Risk Markers in the Acute Coronary Syndromes

Coronary Artery Disease Clinical Trial

— RACS  

Official title:

An Investigation of Activated Factor XII (Fxlla) as a Prognostic Marker.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00521976
• Other study ID #: NSD9253
• Status: Completed
• Start date: November 2002
• Est. completion date: December 2005

Study information

• Verified date: May 2015
• Source: Helse Stavanger HF
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The main aim of this trial is to assess the long-term prognostic value of different types of Factor XIIa in an unselected, single center series of 871 chest pain patients admitted to the emergency unit, employing blood samples collected at admission.

The second purpose of this study is to assess the incremental prognostic value of B-type natriuretic peptide (BNP) and high-sensitive C-reactive protein (hsCRP).

A third purpose of this study is to evaluate the prognostic impact of the Omega-3 Index which is a measure of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to other fatty acids in the erythrocyte membrane.

Description:

BACKGROUND Cardiac troponins are sensitive markers for myocardial injury in ACS and even a minor elevation of cardiac troponins is associated with an increased risk for future adverse coronary events. However, a detectable troponin release occurs only in a part of patients admitted with ACS. The clinical outcomes and further prognosis of patients with ACS with absent TnT release vary widely, and the identification of potential high-risk patients with troponin negative ACS still remains a major problem in clinical routine. Therefore, the aim of this study is focused on identifying new biomarkers for risk stratification.

Activated Factor XII: Activated Factor XII leads to contact activation and a number of pathophysiological processes, including hypotension, inflammation, thrombosis and fibrinolysis, are affected by contact activation following the activation of XIIa. Several studies have demonstrated a relation between XIIa and coronary artery heart disease (CAD) (1,2,3,4) and that XIIa levels post MI predict recurrent coronary occlusive events and play a role as an independent risk marker in these patients (5).

However, the detailed mechanisms of XIIa's actions in CAD still remain uncertain although recent findings in animal studies using FXII deficient mice indicate that Factor XII is essential for arterial thrombus formation (6).

Recent research indicates that in-vivo XIIa exists in multiple types and that in-vivo XIIa can exist in the circulation complexed to a variety of other proteins (7). To date, no data exist on the prognostic value of specific in-vivo types of XIIa on outcome in patients with chest pain and/or ACS.

B-type natriuretic peptide: B-type natriuretic peptide (BNP) is a counter-regulatory peptide hormone predominantly synthesized in the ventricular myocardium. BNP is released into the circulation in response to ventricular dilatation and pressure overload, and reflects ventricular wall stress and tissue hypoxia rather than cell injury per se (8, 9). It is a well known marker of left ventricular dysfunction and heart failure (HF), and it provides prognostic information beyond and above left ventricular ejection fraction (LVEF) in patients with an acute coronary syndrome (ACS) (10). This marker of neurohormonal activation and inflammation plays a pivotal role across the spectrum of ACS, including patients with ST-elevation myocardial infarction (MI) and non ST-elevation ACS (NSTE-ACS). Previous studies have demonstrated that BNP measured in the first days after the onset of symptoms independently predicts mortality, HF, and new MI in this patient population. Elevated natriuretic peptides at presentation have been shown to identify patients with ACS who are at higher risk of death and HF, and it adds information to that provided by the troponins (11-13). However, in a low-risk population the association between elevated BNP and survival is attenuated when adjustment is made for echocardiographic variables (in addition to clinical covariates), as shown by Wang and colleagues. In addition, they did not find any association between baseline BNP and the risk of coronary heart disease (CHD) (14).

High-sensitive C-reactive protein (hsCRP): C-reactive protein (CRP) is an acute-phase reactant that is produced in response to acute injury, infection or other inflammation stimuli. It is a marker for underlying systemic inflammation and plays an important role in the initiation and propagation of atherosclerosis and ultimately to plaque rupture and the ensuing thrombotic complication (15) Elevated levels of CRP were first reported in patients hospitalized with NSTE-ACS in the early 1990s (16, 17). Through the use of appropriate high-sensitive assays, it has been possible to investigate the relationship between plasma CRP levels that previously were considered to be normal and cardiovascular disease (CVD). Nevertheless, it is still under debate which markers should be preferred for risk prediction (18, 19). It has been suggested that the combined evaluation of BNP and CRP may yield incremental prognostic information in the risk stratification of patients with ACS (20), and their combined use has been shown to improve long-term risk prediction of mortality in patients with stable CHD (21). To our knowledge, there are limited data available that directly compare these two markers in a prospective manner in an unselected patient population presenting to the emergency department (ED) with chest pain. In addition, their role in risk stratification in patients with ACS is still under evaluation, and therefore additional investigations are necessary.

Omega- 3 Index: The value of the Omega-3 Index as a prognostic marker in the acute coronary syndromes is still under investigation.

STUDY DESIGN This prospective single center observational non-invasive trial includes 871 men and women admitted with chest pain and potential ACS at the Stavanger University Hospital between November 2002 and October 2003. Blood samples were collected immediately following admission. Patients were stratified according to peak troponin T (TnT) release following admission; i.e. 1) patients with an admission TnT exceeding 0.05 ng/mL, and 2) patients with a peak TnT level of 0.05 ng/mL or lower.

Assessment of a history of previous MI, angina pectoris (AP), congestive heart failure (CHF), diabetes mellitus and arterial hypertension was based on hospital records and personal interview. Electrocardiographic findings at admission were classified according to the presence of ST segment changes.

Written informed consent was obtained from all patients. Survival status, date and cause of death and clinical data were obtained by telephone interview and hospital journal reports at 4 predefined time points (30 days, 6, 12 and 24 months) during the two year follow-up period. In case of incapacity to provide information, the general practitioner or nursery home were contacted for relevant data. Hospital journals were searched for confirmation of reported data.

Primary Outcome Measures:

• During follow-up

• All cause death

• Non-fatal acute myocardial infarction (MI)

• Combined endpoint of all cause death or non-fatal acute MI

• Combined endpoint of cardiovascular death or non-fatal acute MI

Secondary Outcome Measures:

• During follow-up

• Acute hospitalizations for angina

• Myocardial revascularization

STEERING COMMITTEE

• Professor Dennis WT Nilsen MD PhD, Department of Heart Disease, Stavanger University Hospital

• Heidi Grundt MD PhD Department of Medicine, Stavanger University Hospital

• Øyvind Hetland MD PhD, Department of Clinical Chemistry, Stavanger University Hospital

• Ole Kristensen MD, Department of Clinical Chemistry, Stavanger University Hospital

BIOLOGICAL SAMPLE OWNERSHIP. The biological samples are owned by Stavanger University Hospital and their use for scientific purposes is administered by the Steering Committee.

DATA OWNERSHIP AND PUBLICATION OF RESULTS. The RACS Steering Committee has the ownership of all data registered in the RACS database, and any use of these data including the preparation and publication of scientific reports must be approved by the Steering Committee. Scientific articles will be published by RACS investigators or by authors mentioned by name. The author sequence should be approved by the Steering Committee and based upon contribution. Incentives to involve articles as part of a doctoral thesis should be encouraged. All collaborators in the study will be mentioned by name in an Appendix section of the main article from the study. The results will be published in peer-reviewed scientific journals and in magazines for the general public.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 871
• Est. completion date: December 2005
• Est. primary completion date: December 2005
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• adults > 18 years able to give informed consent

• a history of chest pain or other symptoms suggestive of an ACS leading to admission at the emergency unit

Exclusion Criteria:

• < 18 years of age

• Unwillingness or incapacity to provide informed consent

• Prior admission resulting in inclusion in the present study

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Angina Pectoris
• Angina, Unstable
• Chest Pain
• Coronary Artery Disease
• Coronary Disease
• Infarction
• Myocardial Infarction
• Myocardial Ischemia
• Unstable Angina Pectoris

Locations

Country	Name	City	State
Norway	Stavanger University Hospital	Stavanger	Rogaland

Sponsors (3)

Lead Sponsor	Collaborator
Helse Stavanger HF	Axis-Shield, Dundee, UK, Helse Vest

Country where clinical trial is conducted

Norway, 

References & Publications (30)

Aarsetoey H, Pönitz V, Grundt H, Staines H, Harris WS, Nilsen DW. (n-3) Fatty acid content of red blood cells does not predict risk of future cardiovascular events following an acute coronary syndrome. J Nutr. 2009 Mar;139(3):507-13. doi: 10.3945/jn.108.0 — View Citation

Aarsetøy H, Pönitz V, Nilsen OB, Grundt H, Harris WS, Nilsen DW. Low levels of cellular omega-3 increase the risk of ventricular fibrillation during the acute ischaemic phase of a myocardial infarction. Resuscitation. 2008 Sep;78(3):258-64. doi: 10.1016/j — View Citation

Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in "active" coronary artery disease. Am J Cardiol. 1990 Jan 15;65(3):168-72. — View Citation

Brügger-Andersen T, Hetland Ø, Pönitz V, Grundt H, Nilsen DW. The effect of primary percutaneous coronary intervention as compared to tenecteplase on myeloperoxidase, pregnancy-associated plasma protein A, soluble fibrin and D-dimer in acute myocardial in — View Citation

Brügger-Andersen T, Pönitz V, Staines H, Grundt H, Hetland Ø, Nilsen DW. The prognostic utility of D-dimer and fibrin monomer at long-term follow-up after hospitalization with coronary chest pain. Blood Coagul Fibrinolysis. 2008 Oct;19(7):701-7. doi: 10.1 — View Citation

Brügger-Andersen T, Pönitz V, Staines H, Pritchard D, Grundt H, Nilsen DW. B-type natriuretic peptide is a long-term predictor of all-cause mortality, whereas high-sensitive C-reactive protein predicts recurrent short-term troponin T positive cardiac even — View Citation

Cooper JA, Miller GJ, Bauer KA, Morrissey JH, Meade TW, Howarth DJ, Barzegar S, Mitchell JP, Rosenberg RD. Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease. Circulation. 2000 Dec 5;102(23):2816-22. — View Citation

de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP, Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med. 2001 Oct 4;345(14):1014-21. — View Citation

de Lemos JA. The latest and greatest new biomarkers: which ones should we measure for risk prediction in our practice? Arch Intern Med. 2006 Dec 11-25;166(22):2428-30. Erratum in: Arch Intern Med. 2007 Feb 26;167(4):353. — View Citation

Harris WS, Sands SA, Windsor SL, Ali HA, Stevens TL, Magalski A, Porter CB, Borkon AM. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation. Circulation. 2004 Sep 21;110(12):1645-9. Epub 2004 Sep 7. Erratum in: Circulation. 2004 Nov 9;110(19):3156. — View Citation

Kim H, Yang DH, Park Y, Han J, Lee H, Kang H, Park HS, Cho Y, Chae SC, Jun JE, Park WH. Incremental prognostic value of C-reactive protein and N-terminal proB-type natriuretic peptide in acute coronary syndrome. Circ J. 2006 Nov;70(11):1379-84. — View Citation

Kohler HP, Carter AM, Stickland MH, Grant PJ. Levels of activated FXII in survivors of myocardial infarction--association with circulating risk factors and extent of coronary artery disease. Thromb Haemost. 1998 Jan;79(1):14-8. — View Citation

Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med. 1994 Aug 18;331(7):417-24. — View Citation

Maeda K, Tsutamoto T, Wada A, Hisanaga T, Kinoshita M. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction. Am Heart J. 1998 May;135(5 Pt 1):825-32. — View Citation

Miller GJ, Esnouf MP, Burgess AI, Cooper JA, Mitchell JP. Risk of coronary heart disease and activation of factor XII in middle-aged men. Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):2103-6. — View Citation

Mjelva OR, Brügger-Andersen T, Pönitz V, Grundt H, Kontny F, Staines H, Nilsen DW. Long-term prognostic utility of PAPP-A and calprotectin in suspected acute coronary syndrome. Scand Cardiovasc J. 2013 Apr;47(2):88-97. doi: 10.3109/14017431.2013.764571. E — View Citation

Morrow DA, de Lemos JA, Sabatine MS, Murphy SA, Demopoulos LA, DiBattiste PM, McCabe CH, Gibson CM, Cannon CP, Braunwald E. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol. 2003 Apr 16;41(8):1264-72. Erratum in: J Am Coll Cardiol. 2003 May 21;41(10):1852. — View Citation

Naesgaard PA, Pönitz V, Aarsetoey H, Brügger-Andersen T, Grundt H, Harris WS, Staines H, Nilsen DW. Prognostic utility of vitamin D in acute coronary syndrome patients in coastal Norway. Dis Markers. 2015;2015:283178. doi: 10.1155/2015/283178. Epub 2015 F — View Citation

Nakagawa O, Ogawa Y, Itoh H, Suga S, Komatsu Y, Kishimoto I, Nishino K, Yoshimasa T, Nakao K. Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. Evidence for brain natriuretic peptide as an "emergency" cardiac hormone against ventricular overload. J Clin Invest. 1995 Sep;96(3):1280-7. — View Citation

Ndrepepa G, Kastrati A, Braun S, Mehilli J, Niemöller K, von Beckerath N, von Beckerath O, Vogt W, Schömig A. N-terminal probrain natriuretic peptide and C-reactive protein in stable coronary heart disease. Am J Med. 2006 Apr;119(4):355.e1-8. — View Citation

Omland T, Persson A, Ng L, O'Brien R, Karlsson T, Herlitz J, Hartford M, Caidahl K. N-terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes. Circulation. 2002 Dec 3;106(23):2913-8. — View Citation

Pönitz V, Brügger-Andersen T, Pritchard D, Grundt H, Staines H, Nilsen DW; RACS Study Group. Activated factor XII type A predicts long-term mortality in patients admitted with chest pain. J Thromb Haemost. 2009 Feb;7(2):277-87. doi: 10.1111/j.1538-7836.20 — View Citation

Pönitz V, Pritchard D, Grundt H, Mehus MB, Nilsen DW. Changes of plasma activated Factor XII type A (XIIaA) concentrations following percutaneous coronary intervention (PCI). J Thromb Thrombolysis. 2007 Oct;24(2):131-5. Epub 2007 May 11. — View Citation

Pönitz V, Pritchard D, Grundt H, Nilsen DW. Specific types of activated Factor XII increase following thrombolytic therapy with tenecteplase. J Thromb Thrombolysis. 2006 Dec;22(3):199-203. — View Citation

Pritchard D, Polwart R. In-vivo, activated factor XII exists in multiple forms, but predominantly as a 53 kD Species. J Thromb and Haemost 2005; Suppl.1; ISSN 1740-3340.

Richards AM, Nicholls MG, Espiner EA, Lainchbury JG, Troughton RW, Elliott J, Frampton C, Turner J, Crozier IG, Yandle TG. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation. 2003 Jun 10;107(22):2786-92. Epub 2003 May 27. — View Citation

Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115-26. Review. — View Citation

Rothenbacher D, Koenig W, Brenner H. Comparison of N-terminal pro-B-natriuretic peptide, C-reactive protein, and creatinine clearance for prognosis in patients with known coronary heart disease. Arch Intern Med. 2006 Dec 11-25;166(22):2455-60. — View Citation

Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004 Feb 12;350(7):655-63. — View Citation

Zito F, Drummond F, Bujac SR, Esnouf MP, Morrissey JH, Humphries SE, Miller GJ. Epidemiological and genetic associations of activated factor XII concentration with factor VII activity, fibrinopeptide A concentration, and risk of coronary heart disease in men. Circulation. 2000 Oct 24;102(17):2058-62. — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total Mortality.		24 months.
Secondary	Recurrent Troponin-T (TnT) Positive Events	Recurrent Troponin-T (TnT) positive events; Symptoms of coronary ischemia associated with TnT >0.05 ng/mL with a pattern of gradual rise and fall in TnT	24 months.

External Links

•   Norwegian Social Science Data Services