular dysfunction If indicated, repeat angiography to identify procedural complications and need for intervention Troponin greater than upper reference limit and CK-MB
