Understanding the disease and the unmet needs
Quality registry studies:
- Patent coronary artery and myocardial infarction in the era of primary angioplasty: assessment of an old problem in a new setting with data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR).
- Thrombus aspiration in ST-elevation myocardial infarction in Sweden: a short report on real world outcome.
- Long-term mortality after PCI in patients with diabetes mellitus: results from the Swedish Coronary Angiography and Angioplasty Registry.
- Gender perspective on risk factors, coronary lesions and long-term outcome in young patients with ST-elevation myocardial infarction.
- Study of whether patient involvement during hospitalization for acute myocardial infarction is associated with post-discharge treatment outcome.
- Fibrinolytic therapy and bleeding complications: risk predictors from RIKS-HIA.
- Cardiovascular and cancer mortality in very elderly post-myocardial infarction patients receiving statin treatment.
- Relation between renal function, presentation, use of therapies and in-hospital complications in acute coronary syndrome: data from the SWEDEHEART register.
- Platelet function and genetic testing for identification of response to P2Y12 inhibition and the risk of stent thrombosis and myocardial infarction was investigated in a local case-control study (TOPAS) of 169 patient recruited from the Swedish Coronary Angiograpy and Angioplasty Registry (SCAAR). The results verified a difference in the platelet inhibitory effect of clopidogrel between patients with and without stent thrombosis but with a substantial overlap between cases and controls. The design of this study was based on the experiences concerning the pharmacokinetic-pharmacogenetics –pharmacodynamic relationships when comparing the new P2Y12 inhibitor prasugrel versus clopidogrel which was published by the group during the last two years.
- In the regional multi-center study, PUMI, of 250 patients with stable CAD, late enhancement MRI, coronary angiograms and a biomarker program has been performed in order to elucidate the prevalence of and the pathophysiological background to “undetected myocardial injury (UMI). A new and unique soft ware for conjunct analysis of the coronary angiogram and MRI has been developed.
- The single center study, REBUS, monitoring inflammatory and haemostasis parameters long-term (several years) after AMI was started.
- In collaboration with SVA (professor Ulf Bondesson and Mikael Hedeland på SVA) we have studied PDE-5 inhibitors and the NO syntetase activity in pulmonary hypertension and have shown that PDE-5 inhibitors influence the NO-system and give acute hemodynamic effects.
Diagnosis, risk assessment and tailoring of treatment
We try to elucidate the pathophysiological basis and the usefulness of different biomarkers for diagnosis and prognosis of overt or concealed coronary and/or myocardial disease. Currently the underlying mechanisms are investigated by studies using arrays of biomarkers, coronary angiograms, CT-angiograms, MRI and also animal and cell studies.
The group has continued to show the importance of both high sensitivity troponins and Growth dispersion factor 15 (GDF15) as an independent risk factors for cardiovascular death and myocardial infarction as well in acute and chronic coronary artery disease as in healthy elderly subjects. In 2010, one paper dealing with the troponin kinetics in chest pain patients has been accepted for publication and several other research projects are under way. These projects address the importance of hs-troponin concentrations in patients with heart failure and precapillary hypertension (observational study), underlying factors contributing to the release of hs-troponin in patients with stable coronary heart disease (PUMI-study) and finally, the associations of hs-troponin and GDF-15 to cardiovascular morbidities and outcome in the elderly (PIVUS-study and ULLSAM-study). The genetic background to elevated troponin and NT-proBNP in asymptomatic individuals has been analyzed (PIVUS-study and ULLSAM-study) and recently published.
We focus also on novel biomarkers in cardiovascular disease, their underlying pathophysiology and relation to outcome. In several publications we have presented data on the associations of myeloperoxidase, GDF-15 and ST2 to prognosis in patient populations with different manifestations of cardiovascular disease (FRISC II-study, GUSTO IV-study, FAST II- and FASTER I-studies).
The extensive PLATO substudy program of biomarkers of myocardial damage, function and oxidative stress, of renal function, of inflammation, coagulation and endothelial activation and of glucose and lipid metabolism are under analysis and reporting. In a genetic substudy of the PLATO trial in around 10 000 patients the ticagrelor effects were show to be unrelated to the genetic polymorphisms associated with low response to clopidogrel. The genetics program now proceeds with a GWAS analysis which will be reported soon.
The group has pioneered in studying and reporting the incremental prognostic value of the levels of biomarkers of myocardial damage (troponin-I), myocardial function (NT-pro-BNP) and coagulation (D-dimer) concerning the risk of stroke, mortality, myocardialinfarction and bleeding and the usefulness of these biomarkers for better selection of patients benefitting from oral anticoagulation in atrial fibrillation. Analyses of biomarkers in blood samples obtained at randomization (n=6.200) and serial samples (n=2.600) obtained at 3, 6 and 12 months have been performed.
Tracers for PET for diagnosis of amyloidosis in the heart have been developed and evaluated.
Studies utilizing clinical cardiac imaging, in particular echocardiography, but extending to cardiac computer tomography and magnetic resonance have been initiated. Focuses are on left and right ventricular function, heart failure, and valvular heart disease.
Evaluate new (and old) treatments
During the last years we have led three studies of adding oral anticoagulation to the current routine treatment with aspirin and clopdogrel as secondary prevention after acute coronary syndrome. In two phase II trials (APPRAISE, REDEEM) different doses of the oral fXa-inhibitor apixaban respectively the oral direct thrombin inhibitor dabigatran were compared to placebo in 1800 respectively 1600 patients with acute coronary syndrome. Both studies showed similar results with a dose related increase in the risk of bleeding and a trend to a reduction on ischemic events. Recently the phase III trial (APPRAISE-2) comparing the best balance apixaban dose versus placebo was terminated by the safety committee after recrutiment of around 7000 patients because of a raised risk of severe bleeding not compensated by any reduction in ischemic events. The learning experiences form these trials concerning both clinical outcome and underlying mechanisms as evaluated by serial biomarkers are currently under analyses and reporting.
The clinical efficacy and safety of the new reversible P2Y12 inhibitor ticagrelor versus clopidogrel was investigated and reported in the international PLATO trial including 18624 patients with ST-elevation and non-ST-elevation acute coronary syndrome. The results showed that ticagrelor versus clopidogrel improved survival, reduced myocardial infarction and stent thrombosis without increasing the overall risk of bleeding. In a series of subgroup reports consistent results were shown in patients with a planned invasive treatment strategy, with ST-elevation and non-ST-elevation acute coronary syndrome, with a need for CABG, with renal dysfunction, with diabetes and regardless of treatment with proton pump inhibitors. In a platelet substudy ticagrelor was verified to provide more pronounced and consistent inhibition than clopidogrel. The underlying mechanisms and the minimal importance of bradyarrhythmias and dyspnoea with ticagrelor have also been presented.
The clinical efficacy and safety of the now oral direct thrombin inhibitor dabigatran was investigated and reported in the international RELY trial including 18113 patients with atrial fibrillation and a raised risk of stroke. The results showed that dabigatran compared to warfarin reduced ischemic and hemorrhagic stroke and cardiovascular mortality and simultaneously reduced the risk of severe bleeding. In a series of subgroup reports the results have been show to be consistent regardless of previous treatment with warfarin and regardless of the CHADS-score risk classification. The recent approval and recommendation of dabigatran as the most effective oral anticoagulant for stroke prevention in atrial fibrillation was facilitated by the convincing results from the scientific substudy program.
Currently the group is also leading a similar program comparing the new oral fXa inhibitor apixaban versus warfarin for stroke prevention in 18221 patient with atrial fibrillation and a raised risk of stroke (ARISTOTLE). The results from this study will be presented in 2011. Also in this study an extensive biochemical and genetic substudy program investigates the underlying mechanisms and verify the importance of biomarkers for risk stratification in atrial fibrillation.
National coordinator and member of the executive committee for the global RCT, TRACER, comparing a thromin receptor inhibitor with placebo in ACS.
The group is also since two years leading the first phase III trial of a pure anti-inflammatory agent for seondary prevention in patients with coronary atherosclerosis. The STABILITY trial evaluates the clinical efficacy of darapladib inhibiting lipoprotein bound phosphoplipase-A2 versus placebo in around 15000 patients for 3 – 4 years. Additional scientific assets in the study are a substudy of implementation of adherence to current treatment guide-lines, a life-style substudy, a mental status substudy and finally a biomarker and genetics program. This study will be concluded in 2014.
National coordinator (Claes Held) for the HOPE-3 trial that evaluates rosuvastatin and/or candesartan/hydroklortiazid compared with placebo to patients without overt cardiac disease but moderately elevated risk for CAD.
Meta analyses of four phase II studies with new oral anticoagulants after acute coronary syndromes. Manuscript under preparation.
Leading the first large scale randomized study in the world completely driven within the framework of a quality registry: Thrombus aspiration in ST- Elevation myocardial infarction in Scandinavia (TASTEtrial). A multicenter, prospective, randomized controlled clinical registry trial based on the Swedish angiography and angioplasty registry (SCAAR) platform. All 29 PCI centres in Sweden participates.
Comparison of eptifibatide and abciximab in primary percutaneous coronary intervention. This is an example of how a quality registry (Swedeheart/SCAAR) might be used for evaluating treatment in clinical routine.
Implementation of treatment
During 2010 the results of the randomized quality improvement study: European Quality Improvement Programme for Acute Coronary Syndrome (EQUIP) have been analyzed and submitted for publication. The study lead by our group in collaboration with M. Flather, London, and performed in UK, France, Poland, Spain and Italy, showed that a systematic improvement program can significantly improve the management of non-ST elevation acute coronary syndromes.
The long-term analysis of the Swedish Quality Improvement study in AMI, QUICC, was published showing improved clinical outcome in hospitals participating in a Swedish quality improvement initiative.