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Coagulation, Inflammation and Myocardial Dysfunction in Unstable Coronary Artery Disease and the Influence of Glycoprotein IIb/IIIa Inhibition and Low Molecular Weight Heparin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [sv]

Hjärt-kärl sjukdom är den vanligaste dödsorsaken i västvärlden. Samtidigt som antalet patienter med hjärtinfarkt har minskat, har antalet patienter med instabil kranskärlsjukdom d.v.s. svår kärlkramp ökat påtagligt. Diagnosen är nu den vanligaste orsaken till vård på hjärtinfarktavdelningar i Sverige. Modern behandling av instabil kranskärlssjukdom består av en kombination av läkemedel för att minska blodproppsbildning och avlasta hjärtarbetet samt, i de flesta fall, s.k. ballongvidning eller operation av hjärtats kranskärl.

Trots stora behandlingsframsteg är risken för hjärtinfarkt och död hög, såväl på kort som lång sikt. Det finns därför ett stort behov av ytterligare förbättrad behandling utan att samtidigt erhålla oacceptabelt hög risk för allvarliga biverkningar. För att erbjuda en effektiv behandling till patienter med hög risk och samtidigt undvika dyr och potentiellt riskfylld behandling till patienter med låg risk behövs också bättre instrument för tidig riskbedömning.

Syftet med avhandlingen var att undersöka en stor grupp patienter med instabil kranskärlssjukdom avseende säkerhet och effektivitet av en behandlingskombination av två moderna blodproppshämmande läkemedel, dalteparin och abciximab (ca 1000 patienter). Syftet var också att studera hur denna behandling påverkar system för inflammation och koagulation (ca 400 patienter). Dessutom ville vi värdera hur blodnivåer av markörer för inflammation, hjärtmuskelskada och nedsatt hjärtfunktion kan förutsäga risken för framtida komplikationer (ca 7000 patienter).

Tillägg av abciximab till dalteparin minskade inte risken för dödsfall eller hjärtinfarkt inom trettio dagar. Däremot ökade antalet blödningskomplikationer. Totala antalet blödningar var emellertid relativt lågt och behandlingen syntes vara lika säker som kombinationen av abciximab och det internationellt mycket använda blodproppshämmande medlet heparin. Trots den kraftfulla behandlingskombinationen skedde en samtidig aktivering av system för såväl inflammation som koagulation. Detta kan vara en orsak till den observerade avsaknaden av behandlingseffekt av abciximab. Att hindra denna aktivering skulle samtidigt kunna innebära möjligheter för nya behandlingsstrategier.

Förhöjda nivåer av markörer för hjärtmuskelskada (troponin T), inflammation (CRP), nedsatt hjärtfunktion (proBNP) eller nedsatt njurfunktion (kreatininclearance) ökade risken för dödlig utgång både på kort och lång sikt, oberoende av andra riskfaktorer. En kombination av två av dessa markörer gav den högsta risken för dödlig utgång. Således dog endast 0.3 % av patienter med låga nivåer av proBNP och normal njurfunktion inom ett år, jämfört med 25.7 % av patienter med höga nivåer av proBNP och nedsatt njurfunktion. Förhöjda nivåer av troponin T eller nedsatt kreatininclearance (men inte av CRP eller proBNP) ökade dessutom risken för hjärtinfarkt.

Resultaten i avhandlingsarbetet har givit kliniskt tillämpbar kunskap om hur kärlkrampspatienter med hög respektive låg risk kan selekteras tidigt efter inkomst till sjukhus och ny kunskap om behandlingseffekt av abciximab och dalteparin. Resultaten har redovisats på internationella kongresser och i högt rankade medicinska tidskrifter och har citerats i europeiska och amerikanska ”guidelines” för behandling av instabil kranskärlssjukdom.

Abstract [en]

Patients with unstable coronary artery disease (CAD) have an increased risk of subsequent myocardial infarction and death. This study evaluated the safety and efficacy of treatment with glycoprotein IIb/IIIa inhibition in addition to aspirin, low molecular-weight heparin and its influence on coagulation and inflammation. Also, early and differentiated risk assessment utilising markers of inflammation, myocardial damage and dysfunction were evaluated.

The Global Utilisation of Strategies To open Occluded arteries- IV (GUSTO-IV) trial randomised 7800 patients with unstable CAD to 24 or 48 hours infusion of abciximab or placebo in addition to routine treatment with aspirin and unfactionated heparin or dalteparin. Baseline levels of creatinine, C-reactive protein (CRP), Troponin-T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were analysed. At selected sites, all patients received subcutaneous dalteparin (n=974), in stead of unfractionated heparin infusion (n=6826). In a sub-population of dalteparin treated patients (n=404), serial measurements of markers of inflammation , coagulation and fibrinolysis were also performed.

Addition of abciximab to dalteparin as the primary treatment of unstable CAD was not associated with any significant reduction in cardiac events but a doubled risk of bleedings. The combination of abciximab and dalteparin seemed to be as safe as when used with unfractionated heparin. Despite full dose dalteparin and aspirin there was a simultaneous activation of the inflammation, coagulation and fibrinolysis systems without any influence of the abciximab treatment.

Elevated levels of CRP, TnT, and NT-proBNP and reduced creatinine clearance were independently related to short and long-term mortality. The best prediction of high and low risk was provided by a combination of NT-proBNP and creatinine clearance. Any detectable elevation of TnT and reduced creatinine clearance, but neither elevation of CRP nor NT-proBNP, were also independently associated to a raised risk of subsequent myocardial infarction.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 63
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1241
Keywords [en]
Medicine, Acute coronary syndrome, Angina, Mortality, Myocardial infarction, Glycoprotein IIb/IIIa inhibition, Troponin, C-reactive protein, Coagulation, Natriuretic peptide
Keywords [sv]
Medicin
National Category
Dermatology and Venereal Diseases
Research subject
Cardiology
Identifiers
URN: urn:nbn:se:uu:diva-3372ISBN: 91-554-5580-8 (print)OAI: oai:DiVA.org:uu-3372DiVA, id: diva2:162534
Public defence
2003-05-16, Grönwallsalen, Ingång 70, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2003-04-14 Created: 2003-04-14 Last updated: 2009-08-14Bibliographically approved
List of papers
1. Safety and efficacy of abciximab combined with dalteparin in treatment of acute coronary syndromes
Open this publication in new window or tab >>Safety and efficacy of abciximab combined with dalteparin in treatment of acute coronary syndromes
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2002 In: Eur Heart J, Vol. 23, p. 1538-1545Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90239 (URN)
Available from: 2003-04-14 Created: 2003-04-14Bibliographically approved
2. Activation of the inflammation, coagulation, and fibrinolysis systems, without influence of abciximab infusion in patients with non-ST–elevation acute coronary syndromes treated with dalteparin: a GUSTO IV substudy
Open this publication in new window or tab >>Activation of the inflammation, coagulation, and fibrinolysis systems, without influence of abciximab infusion in patients with non-ST–elevation acute coronary syndromes treated with dalteparin: a GUSTO IV substudy
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2004 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 147, no 2, p. 267-274Article in journal (Refereed) Published
Abstract [en]

Background

In acute coronary syndromes, the inflammation and the coagulation systems are activated, implying an impaired outcome. In addition to platelet inhibition, recent evidence suggests that the glycoprotein IIb/IIIa receptor inhibitor abciximab attenuates inflammation and coagulation activity.

Methods

The Swedish Global Utilization of Strategies To open Occluded arteries-IV (GUSTO-IV) substudy included 404 patients with non-ST–elevation acute coronary syndromes. In addition to aspirin and dalteparin, all patients were randomized to receive abciximab infusion for 24 hours or 48 hours or corresponding placebo without early coronary revascularization. Plasma samples were obtained at baseline and 24, 48, and 72 hours.

Results

The median levels of the coagulation markers thrombin/antithrombin complex and soluble fibrin increased significantly from 3.1 to 3.7 ug/L (baseline to peak; P <.001) and from 20 to 23 nmol/L (P <.001), respectively. The fibrinolysis marker, tissue plasminogen-activator, also increased its median levels, from 11.7 to 17.5 ug/L (P <.001), whereas the median level of plasminogen-activator-inhibitor was unchanged. The inflammatory markers interleukin-6, C-reactive protein, and fibrinogen also increased their median levels (5.4–7.8 ng/L, P <.001; 4.4–8.7 mg/L, P <.001; 3.3–3.9 g/L, P <.001). However, there were no differences in median levels or in changes of median levels of any marker at any point between the placebo group and any of the abciximab groups.

Conclusions

In non-ST–elevation acute coronary syndrome, there was a simultaneous activation of the inflammation, coagulation, and fibrinolysis systems, despite aspirin and dalteparin treatment. Prolonged treatment with abciximab had no influence of the activation of these systems.

Unstable coronary artery disease (CAD) intricately involves inflammatory mediators in the development of an atherosclerotic plaque and in thrombus formation by platelet aggregation.1 Acute phase elevation of inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen are important predictors of the short- and long-term prognosis in unstable CAD.2, 3 and 4 Activation of the coagulation and fibrinolysis systems, as demonstrated with elevated markers of thrombin generation, thrombin activity, and fibrin turnover, also have been found in the acute phase of unstable CAD and are associated with an adverse outcome.5, 6 and 7 Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors potently inhibit platelet aggregation and reduce the incidence of ischemic events in patients undergoing percutaneuos coronary interventions8, 9 and 10 and in patients with unstable CAD.11 The GP IIb/IIIa inhibitor abciximab, in addition to its antithrombotic effect, also suppresses the rise in levels of inflammatory markers after percutaneous coronary interventions.12 This anti-inflammatory effect might be related to abciximab's cross-reaction with other integrin receptors.13 Furthermore, by inhibiting platelet aggregation, abciximab might also attenuate the coagulation and fibrinolysis activation as shown in vitro and in vivo.14 and 15

The Global Utilization of Strategies To Open occluded arteries in acute coronary syndromes (GUSTO IV-ACS) trial unexpectedly failed to show any benefit of abciximab treatment in a high risk ACS population not undergoing early coronary revascularization.16 In the GUSTO IV-ACS low-molecular weight heparin substudy,17 dalteparin was used as the anticoagulant. Dalteparin, which is an inhibitor of the coagulation cascade, mainly by inhibition of factor Xa and less of factor IIa, has previously been shown to reduce the generation and activity of thrombin in unstable coronary disease.18 There is evidence that a combination of abciximab and a low-molecular-weight heparin have additive effects on the lag-time to platelet aggregation,19 and there are several theoretical advantages with the combination treatment. There was still no significant reduction in clinical events with abciximab in combination with dalteparin.17 The aim of this Swedish substudy of GUSTO IV-ACS was to evaluate the influence of abciximab infusion on markers on inflammation, coagulation, and fibrinolysis in patients with unstable CAD treated with aspirin and subcutaneous dalteparin.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90240 (URN)10.1016/j.ahj.2003.09.014 (DOI)14760324 (PubMedID)
Available from: 2003-04-14 Created: 2003-04-14 Last updated: 2017-12-14Bibliographically approved
3. Troponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: a GUSTO-IV substudy
Open this publication in new window or tab >>Troponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: a GUSTO-IV substudy
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2003 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 41, no 6, p. 916-24Article in journal (Refereed) Published
Keywords
Acute Disease, Aged, C-Reactive Protein/*analysis, Cohort Studies, Coronary Arteriosclerosis/*blood/*complications/mortality, Female, Humans, Male, Middle Aged, Myocardial Infarction/*blood/*etiology/mortality, Outcome Assessment (Health Care), Predictive Value of Tests, Risk Assessment, Survival Rate, Time Factors, Troponin/*blood
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-71862 (URN)10.1016/S0735-1097(02)02969-8 (DOI)12651034 (PubMedID)
Available from: 2005-05-13 Created: 2005-05-13 Last updated: 2017-11-21Bibliographically approved
4. N-Terminal Pro–Brain Natriuretic Peptide and Other Risk Markers for the Separate Prediction of Mortality and Subsequent Myocardial Infarction in Patients With Unstable Coronary Artery Disease: A Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV Substudy
Open this publication in new window or tab >>N-Terminal Pro–Brain Natriuretic Peptide and Other Risk Markers for the Separate Prediction of Mortality and Subsequent Myocardial Infarction in Patients With Unstable Coronary Artery Disease: A Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV Substudy
Show others...
2003 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 108, no 3, p. 275-281Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Biochemical markers are useful for prediction of cardiac events in patients with non-ST-segment-elevation acute coronary syndrome (ACS). The associations between N-terminal pro-brain natriuretic peptide (NT-proBNP) and other biochemical and clinical risk indicators, as well as their prognostic value concerning the individual end points of death and myocardial infarction (MI), were elucidated in a large cohort of ACS patients. METHODS AND RESULTS: NT-proBNP, troponin T, and C-reactive protein (CRP) were analyzed in blood samples obtained at a median of 9.5 hours from symptom onset in 6809 of 7800 ACS patients in the Global Utilization of Strategies To Open occluded arteries-IV (GUSTO-IV) trial. Levels of NT-proBNP were correlated independently with age, female gender, low body weight, diabetes, renal dysfunction, history of MI, heart failure, heart rate, ongoing myocardial damage, and time since onset of ischemia. Increasing quartiles of NT-proBNP were related to short- and long-term mortality that reached 1.8%, 3.9%, 7.7%, and 19.2%, (P<0.001), respectively, at 1 year. Levels of troponin T, CRP, heart rate, and creatinine clearance, in addition to ST-segment depression, were also correlated independently with 1-year mortality, but NT-proBNP was the marker with the strongest relation. In contrast, only troponin T, creatinine clearance, and ST-segment depression were independently related to future MI. The combination of NT-proBNP and creatinine clearance provided the best prediction, with a 1-year mortality of 25.7% with both markers in the top quartile vs 0.3% with both markers in the bottom quartile. CONCLUSIONS: The use of NT-proBNP appears to add critical prognostic insight to the assessment of patients with ACS.

Keywords
angina, myocardial infarction, coronary disease, natriuretic peptides, mortality
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90242 (URN)10.1161/01.CIR.0000079170.10579.DC (DOI)12847065 (PubMedID)
Available from: 2003-04-14 Created: 2003-04-14 Last updated: 2017-12-14Bibliographically approved

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