Articles
21 September 2004

Meta-Analysis: Glycosylated Hemoglobin and Cardiovascular Disease in Diabetes Mellitus

Publication: Annals of Internal Medicine
Volume 141, Number 6

Abstract

Background:

In persons with diabetes, chronic hyperglycemia (assessed by glycosylated hemoglobin level) is related to the development of microvascular disease; however, the relation of glycosylated hemoglobin to macrovascular disease is less clear.

Purpose:

To conduct a meta-analysis of observational studies of the association between glycosylated hemoglobin and cardiovascular disease in diabetic persons.

Data Sources:

Search of the MEDLINE database by using Medical Subject Heading search terms and key words related to glycosylated hemoglobin, diabetes, and cardiovascular disease.

Study Selection:

Prospective cohort studies with data on glycosylated hemoglobin levels and incident cardiovascular disease.

Data Extraction:

Relative risk estimates were derived or abstracted from each cohort study that met the inclusion criteria.

Data Synthesis:

Adjusted relative risk estimates for glycosylated hemoglobin (total glycosylated hemoglobin, hemoglobin A1, or hemoglobin A1c levels) and cardiovascular disease events (coronary heart disease and stroke) were pooled by using random-effects models. Three studies involved persons with type 1 diabetes (n = 1688), and 10 studies involved persons with type 2 diabetes (n = 7435). The pooled relative risk for cardiovascular disease was 1.18; this represented a 1–percentage point increase in glycosylated hemoglobin level (95% CI, 1.10 to 1.26) in persons with type 2 diabetes. Results in persons with type 1 diabetes were similar but had a wider CI (pooled relative risk, 1.15 [CI, 0.92 to 1.43]).

Limitations:

This review largely reflects the limitations of the literature. Important concerns were residual confounding, the possibility of publication bias, the small number of studies, and the heterogeneity of study results.

Conclusions:

Pending confirmation from large, ongoing clinical trials, this analysis shows that observational studies are consistent with limited clinical trial data and suggests that chronic hyperglycemia is associated with an increased risk for cardiovascular disease in persons with diabetes.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
Haffner SMLehto SRonnemaa TPyorala KLaakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-34. [PMID: 9673301]
2.
Saydah SHMiret MSung JVaras CGause DBrancati FL. Postchallenge hyperglycemia and mortality in a national sample of U.S. adults. Diabetes Care. 2001;24:1397-402. [PMID: 11473076]
3.
National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995.
4.
Moss SEKlein RKlein BE. Cause-specific mortality in a population-based study of diabetes. Am J Public Health. 1991;81:1158-62. [PMID: 1951827]
5.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53. [PMID: 9742976]
6.
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-86. [PMID: 8366922]
7.
Gaster BHirsch IB. The effects of improved glycemic control on complications in type 2 diabetes. Arch Intern Med. 1998;158:134-40. [PMID: 9448551]
8.
Klein RKlein BEMoss SEDavis MDDeMets DL. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA. 1988;260:2864-71. [PMID: 3184351]
9.
Klein RKlein BEMoss SE. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Ann Intern Med. 1996;124:90-6. [PMID: 8554220]
10.
Klein RKlein BEMoss SECruickshanks KJ. Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Arch Intern Med. 1994;154:2169-78. [PMID: 7944837]
11.
Shichiri MKishikawa HOhkubo YWake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;23 Suppl 2 B21-9. [PMID: 10860187]
12.
Genuth SEastman RKahn RKlein RLachin JLebovitz Het al . Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 2003;26 Suppl 1 S28-32. [PMID: 12502617]
13.
Fuller JHShipley MJRose GJarrett RJKeen H. Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study. Br Med J (Clin Res Ed). 1983;287:867-70. [PMID: 6412862]
14.
Balkau BShipley MJarrett RJPyorala KPyorala MForhan Aet al . High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study. Diabetes Care. 1998;21:360-7. [PMID: 9540016]
15.
Coutinho MGerstein HCWang YYusuf S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999;22:233-40. [PMID: 10333939]
16.
Goldstein DELittle RRLorenz RAMalone JINathan DMPeterson CMet al . Tests of glycemia in diabetes. Diabetes Care. 2003;26 Suppl 1 S106-8. [PMID: 12502632]
17.
Rohlfing CLWiedmeyer HMLittle RREngland JDTennill AGoldstein DE. Defining the relationship between plasma glucose and HbA(1c): analysis of glucose profiles and HbA(1c) in the Diabetes Control and Complications Trial. Diabetes Care. 2002;25:275-8. [PMID: 11815495]
18.
Meigs JBNathan DMCupples LAWilson PWSinger DE. Tracking of glycated hemoglobin in the original cohort of the Framingham Heart Study. J Clin Epidemiol. 1996;49:411-7. [PMID: 8621991]
19.
Rohlfing CWiedmeyer HMLittle RGrotz VLTennill AEngland Jet al . Biological variation of glycohemoglobin. Clin Chem. 2002;48:1116-8. [PMID: 12089188]
20.
Sacks DBBruns DEGoldstein DEMaclaren NKMcDonald JMParrott M. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2002;48:436-72. [PMID: 11861436]
21.
Standards of medical care in diabetes. Diabetes Care. 2004;27 Suppl 1 S15-35. [PMID: 14693923]
22.
Golden SBoulware LBrancati FBerkenblit GChander GMarinopoulos Set al . Use of glycated hemoglobin and microalbuminuria in the monitoring of diabetes mellitus. Evidence Report/Technology Assessment no. 84. Rockville, MD: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services; 2003.
23.
Fu CCChang CJTseng CHChen MSKao CSWu TJet al . Development of macrovascular diseases in NIDDM patients in northern Taiwan. A 4-yr follow-up study. Diabetes Care. 1993;16:137-43. [PMID: 8422768]
24.
Florkowski CMScott RSMoir CLGraham PJ. Lipid but not glycaemic parameters predict total mortality from type 2 diabetes mellitus in Canterbury, New Zealand. Diabet Med. 1998;15:386-92. [PMID: 9609360]
25.
Gall MABorch-Johnsen KHougaard PNielsen FSParving HH. Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes. 1995;44:1303-9. [PMID: 7589828]
26.
Standl EBalletshofer BDahl BWeichenhain BStiegler HHormann Aet al . Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: the Munich General Practitioner Project. Diabetologia. 1996;39:1540-5. [PMID: 8960840]
27.
Lehto SRonnemaa TPyorala KLaakso M. Poor glycemic control predicts coronary heart disease events in patients with type 1 diabetes without nephropathy. Arterioscler Thromb Vasc Biol. 1999;19:1014-9. [PMID: 10195930]
28.
Olson JCErbey JRForrest KYWilliams KBecker DJOrchard TJ. Glycemia (or, in women, estimated glucose disposal rate) predict lower extremity arterial disease events in type 1 diabetes. Metabolism. 2002;51:248-54. [PMID: 11833057]
29.
Orchard TJOlson JCErbey JRWilliams KForrest KYSmithline Kinder Let al . Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care. 2003;26:1374-9. [PMID: 12716791]
30.
Lehto SRonnemaa TPyorala KLaakso M. Risk factors predicting lower extremity amputations in patients with NIDDM. Diabetes Care. 1996;19:607-12. [PMID: 8725860]
31.
Lehto SRonnemaa TPyorala KLaakso M. Predictors of stroke in middle-aged patients with non–insulin-dependent diabetes. Stroke. 1996;27:63-8. [PMID: 8553405]
32.
Lehto SRonnemaa THaffner SMPyorala KKallio VLaakso M. Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes. 1997;46:1354-9. [PMID: 9231662]
33.
Moss SEKlein RKlein BE. The 14-year incidence of lower-extremity amputations in a diabetic population. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care. 1999;22:951-9. [PMID: 10372248]
34.
Kilpatrick ESRumley AGDominiczak MHSmall M. Glycated haemoglobin values: problems in assessing blood glucose control in diabetes mellitus. BMJ. 1994;309:983-6. [PMID: 7950717]
35.
Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987;9:1-30. [PMID: 3678409]
36.
Kuusisto JMykkanen LPyorala KLaakso M. Non–insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects. Stroke. 1994;25:1157-64. [PMID: 8202973]
37.
DerSimonian RLaird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-88. [PMID: 3802833]
38.
Stata Statistical Software: Release 8.0. College Station, TX: Stata Corp; 2003.
39.
Adler AINeil HAManley SEHolman RRTurner RC. Hyperglycemia and hyperinsulinemia at diagnosis of diabetes and their association with subsequent cardiovascular disease in the United Kingdom Prospective Diabetes Study (UKPDS 47). Am Heart J. 1999;138:S353-9. [PMID: 10539797]
40.
Stratton IMAdler AINeil HAMatthews DRManley SECull CAet al . Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-12. [PMID: 10938048]
41.
Turner RCMillns HNeil HAStratton IMManley SEMatthews DRet al . Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316:823-8. [PMID: 9549452]
42.
Adler AIStevens RJNeil AStratton IMBoulton AJHolman RR. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care. 2002;25:894-9. [PMID: 11978687]
43.
Kothari VStevens RJAdler AIStratton IMManley SENeil HAet al . UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine. Stroke. 2002;33:1776-81. [PMID: 12105351]
44.
Moss SEKlein RKlein BEMeuer SM. The association of glycemia and cause-specific mortality in a diabetic population. Arch Intern Med. 1994;154:2473-9. [PMID: 7979844]
45.
Moss SEKlein RKlein BE. The prevalence and incidence of lower extremity amputation in a diabetic population. Arch Intern Med. 1992;152:610-6. [PMID: 1546925]
46.
Moss SEKlein RKlein BE. Long-term incidence of lower-extremity amputations in a diabetic population. Arch Fam Med. 1996;5:391-8. [PMID: 8664997]
47.
Forrest KYBecker DJKuller LHWolfson SKOrchard TJ. Are predictors of coronary heart disease and lower-extremity arterial disease in type 1 diabetes the same? A prospective study. Atherosclerosis. 2000;148:159-69. [PMID: 10580182]
48.
Lloyd CEKuller LHEllis DBecker DJWing RROrchard TJ. Coronary artery disease in IDDM. Gender differences in risk factors but not risk. Arterioscler Thromb Vasc Biol. 1996;16:720-6. [PMID: 8640398]
49.
Niskanen LTurpeinen APenttila IUusitupa MI. Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis. Diabetes Care. 1998;21:1861-9. [PMID: 9802734]
50.
Toyry JPNiskanen LKMantysaari MJLansimies EAUusitupa MI. Occurrence, predictors, and clinical significance of autonomic neuropathy in NIDDM. Ten-year follow-up from the diagnosis. Diabetes. 1996;45:308-15. [PMID: 8593935]
51.
Uusitupa MINiskanen LKSiitonen OVoutilainen EPyorala K. Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non–insulin-dependent) diabetic and non-diabetic subjects. Diabetologia. 1993;36:1175-84. [PMID: 8270133]
52.
Agewall SWikstrand JLjungman SFagerberg B. Usefulness of microalbuminuria in predicting cardiovascular mortality in treated hypertensive men with and without diabetes mellitus. Risk Factor Intervention Study Group. Am J Cardiol. 1997;80:164-9. [PMID: 9230153]
53.
Mattock MBBarnes DJViberti GKeen HBurt DHughes JMet al . Microalbuminuria and coronary heart disease in NIDDM: an incidence study. Diabetes. 1998;47:1786-92. [PMID: 9792549]
54.
Roselli della Rovere GLapolla ASartore GRossetti CZambon SMinicuci Net al . Plasma lipoproteins, apoproteins and cardiovascular disease in type 2 diabetic patients. A nine-year follow-up study. Nutr Metab Cardiovasc Dis. 2003;13:46-51. [PMID: 12772437]
55.
Huang ESMeigs JBSinger DE. The effect of interventions to prevent cardiovascular disease in patients with type 2 diabetes mellitus. Am J Med. 2001;111:633-42. [PMID: 11755507]
56.
Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VIII. Evaluation of insulin therapy: final report. Diabetes. 1982;31 Suppl 5 1-81. [PMID: 6757026]
57.
Malmberg KRyden LEfendic SHerlitz JNicol PWaldenstrom Aet al . Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995;26:57-65. [PMID: 7797776]
58.
Abraira CColwell JNuttall FSawin CTHenderson WComstock JPet al . Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Arch Intern Med. 1997;157:181-8. [PMID: 9009975]
59.
Beckman JACreager MALibby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287:2570-81. [PMID: 12020339]
60.
Feener EPKing GL. Vascular dysfunction in diabetes mellitus. Lancet. 1997;350 Suppl 1 SI9-13. [PMID: 9250277]
61.
Sheetz MJKing GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA. 2002;288:2579-88. [PMID: 12444865]
62.
Vlassara H. Recent progress in advanced glycation end products and diabetic complications. Diabetes. 1997;46 Suppl 2 S19-25. [PMID: 9285494]
63.
Witztum JLMahoney EMBranks MJFisher MElam RSteinberg D. Nonenzymatic glucosylation of low-density lipoprotein alters its biologic activity. Diabetes. 1982;31:283-91. [PMID: 6818075]
64.
Schmidt AMYan SDWautier JLStern D. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res. 1999;84:489-97. [PMID: 10082470]
65.
Libby PPlutzky J. Diabetic macrovascular disease: the glucose paradox? [Editorial]. Circulation. 2002;106:2760-3. [PMID: 12450998]
66.
Wild SHDunn CJMcKeigue PMComte S. Glycemic control and cardiovascular disease in type 2 diabetes: a review. Diabetes Metab Res Rev. 1999;15:197-204. [PMID: 10441042]
67.
Laakso MKuusisto J. Epidemiological evidence for the association of hyperglycaemia and atherosclerotic vascular disease in non–insulin-dependent diabetes mellitus. Ann Med. 1996;28:415-8. [PMID: 8949972]
68.
Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes. 1999;48:937-42. [PMID: 10331395]
69.
Donahue RPOrchard TJ. Diabetes mellitus and macrovascular complications. An epidemiological perspective. Diabetes Care. 1992;15:1141-55. [PMID: 1396012]
70.
Gerich JE. Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Arch Intern Med. 2003;163:1306-16. [PMID: 12796066]
71.
Nathan DMLachin JCleary POrchard TBrillon DJBacklund JYet al . Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med. 2003;348:2294-303. [PMID: 12788993]
72.
de Vegt FDekker JMRuhe HGStehouwer CDNijpels GBouter LMet al . Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia. 1999;42:926-31. [PMID: 10491751]
73.
Khaw KTWareham NLuben RBingham SOakes SWelch Aet al . Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ. 2001;322:15-8. [PMID: 11141143]
74.
Park SBarrett-Connor EWingard DLShan JEdelstein S. GHb is a better predictor of cardiovascular disease than fasting or postchallenge plasma glucose in women without diabetes. The Rancho Bernardo Study. Diabetes Care. 1996;19:450-6. [PMID: 8732708]
75.
Meigs JBNathan DMD'Agostino RB SrWilson PW. Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care. 2002;25:1845-50. [PMID: 12351489]
76.
Harrell F, Conroy R. What are some of the problems with stepwise regression? Stata frequently asked questions. Accessed at www.stata.com/support/faqs/stat/stepwise.html on 17 June 2004
77.
Harrell FE. Regression Modeling Strategies with Applications to Linear Models, Logistic Regression, and Survival Analysis. New York: Springer; 2001.

Comments

0 Comments
Sign In to Submit A Comment

Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 141Number 621 September 2004
Pages: 421 - 431

History

Published online: 21 September 2004
Published in issue: 21 September 2004

Keywords

Authors

Affiliations

Elizabeth Selvin, MPH
From Johns Hopkins University Bloomberg School of Public Health and Johns Hopkins University School of Medicine, Baltimore, Maryland.
Spyridon Marinopoulos, MD, MBA
From Johns Hopkins University Bloomberg School of Public Health and Johns Hopkins University School of Medicine, Baltimore, Maryland.
Gail Berkenblit, MD, PhD
From Johns Hopkins University Bloomberg School of Public Health and Johns Hopkins University School of Medicine, Baltimore, Maryland.
Tejal Rami, MPH
From Johns Hopkins University Bloomberg School of Public Health and Johns Hopkins University School of Medicine, Baltimore, Maryland.
Frederick L. Brancati, MD, MHS
From Johns Hopkins University Bloomberg School of Public Health and Johns Hopkins University School of Medicine, Baltimore, Maryland.
Neil R. Powe, MD, MPH, MBA
From Johns Hopkins University Bloomberg School of Public Health and Johns Hopkins University School of Medicine, Baltimore, Maryland.
Sherita Hill Golden, MD, MHS
From Johns Hopkins University Bloomberg School of Public Health and Johns Hopkins University School of Medicine, Baltimore, Maryland.
Grant Support: By the Agency for Healthcare Research and Quality (contract no. 290-97-0006). Ms. Selvin was supported by a grant from the National Heart, Lung, and Blood Institute (grant no. T32HL07024). Dr. Golden was supported by a grant from the Robert Wood Johnson Foundation Minority Medical Faculty Development Program. Dr. Brancati was supported by a Mid-Career Award for Patient-Oriented Research from the National Institutes of Health (contract no. K24-DK6222-O1). Dr. Powe was supported in part by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (grant no. K24DK02643).
Disclosures: None disclosed.
Corresponding Author: Sherita Hill Golden, MD, MHS, Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, 2024 East Monument Street, Suite 2-616, Baltimore, MD 21205; e-mail, [email protected].
Current Author Addresses: Ms. Selvin, Ms. Rami, and Drs. Brancati, Powe, and Golden: Johns Hopkins University, Welch Center for Prevention, Epidemiology and Clinical Research, 2024 East Monument Street, Suite 2-600, Baltimore, MD 21205.
Dr. Marinopoulos: Johns Hopkins University, 10753 Falls Road, Suite 325, Lutherville, MD 21093.
Dr. Berkenblit: Johns Hopkins Outpatient Center, 601 North Caroline Street, Suite 7143, Baltimore, MD 21287.
Author Contributions: Conception and design: E. Selvin, S. Marinopoulos, T. Rami, F.L. Brancati, N.R. Powe, S.H. Golden.
Analysis and interpretation of the data: E. Selvin, S. Marinopoulos, G. Berkenblit, T. Rami, F.L. Brancati, N.R. Powe, S.H. Golden.
Drafting of the article: E. Selvin, S.H. Golden.
Critical revision of the article for important intellectual content: E. Selvin, S. Marinopoulos, G. Berkenblit, F.L. Brancati, N.R. Powe, S.H. Golden.
Final approval of the article: E. Selvin, S. Marinopoulos, G. Berkenblit, T. Rami, F.L. Brancati, N.R. Powe, S.H. Golden.
Statistical expertise: E. Selvin.
Obtaining of funding: F.L. Brancati, N.R. Powe, S.H. Golden.
Administrative, technical, or logistic support: T. Rami, N.R. Powe.
Collection and assembly of data: E. Selvin, S. Marinopoulos, G. Berkenblit, T. Rami, S.H. Golden.

Metrics & Citations

Metrics

Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format





Download article citation data for:
Elizabeth Selvin, Spyridon Marinopoulos, Gail Berkenblit, et al. Meta-Analysis: Glycosylated Hemoglobin and Cardiovascular Disease in Diabetes Mellitus. Ann Intern Med.2004;141:421-431. [Epub 21 September 2004]. doi:10.7326/0003-4819-141-6-200409210-00007

View More

Login Options:
Purchase

You will be redirected to acponline.org to sign-in to Annals to complete your purchase.

Access to EPUBs and PDFs for FREE Annals content requires users to be registered and logged in. A subscription is not required. You can create a free account below or from the following link. You will be redirected to acponline.org to create an account that will provide access to Annals. If you are accessing the Free Annals content via your institution's access, registration is not required.

Create your Free Account

You will be redirected to acponline.org to create an account that will provide access to Annals.

View options

PDF/EPUB

View PDF/EPUB

Related in ACP Journals

Full Text

View Full Text

Figures

Tables

Media

Share

Share

Copy the content Link

Share on social media