CONGRESS REPORT
The emerging role
of
the platelet in the
progression and management atherothrombotic disease (American Heart Association Meeting, Louisiana, November 2004)
of
New
Orleans,
The satellite session on the role of patients who have arterial inflam- over 150,000 subjects, indicating platelets in the progression and mation. Also circulating endotheial the benefits of long-term antimanagement of atherothrombotic cells (CECs) were found to be an platelet therapy in prevention of disease was chaired by E. Magnus early and specific marker of arterial cardiovascular death, myocardial Ohman (North Carolina, US). This inflammation which is independent infarction, and stroke in high-risk session was sponsored by the of troponin for non-ST-elevation vascular patients. Administration of University of Michigan Medical acute coronary syndrome (ACS). clopidogrel before percutaneous School supported by an educational The role of adipocytes in inflam- coronary intervention (PCI) results grant from the Bristol-Myers mation was also discussed. Adipo- in reduced levels of sCD40L, PSquibb/Sanofi-Synthelabo partner- cytes, previously perceived as being selectin and CRP after the proship. The topic of this session was inert cells, have now been shown to cedure. This implies that in addition the role of inflammation in the play a vital role in driving arterial to the direct effect on platelet inpathophysiological process leading inflammation, through elaboration hibition, these agents may also exert to the development of athero- of fat cell proteins such as their effect through attenuation of thrombosis. Atherothrombosis is adiponectin, leptin, resistin, and the inflammatory process. New characterised by a sudden athero- interleukin-6. Finally, the specific clinical trials will be investigating sclerotic plaque disruption leading and independent markers for risk of the use of combination therapies to platelet activation and thrombus MI or death in ACS, soluble CD40 for acute myocardial infarction formation. Atherothrombosis is a ligant (sCD40L) and myeloperoxid- (CLARITY), conditions such as common pathological cause of all ase were discussed. Myeloperoxidase atrial fibrillation where vascular major clinical manifestations of levels are an especially good pre- events are due to a combination of vascular disease, such as myocardial dictor of MI or death when troponin venous and arterial thrombotic infarction, ischaemic stroke, angina, T levels are low, in patients with events (ACTIVE), and for secondtransient ischaemic attack and per- ACS. High levels of sCD40L were ary prevention (CHARISMA) and ipheral arterial disease. Athero- found to be predictive ofenhanced strokes (PROFESS). While antithrombosis a leading cause of death inflammatory response and re- platelet agents have become an stenosis after coronary angioplasty. integral part of the management of worldwide. The testing of panels of marker patients with vascular disease, more Central role of Inflammation In proteins will make for easier and evidence is needed in high-risk more accurate gauging of the in- primary prevention settings such as atherothrombosis patients with diabetes, those with E. Topol (Ohio, US) discussed recent flammation process in the future. metabolic syndrome, as well as in a findings that stress the importance number ofother conditions that are of inflammation as the trigger for Benefit of antiplatelet therapy related to thrombotic events, atherothrombotic events. The role beyond acute ischaemic events of high-sensitivity C reactive protein S. Yusuf (Ontario, Canada) pre- according to the speaker. (CRP) as both a marker and me- sented a large body of data based diator of inflammation has been on more than 300 trials, involving New horizons: ongoing clinical trials and their potential Impact established through studies introIn clinical practice ducing CRP into mice (a species J. van Tuyn, M. Sabaine (Boston, US) discussed that does not carry the CRP gene) Leiden University Medical Centre, Leiden. data from ongoing clinical trials on and sampling the coronary sinus of E-mail: [email protected] 24
N2tharlands Heart Journal, Volume 13, Number 1, January 2005
CONGRESS REPORT
the use of clopidogrel across the spectrum of coronary atherothrombosis. Clopidogrel, an ADPreceptor antagonist, is well established as an integral part ofthe antiplatelet regimen after PCI using a stent. Data from the CREDO (Clopidogrel for the Reduction of Events During Observation) study support pre-treatment with dopidogrel in the setting of PCI as well as prolonged treatment for up to one year after PCI. However, the optimal dose and timing of dopidogrel pre-PCI requires further study. The addition of clopidogrel to standard therapy with aspirin and heparin in patients with non-ST-elevation ACS in the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial resulted in a statistically significant 20% reduction in the composite of cardiovascular death, MI or stroke. Subsequent analysis revealed that the benefits ofdopidogrel existed across all risk strata, were apparent within hours of receiving the loading dose, and appeared to outweigh the risk, even in patients who proceeded to CABG during the index hospitalisation. Next, the speaker discussed the use of dopidogrel for patients with ST-elevation MI undergoing fibrinolysis, in whom infarct-related artery reocclusion is a major cause of morbidity and mortality. Preliminary data from pilot studies suggest a benefit for clopidogrel, and two large-scale clinical trials, CLARITYTIMI 28 and COMMIT, are currently studying the issue. In patients with a history of atherosclerotic disease, clopidogrel alone was shown to be marginally superior to aspirin alone in the CAPRIE trial. The ongoing CHARISMA trial is now examining clopidogrel plus aspirin against aspirin alone in this
population.
Emerging Issues In thlenopyridine therapy S. Steinhubl (Lexington, US) focussed on the inter-individual
variability in response to clopidogrel. A small subset of patients
treated with antiplatelet agents sustain an ischaemic event while on therapy. Such events likely result from multiple mechanisms, both genetic and environmental, one of which may be variability in the response to the antiplatelet agent. Ongoing clinical investigations are evaluating the response of antiplatelet agents on a variety of emerging laboratory tests to assess platelet aggregation and activity. One possible target may be the P2Yl2 receptor, which was found to influence arterial thrombosis in animal models. Data from CREDO suggest that inflammatory status (as measured by CRP levels) appears to influence the degree of benefit of antiplatelet therapy, but this requires further research. A new clinical study that may provide more insight here is RESISTOR (Research Evaluation to Study Individuals who Show Thromboxane Or P2Y12 Receptor Resistance). However, according to the speaker, no tests have yet been shown to be predictive ofrelevant clinical outcomes. Until future investigations delineate the clinical relevance of assays on platelet activity, antiplatelet therapy for an individual patient should be directed by the current evidencebased medical literature relevant to the specific medical condition.
Measuring performance: Improving patient outcomes through guideline adherence E. Magnus Obman (North Carolina, US) discussed recent findings from CRUSADE (Can rapid risk stratification ofunstable patients suppress adverse outcomes with early implementation ofAmerican College of Cardiology/American Heart Association guidelines) a collaborative project between emergency medicine and cardiology with the aim to explore whether ACC/ AHA-recommended therapies were applied in different hospitals and to improve adherence to ACC/AHA guidelines. To date approximately 102,000 patients from 422 active sites all over the US have been
Netherands Heart Journal, Volume 13, Number 1, January 2005
recruited. CRUSADE is now in its quality improvement phase (CRUSADE CQI project), where hospitals are provided with strategies to improve adherence to ACC/ AHA guidelines. CRUSADE CQI has identified significant gaps in adherence to the AHA/ACC guidelines. A recent adherence GAP analysis of 45,000 physicians in California showed that the percentage of patients receiving the recommended care for hypertension, congestive heart failure, colon cancer, diabetes and hip fracture was only 65, 64, 56, 45 and 23%, respectively. Analysis among participating hospitals demonstrated that hospitals with better overall adherence to guidelines had reduced mortality rates. According to the national committee for quality assurance the cost of failure to deliver best-practice care is 57,000 deaths and $1.6 billion in avoidable hospital costs per year. As part ofthe CRUSADE CQI project, the centre for medicare and medicaid services will introduce pay-for-performance based compensation for 20 to 30% ofphysicians' salary in the next five to ten years. Pacificare health care reported a 3 to 5% improvement in physician performance over three years from 1998 to 2001, however after one year of starting to pay bonuses the improvement was 34%.
Conclusions Ever more data support the use of dual antiplatelet therapy in established and in new patient groups. The mechanisms through which antiplatelet agents work are under investigation. The clinical implications of inter-patient variability in response to antiplatelet agents are currently still unknown, and need to be further investigated. In the future, testing a panel ofbiomarker proteins will allow for more accurate gauging of the inflammation process, and easier recognition of patients at risk. At present, patient care in many hospitals can be improved by better guideline adherence. U
25
The emerging role
of
the platelet in the
progression and management atherothrombotic disease (American Heart Association Meeting, Louisiana, November 2004)
of
New
Orleans,
The satellite session on the role of patients who have arterial inflam- over 150,000 subjects, indicating platelets in the progression and mation. Also circulating endotheial the benefits of long-term antimanagement of atherothrombotic cells (CECs) were found to be an platelet therapy in prevention of disease was chaired by E. Magnus early and specific marker of arterial cardiovascular death, myocardial Ohman (North Carolina, US). This inflammation which is independent infarction, and stroke in high-risk session was sponsored by the of troponin for non-ST-elevation vascular patients. Administration of University of Michigan Medical acute coronary syndrome (ACS). clopidogrel before percutaneous School supported by an educational The role of adipocytes in inflam- coronary intervention (PCI) results grant from the Bristol-Myers mation was also discussed. Adipo- in reduced levels of sCD40L, PSquibb/Sanofi-Synthelabo partner- cytes, previously perceived as being selectin and CRP after the proship. The topic of this session was inert cells, have now been shown to cedure. This implies that in addition the role of inflammation in the play a vital role in driving arterial to the direct effect on platelet inpathophysiological process leading inflammation, through elaboration hibition, these agents may also exert to the development of athero- of fat cell proteins such as their effect through attenuation of thrombosis. Atherothrombosis is adiponectin, leptin, resistin, and the inflammatory process. New characterised by a sudden athero- interleukin-6. Finally, the specific clinical trials will be investigating sclerotic plaque disruption leading and independent markers for risk of the use of combination therapies to platelet activation and thrombus MI or death in ACS, soluble CD40 for acute myocardial infarction formation. Atherothrombosis is a ligant (sCD40L) and myeloperoxid- (CLARITY), conditions such as common pathological cause of all ase were discussed. Myeloperoxidase atrial fibrillation where vascular major clinical manifestations of levels are an especially good pre- events are due to a combination of vascular disease, such as myocardial dictor of MI or death when troponin venous and arterial thrombotic infarction, ischaemic stroke, angina, T levels are low, in patients with events (ACTIVE), and for secondtransient ischaemic attack and per- ACS. High levels of sCD40L were ary prevention (CHARISMA) and ipheral arterial disease. Athero- found to be predictive ofenhanced strokes (PROFESS). While antithrombosis a leading cause of death inflammatory response and re- platelet agents have become an stenosis after coronary angioplasty. integral part of the management of worldwide. The testing of panels of marker patients with vascular disease, more Central role of Inflammation In proteins will make for easier and evidence is needed in high-risk more accurate gauging of the in- primary prevention settings such as atherothrombosis patients with diabetes, those with E. Topol (Ohio, US) discussed recent flammation process in the future. metabolic syndrome, as well as in a findings that stress the importance number ofother conditions that are of inflammation as the trigger for Benefit of antiplatelet therapy related to thrombotic events, atherothrombotic events. The role beyond acute ischaemic events of high-sensitivity C reactive protein S. Yusuf (Ontario, Canada) pre- according to the speaker. (CRP) as both a marker and me- sented a large body of data based diator of inflammation has been on more than 300 trials, involving New horizons: ongoing clinical trials and their potential Impact established through studies introIn clinical practice ducing CRP into mice (a species J. van Tuyn, M. Sabaine (Boston, US) discussed that does not carry the CRP gene) Leiden University Medical Centre, Leiden. data from ongoing clinical trials on and sampling the coronary sinus of E-mail: [email protected] 24
N2tharlands Heart Journal, Volume 13, Number 1, January 2005
CONGRESS REPORT
the use of clopidogrel across the spectrum of coronary atherothrombosis. Clopidogrel, an ADPreceptor antagonist, is well established as an integral part ofthe antiplatelet regimen after PCI using a stent. Data from the CREDO (Clopidogrel for the Reduction of Events During Observation) study support pre-treatment with dopidogrel in the setting of PCI as well as prolonged treatment for up to one year after PCI. However, the optimal dose and timing of dopidogrel pre-PCI requires further study. The addition of clopidogrel to standard therapy with aspirin and heparin in patients with non-ST-elevation ACS in the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial resulted in a statistically significant 20% reduction in the composite of cardiovascular death, MI or stroke. Subsequent analysis revealed that the benefits ofdopidogrel existed across all risk strata, were apparent within hours of receiving the loading dose, and appeared to outweigh the risk, even in patients who proceeded to CABG during the index hospitalisation. Next, the speaker discussed the use of dopidogrel for patients with ST-elevation MI undergoing fibrinolysis, in whom infarct-related artery reocclusion is a major cause of morbidity and mortality. Preliminary data from pilot studies suggest a benefit for clopidogrel, and two large-scale clinical trials, CLARITYTIMI 28 and COMMIT, are currently studying the issue. In patients with a history of atherosclerotic disease, clopidogrel alone was shown to be marginally superior to aspirin alone in the CAPRIE trial. The ongoing CHARISMA trial is now examining clopidogrel plus aspirin against aspirin alone in this
population.
Emerging Issues In thlenopyridine therapy S. Steinhubl (Lexington, US) focussed on the inter-individual
variability in response to clopidogrel. A small subset of patients
treated with antiplatelet agents sustain an ischaemic event while on therapy. Such events likely result from multiple mechanisms, both genetic and environmental, one of which may be variability in the response to the antiplatelet agent. Ongoing clinical investigations are evaluating the response of antiplatelet agents on a variety of emerging laboratory tests to assess platelet aggregation and activity. One possible target may be the P2Yl2 receptor, which was found to influence arterial thrombosis in animal models. Data from CREDO suggest that inflammatory status (as measured by CRP levels) appears to influence the degree of benefit of antiplatelet therapy, but this requires further research. A new clinical study that may provide more insight here is RESISTOR (Research Evaluation to Study Individuals who Show Thromboxane Or P2Y12 Receptor Resistance). However, according to the speaker, no tests have yet been shown to be predictive ofrelevant clinical outcomes. Until future investigations delineate the clinical relevance of assays on platelet activity, antiplatelet therapy for an individual patient should be directed by the current evidencebased medical literature relevant to the specific medical condition.
Measuring performance: Improving patient outcomes through guideline adherence E. Magnus Obman (North Carolina, US) discussed recent findings from CRUSADE (Can rapid risk stratification ofunstable patients suppress adverse outcomes with early implementation ofAmerican College of Cardiology/American Heart Association guidelines) a collaborative project between emergency medicine and cardiology with the aim to explore whether ACC/ AHA-recommended therapies were applied in different hospitals and to improve adherence to ACC/AHA guidelines. To date approximately 102,000 patients from 422 active sites all over the US have been
Netherands Heart Journal, Volume 13, Number 1, January 2005
recruited. CRUSADE is now in its quality improvement phase (CRUSADE CQI project), where hospitals are provided with strategies to improve adherence to ACC/ AHA guidelines. CRUSADE CQI has identified significant gaps in adherence to the AHA/ACC guidelines. A recent adherence GAP analysis of 45,000 physicians in California showed that the percentage of patients receiving the recommended care for hypertension, congestive heart failure, colon cancer, diabetes and hip fracture was only 65, 64, 56, 45 and 23%, respectively. Analysis among participating hospitals demonstrated that hospitals with better overall adherence to guidelines had reduced mortality rates. According to the national committee for quality assurance the cost of failure to deliver best-practice care is 57,000 deaths and $1.6 billion in avoidable hospital costs per year. As part ofthe CRUSADE CQI project, the centre for medicare and medicaid services will introduce pay-for-performance based compensation for 20 to 30% ofphysicians' salary in the next five to ten years. Pacificare health care reported a 3 to 5% improvement in physician performance over three years from 1998 to 2001, however after one year of starting to pay bonuses the improvement was 34%.
Conclusions Ever more data support the use of dual antiplatelet therapy in established and in new patient groups. The mechanisms through which antiplatelet agents work are under investigation. The clinical implications of inter-patient variability in response to antiplatelet agents are currently still unknown, and need to be further investigated. In the future, testing a panel ofbiomarker proteins will allow for more accurate gauging of the inflammation process, and easier recognition of patients at risk. At present, patient care in many hospitals can be improved by better guideline adherence. U
25
