MAIN SESSION
Acute coronary syndrome without ST
elevation:
what
is new?
Stockholm, 4 September 2005 The purpose of this main session, organised by the European Society of Cardiology and the American College of Cardiology, was to provide an overview of recent developments in the diagnosis and treatment of patients with non-ST-elevation acute coronary syndromes (ACS). KM. Fox (London, UK) and RA. Harrington (Durham, US) chaired the session.
infarction or heart failure. In summary, troponin and BNP are the biomarkers that are closest to meeting criteria as an ideal biomaker with prognostic and therapeutic implications. Inflammation markers show promise, but there is no clear winner yet. In the future, multimarker strategies that incorporate panels of cardiac biomarkers are likely to emerge as an important clinical tool.
The first speaker,J.A. De Lemos(Dallas, US), focussed on the use of novel biomarkers. Cardiac biomarkers play an important role in risk stratification and choice of treatment strategy for patients with ACS. Over the past decade, there has been a progressive evolution of cardiac marker testing. The superiority of troponin T and I measurement in the diagnosis of myocardial damage has been clearly demonstrated in numerous studies. In addition to biomarkers of myocyte necrosis, markers of neurohormonal activation, such as B-type natriuretic peptide (BNP), have recently shown to be a great predictor of short- and long-term prognosis in patients with non-ST-elevation ACS. Other promising biomarkers are high-sensitivity C-reactive protein (hsCRP, a marker of inflammation), myeloperoxidase (another marker of inflammation) and soluble CD40 ligand. Recently it was shown that high hs-CRP levels are an independent predictor of two-year clinical outcome in patients with ACS. The TACTICS-TIMI-18 (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombosis in Myocardial Infarction-18) investigators assessed whether the use ofa multimarker panel (using troponin, hs-CRP and BNP) identified more patients (with nonST-elevation ACS) at elevated risk than a strategy that solely used CK-MB or troponin. The 30-day risk of death increased in proportion to the number of cardiac biomarkers elevated at baseline, with a near doubling ofthe mortality risk for each additional biomarker that was elevated. An increasing number ofpositive markers conferred an increasing risk of death, myocardial
F.E. Rademakers (Leuven, Belgium) discussed the role of noninvasive imaging modalities in the diagnosis of ACS. Noninvasive imaging in patients with non-STelevation ACS allows risk stratification, evaluation of infarct size and evaluation of the myocardial area at risk, which has a great impact on patient management. Several methods have been introduced to measure the infarct size and myocardial area at risk. Nuclear imaging techniques are currently well-accepted and validated clinical tools for the quantification ofinfarct size and extent ofischaemia/area at risk. However, with modem acquisition techniques, MRI can gather information on the myocardial function, perfusion, viability and coronary anatomy in a single scanning session. The myocardial area at risk can be easily measured by distracting the area with delayed enhancement from the area with myocardial oedema. Recently, strain rate imaging with echo was introduced as a new technique to determine the transmural extent of myocardial infarction. Zhang et al. demonstrated that peak myocardial deformation by stain rate imaging could differentiate transmural from nontransmural infarction. Currently, the use of CT in the diagnosis ofACS is still in an early stage and the technique should be improved to gather information of value. In future, plaque imaging with CT is likely to emerge as a new diagnostic tool. The speaker concluded 'although more studies investigating the cost-effectiveness of noninvasive imaging are warranted, there is enough evidence that noninvasive imaging should have a role in the stratification of patients with non-ST-elevation ACS'.
S.LM.A. Beems Leiden University Medical Center, Leiden E-mail: [email protected]
ML. Simoons(Rotterdam, the Netherlands) provided an overview of recent developments in the use of antiplatelet drugs in the treatment of patients with non-ST-elevation ACS. Numerous studies investi-
12
Netherlands Heart Journal, Volume 13, Supplement 2, November 2005 Cis
27th Congress of the European Society of Cardiology
gating the effect of aspirin drew similar, impressive conclusions: aspirin therapy results in a major risk reduction in any serious vascular adverse events. However, evidence is mounting that aspirin alone 'is not enough'. Most patients take advantage of the concomitant use ofclopidogrel, although the absolute beneficial effect of clopidogrel on top of aspirin therapy is modest (absolute risk reduction 2%). The use of antiplatelet therapy in non-ST-elevation ACS is further witnessed by the reduction in major clinical outcomes by using parenteral glycoprotein IIb/IIIa receptor blockers. Concomitant glycoprotein IIb/IIIa inhibition in patients treated with percutaneous coronary intervention resulted in an absolute 1% decline of 30day mortality and myocardial infarction rate. No beneficial effect of IIb/AIIa receptor antagonists could be demonstrated on top ofaspirin/clopidogrel therapy in conservatively treated patients, nor in patients undergoing elective percutaneous coronary intervention. Beneficial evidence has to be weighted against the moderate increased risk of bleeds with the use of clopidogrel and glycoprotein IIb/AIla inhibition. In addition, a recent review stressed the high rate of treatment failure with any antiplatelet treatment regimen due to drug resistance. It is estimated that 8 to 56% of all ACS patients do not adequately respond to aspirin, whereas 25% respond inadequately to clopidogrel. Key challenges for future research are to standardise a definition ofaspirin resistance and to compare whether different measures of platelet activation, either alone or in combination, independently predict cardiovascular event. The fourth speaker, D.L. Bhatt (Cleveland, US), discussed recently published trials regarding the role of antithrombotic therapy in ACS. Two randomised studies have shown an improved global outcome by the combination of aspirin plus warfarin when compared with aspirin alone for patients with ACS. SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularisation and Glycoprotein Ilb/IIIa Inhibitors) compared the outcomes of patients with non-STsegment elevation ACS treated with enoxaparin vs. unfractionated heparin combined with an early invasive strategy. At 30-day follow-up, there was no difference in the composite endpoint of all-cause mortality or nonfatal myocardial infarction. OASIS-5 (Organisation to Assess Strategies for Ischaemic Syndromes) showed that fondaparinux, a new antithrombotic therapy, was as effective as enoxaparin in preventing heart attacks, death and ischaemia (reduction in blood supply to the tissues) nine days after an event but demonstrated a dramatic reduction in major bleeding. Cangelor is a new injectable short-acting antithrombotic drug that prevents the activation and
#W
Netherlands Heart Joumnal, Volume 13, Supplement 2, November 2005
aggregation ofplatelets in the clotting process. It acts directly on the P2Y12 platelet receptor. Initial clinical studies show that cangelor does not increase bleeding rates and is as effective as clopidogrel. Furthermore, the combination of cangelor and clopidogrel confers greater antagonism of P2Y12 than either antagonist alone. The speaker concluded that an early invasive treatment strategy with concomitant antithrombotic and antiplatelet therapy is preferred for patients with a non-ST-segment elevation acute coronary syndrome. Future studies should investigate the optimal timing and combination of antithrombotic drugs. Finally, S.M. Cobbe (Glasgow, UK), focussed on how and when to prescribe statins. In the last decade, three large randomised trials have investigated the safety and efficacy of statin treatment early afterACS: MIRACLE (Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering), the A to Z (Aggrastat to Zocor) and PROVE IT (Pravastatin orAtorvastatin Evaluation and Infection Therapy). Although a significant reduction in the primary clinical endpoint was reported in the MIRACLE and the PROVE IT, no clear beneficial effect was seen in the A to Z study. As the magnitude of LDL cholesterol (LDL-C) reduction in the A to Z trial was larger than the magnitude of LDLC reduction in PROVE IT, other mechanisms than only LDL-C lowering might have contributed to this discrepancy. There is accumulating evidence that statins reduce LDL-C, but also improve endothelial and platelet function, inhibit coagulation and last but not least reduce inflammation. In both PROVE IT arms, statin treatment reduced plasma CRP values. Interestingly, there was almost no correlation between the magnitude of treatment effect on LDL-C and the magnitude of the effect on CRP. Moreover, at 2.5 year follow-up, the vascular event rate was lower in patients with plasma CRP
Acute coronary syndrome without ST
elevation:
what
is new?
Stockholm, 4 September 2005 The purpose of this main session, organised by the European Society of Cardiology and the American College of Cardiology, was to provide an overview of recent developments in the diagnosis and treatment of patients with non-ST-elevation acute coronary syndromes (ACS). KM. Fox (London, UK) and RA. Harrington (Durham, US) chaired the session.
infarction or heart failure. In summary, troponin and BNP are the biomarkers that are closest to meeting criteria as an ideal biomaker with prognostic and therapeutic implications. Inflammation markers show promise, but there is no clear winner yet. In the future, multimarker strategies that incorporate panels of cardiac biomarkers are likely to emerge as an important clinical tool.
The first speaker,J.A. De Lemos(Dallas, US), focussed on the use of novel biomarkers. Cardiac biomarkers play an important role in risk stratification and choice of treatment strategy for patients with ACS. Over the past decade, there has been a progressive evolution of cardiac marker testing. The superiority of troponin T and I measurement in the diagnosis of myocardial damage has been clearly demonstrated in numerous studies. In addition to biomarkers of myocyte necrosis, markers of neurohormonal activation, such as B-type natriuretic peptide (BNP), have recently shown to be a great predictor of short- and long-term prognosis in patients with non-ST-elevation ACS. Other promising biomarkers are high-sensitivity C-reactive protein (hsCRP, a marker of inflammation), myeloperoxidase (another marker of inflammation) and soluble CD40 ligand. Recently it was shown that high hs-CRP levels are an independent predictor of two-year clinical outcome in patients with ACS. The TACTICS-TIMI-18 (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombosis in Myocardial Infarction-18) investigators assessed whether the use ofa multimarker panel (using troponin, hs-CRP and BNP) identified more patients (with nonST-elevation ACS) at elevated risk than a strategy that solely used CK-MB or troponin. The 30-day risk of death increased in proportion to the number of cardiac biomarkers elevated at baseline, with a near doubling ofthe mortality risk for each additional biomarker that was elevated. An increasing number ofpositive markers conferred an increasing risk of death, myocardial
F.E. Rademakers (Leuven, Belgium) discussed the role of noninvasive imaging modalities in the diagnosis of ACS. Noninvasive imaging in patients with non-STelevation ACS allows risk stratification, evaluation of infarct size and evaluation of the myocardial area at risk, which has a great impact on patient management. Several methods have been introduced to measure the infarct size and myocardial area at risk. Nuclear imaging techniques are currently well-accepted and validated clinical tools for the quantification ofinfarct size and extent ofischaemia/area at risk. However, with modem acquisition techniques, MRI can gather information on the myocardial function, perfusion, viability and coronary anatomy in a single scanning session. The myocardial area at risk can be easily measured by distracting the area with delayed enhancement from the area with myocardial oedema. Recently, strain rate imaging with echo was introduced as a new technique to determine the transmural extent of myocardial infarction. Zhang et al. demonstrated that peak myocardial deformation by stain rate imaging could differentiate transmural from nontransmural infarction. Currently, the use of CT in the diagnosis ofACS is still in an early stage and the technique should be improved to gather information of value. In future, plaque imaging with CT is likely to emerge as a new diagnostic tool. The speaker concluded 'although more studies investigating the cost-effectiveness of noninvasive imaging are warranted, there is enough evidence that noninvasive imaging should have a role in the stratification of patients with non-ST-elevation ACS'.
S.LM.A. Beems Leiden University Medical Center, Leiden E-mail: [email protected]
ML. Simoons(Rotterdam, the Netherlands) provided an overview of recent developments in the use of antiplatelet drugs in the treatment of patients with non-ST-elevation ACS. Numerous studies investi-
12
Netherlands Heart Journal, Volume 13, Supplement 2, November 2005 Cis
27th Congress of the European Society of Cardiology
gating the effect of aspirin drew similar, impressive conclusions: aspirin therapy results in a major risk reduction in any serious vascular adverse events. However, evidence is mounting that aspirin alone 'is not enough'. Most patients take advantage of the concomitant use ofclopidogrel, although the absolute beneficial effect of clopidogrel on top of aspirin therapy is modest (absolute risk reduction 2%). The use of antiplatelet therapy in non-ST-elevation ACS is further witnessed by the reduction in major clinical outcomes by using parenteral glycoprotein IIb/IIIa receptor blockers. Concomitant glycoprotein IIb/IIIa inhibition in patients treated with percutaneous coronary intervention resulted in an absolute 1% decline of 30day mortality and myocardial infarction rate. No beneficial effect of IIb/AIIa receptor antagonists could be demonstrated on top ofaspirin/clopidogrel therapy in conservatively treated patients, nor in patients undergoing elective percutaneous coronary intervention. Beneficial evidence has to be weighted against the moderate increased risk of bleeds with the use of clopidogrel and glycoprotein IIb/AIla inhibition. In addition, a recent review stressed the high rate of treatment failure with any antiplatelet treatment regimen due to drug resistance. It is estimated that 8 to 56% of all ACS patients do not adequately respond to aspirin, whereas 25% respond inadequately to clopidogrel. Key challenges for future research are to standardise a definition ofaspirin resistance and to compare whether different measures of platelet activation, either alone or in combination, independently predict cardiovascular event. The fourth speaker, D.L. Bhatt (Cleveland, US), discussed recently published trials regarding the role of antithrombotic therapy in ACS. Two randomised studies have shown an improved global outcome by the combination of aspirin plus warfarin when compared with aspirin alone for patients with ACS. SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularisation and Glycoprotein Ilb/IIIa Inhibitors) compared the outcomes of patients with non-STsegment elevation ACS treated with enoxaparin vs. unfractionated heparin combined with an early invasive strategy. At 30-day follow-up, there was no difference in the composite endpoint of all-cause mortality or nonfatal myocardial infarction. OASIS-5 (Organisation to Assess Strategies for Ischaemic Syndromes) showed that fondaparinux, a new antithrombotic therapy, was as effective as enoxaparin in preventing heart attacks, death and ischaemia (reduction in blood supply to the tissues) nine days after an event but demonstrated a dramatic reduction in major bleeding. Cangelor is a new injectable short-acting antithrombotic drug that prevents the activation and
#W
Netherlands Heart Joumnal, Volume 13, Supplement 2, November 2005
aggregation ofplatelets in the clotting process. It acts directly on the P2Y12 platelet receptor. Initial clinical studies show that cangelor does not increase bleeding rates and is as effective as clopidogrel. Furthermore, the combination of cangelor and clopidogrel confers greater antagonism of P2Y12 than either antagonist alone. The speaker concluded that an early invasive treatment strategy with concomitant antithrombotic and antiplatelet therapy is preferred for patients with a non-ST-segment elevation acute coronary syndrome. Future studies should investigate the optimal timing and combination of antithrombotic drugs. Finally, S.M. Cobbe (Glasgow, UK), focussed on how and when to prescribe statins. In the last decade, three large randomised trials have investigated the safety and efficacy of statin treatment early afterACS: MIRACLE (Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering), the A to Z (Aggrastat to Zocor) and PROVE IT (Pravastatin orAtorvastatin Evaluation and Infection Therapy). Although a significant reduction in the primary clinical endpoint was reported in the MIRACLE and the PROVE IT, no clear beneficial effect was seen in the A to Z study. As the magnitude of LDL cholesterol (LDL-C) reduction in the A to Z trial was larger than the magnitude of LDLC reduction in PROVE IT, other mechanisms than only LDL-C lowering might have contributed to this discrepancy. There is accumulating evidence that statins reduce LDL-C, but also improve endothelial and platelet function, inhibit coagulation and last but not least reduce inflammation. In both PROVE IT arms, statin treatment reduced plasma CRP values. Interestingly, there was almost no correlation between the magnitude of treatment effect on LDL-C and the magnitude of the effect on CRP. Moreover, at 2.5 year follow-up, the vascular event rate was lower in patients with plasma CRP
