Report of the European Society of Cardiology Cardiovascular Round Table regulatory workshop update of the evaluation of new agents for the treatment of acute coronary syndrome: Executive summary
Restricted accessResearch articleFirst published online December, 2019
Report of the European Society of Cardiology Cardiovascular Round Table regulatory workshop update of the evaluation of new agents for the treatment of acute coronary syndrome: Executive summary
Regulatory authorities interpret the results of randomized controlled trials according to published principles. The European Medicines Agency (EMA) is planning a revision of the 2000 and 2003 guidance documents on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (ACS) to achieve consistency with current knowledge in the field. This manuscript summarizes the key output from a collaborative workshop, organized by the Cardiovascular Round Table and the European Affairs Committee of the European Society of Cardiology, involving clinicians, academic researchers, trialists, European and US regulators, and pharmaceutical industry researchers. Specific questions in four key areas were selected as priorities for changes in regulatory guidance: patient selection, endpoints, methodologic issues and issues related to the research for novel agents. Patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) should be studied separately for therapies aimed at the specific pathophysiology of either condition, particularly for treatment of the acute phase, but can be studied together for other treatments, especially long-term therapy. Unstable angina patients should be excluded from acute phase ACS trials. In general, cardiovascular death and reinfarction are recommended for primary efficacy endpoints; other endpoints may be considered if specifically relevant for the therapy under study. New agents or interventions should be tested against a background of evidence-based therapy with expanded follow-up for safety assessment. In conclusion, new guidance documents for randomized controlled trials in ACS should consider changes regarding patient and endpoint selection and definitions, and trial designs. Specific requirements for the evaluation of novel pharmacological therapies need further clarification.
European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Concept paper on the need for revision of the points to consider on the clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98 and CPMP/EWP/967/01), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500175594.pdf (2014, accessed on 22 April 2015).
4.
ThygesenKAlpertJSJaffeAS, et al. Third universal definition of myocardial infarction. Eur Heart J2012; 33: 2551–2567.
5.
FoxKAAndersonFAJrGoodmanSG, et al. Time course of events in acute coronary syndromes: Implications for clinical practice from the GRACE registry. Nat Clin Pract Cardiovasc Med2008; 5: 580–589.
6.
MontalescotGDallongevilleJVanBE, et al. STEMI and NSTEMI: Are they so different? 1 Year outcomes in acute myocardial infarction as defined by the ESC/ACC definition (the OPERA registry). Eur Heart J2007; 28: 1409–1417.
7.
FoxKACarruthersKFDunbarDR, et al. Underestimated and under-recognized: The late consequences of acute coronary syndrome (GRACE UK-Belgian Study). Eur Heart J2010; 31: 2755–2764.
8.
StegPGJamesSKAtarD, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J2012; 33: 2569–2619.
9.
RoffiMPatronoCColletJP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J2016; 37: 267–315.
10.
GershlickAHKhanJNKellyDJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: The CvLPRIT trial. J Am Coll Cardiol2015; 65: 963–972.
11.
IbanezBMacayaCSanchez-BruneteV, et al. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. Circulation2013; 128: 1495–1503.
12.
LaylandJOldroydKGCurzenN, et al. Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: The British Heart Foundation FAMOUS-NSTEMI randomized trial. Eur Heart J2015; 36: 100–111.
13.
YusufSZhaoFMehtaSR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med2001; 345: 494–502.
14.
WallentinLBeckerRCBudajA, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med2009; 361: 1045–1057.
15.
WiviottSDBraunwaldEMcCabeCH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes.N Engl J Med2007; 357: 2001–2015.
16.
PittBRemmeWZannadF. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med2003; 348: 1309–1321.
17.
CannonCPBlazingMAGiuglianoRP, et al. Ezetimibe added to statin therapy after acute coronary syndromes.N Engl J Med2015; 372: 2387–2397.
18.
MegaJLBraunwaldEWiviottSD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med2012; 366: 9–19.
19.
MehtaCGaoPBhattDL, et al. Optimizing trial design: Sequential, adaptive, and enrichment strategies. Circulation2009; 119: 597–605.
20.
ShroffGRHeubnerBMHerzogCA. Incidence of acute coronary syndrome in the general Medicare population, 1992 to 2009: A real-world perspective. JAMA Intern Med2014; 174: 1689–1690.
21.
DudasKBjorckLJernbergT, et al. Differences between acute myocardial infarction and unstable angina: A longitudinal cohort study reporting findings from the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). BMJ Open2013; 3.
22.
LohJPPendyalaLKKitabataH, et al. Comparison of outcomes after percutaneous coronary intervention among different coronary subsets (stable and unstable angina pectoris and ST-segment and non-ST-segment myocardial infarction). Am J Cardiol2014; 113: 1794–1801.
23.
D’SouzaMSarkisianLSaabyL, et al. Diagnosis of unstable angina pectoris has declined markedly with the advent of more-sensitive troponin assays. Am J Med2015; 128: 852–860.
24.
KrumholzHMNormandSLWangY. Trends in hospitalizations and outcomes for acute cardiovascular disease and stroke, 1999–2011. Circulation2014; 130: 966–975.
25.
BraunwaldEMorrowDA. Unstable angina: Is it time for a requiem?Circulation2013; 127: 2452–2457.
26.
BonacaMSciricaBSabatineM, et al. Prospective evaluation of the prognostic implications of improved assay performance with a sensitive assay for cardiac troponin I. J Am Coll Cardiol2010; 55: 2118–2124.
27.
MillsNLLeeKKMcAllisterDA, et al. Implications of lowering threshold of plasma troponin concentration in diagnosis of myocardial infarction: Cohort study. Br Med J2012; 344: e1533.
28.
GittAKHochadelMZahnR, et al. Higher in-hospital mortality of NSTEMI as compared to unstable angina despite higher rate of invasive therapy in clinical practice: Results of the EHS ACS Registry [abstract]. J Am Coll Cardiol2015; 65: A189.
29.
FoxKADabbousOHGoldbergRJ, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: Prospective multinational observational study (GRACE). Br Med J2006; 333: 1091.
30.
AntmanEMCohenMBerninkPJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA2000; 284: 835–842.
31.
National Institute for Health Care and Excellence (NICE). Unstable angina and NSTEMI: The early management of unstable angina and non-ST-segment-elevation myocardial infarction, https://www.nice.org.uk/guidance/cg9 (2013, accessed on 5 May 2015).
32.
BoersmaEPieperKSSteyerbergEW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation2000; 101: 2557–2567.
33.
BuenoHFernandez-AvilesF. Use of risk scores in acute coronary syndromes. Heart2012; 98: 162–168.
34.
PocockSBuenoHLicourM, et al. Predictors of one-year mortality at hospital discharge after acute coronary syndromes: A new risk score from the EPICOR (long-tErm follow uP of antithrombotic management patterns In acute CORonary syndrome patients) study. Eur Heart J Acute Cardiovasc Care2015; 4: 509–517.
35.
FoxKAFitzGeraldGPuymiratE, et al. Should patients with acute coronary disease be stratified for management according to their risk? Derivation, external validation and outcomes using the updated GRACE risk score. BMJ Open2014; 4: e004425.
36.
BackusBESixAJKelderJH, et al. Risk scores for patients with chest pain: Evaluation in the emergency department. Curr Cardiol Rev2011; 7: 2–8.
37.
VerheugtFWClemmensenPMehranR, et al. Antithrombotic outcome trials in acute coronary syndromes: Seeking the optimal balance between safety and efficacy. Eur Heart J2013; 34: 1621–1629.
38.
WildiKGimenezMRTwerenboldR, et al. Misdiagnosis of myocardial infarction related to limitations of the current regulatory approach to define clinical decision values for cardiac troponin. Circulation2015; 131: 2032–2040.
39.
SandovalYSmithSWThordsenSE, et al. Supply/demand type 2 myocardial infarction: Should we be paying more attention?J Am Coll Cardiol2014; 63: 2079–2087.
40.
MehranRRaoSVBhattDL, et al. Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the bleeding academic research consortium. Circulation2011; 123: 2736–2747.
41.
SchulmanSKearonC. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost2005; 3: 692–694.
42.
PuteraMRoarkRLopesRD, et al. Translation of acute coronary syndrome therapies: From evidence to routine clinical practice. Am Heart J2015; 169: 266–273.
43.
PocockSJClaytonTCStoneGW. Challenging issues in clinical trial design: Part 4 of a 4-part series on statistics for clinical trials. J Am Coll Cardiol2015; 66: 2886–2898.
44.
van DomburgRTSonnenscheinKNieuwlaatR, et al. Sustained benefit 20 years after reperfusion therapy in acute myocardial infarction. J Am Coll Cardiol2005; 46: 15–20.
45.
FordIMurrayHPackardCJ, et al. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med2007; 357: 1477–1486.
46.
PackardCJFordIMurrayH, et al. Lifetime clinical and economic benefits of statin-based LDL lowering in the 20-year followup of the West of Scotland Coronary Prevention study (AHA late breaking abstract). Circulation2014; 130: 2112.
ArmstrongPWGrangerCBAdamsPX, et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: A randomized controlled trial. JAMA2007; 297: 43–51.
49.
NichollsSJKasteleinJJSchwartzGG, et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: The VISTA-16 randomized clinical trial. JAMA2014; 311: 252–262.
50.
O’DonoghueMLBraunwaldEWhiteHD, et al. Effect of darapladib on major coronary events after an acute coronary syndrome: The SOLID-TIMI 52 randomized clinical trial. JAMA2014; 312: 1006–1015.
RoncalliJMouquetFPiotC, et al. Intracoronary autologous mononucleated bone marrow cell infusion for acute myocardial infarction: Results of the randomized multicenter BONAMI trial. Eur Heart J2011; 32: 1748–1757.
53.
SinnaevePChicheJDGillijnsH, et al. Overexpression of a constitutively active protein kinase G mutant reduces neointima formation and in-stent restenosis. Circulation2002; 105: 2911–2916.
54.
WhiteHDHeldCStewartR, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med2014; 370: 1702–1711.
55.
RosensonRSElliottMStasivY, et al. Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease. Eur Heart J2011; 32: 999–1005.
56.
RosensonRSHislopCElliottM, et al. Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients. J Am Coll Cardiol2010; 56: 1079–1088.
57.
RosensonRSHislopCMcConnellD, et al. Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): A phase II double-blind, randomised, placebo-controlled trial. Lancet2009; 373: 649–658.
58.
GrangerCBMahaffeyKWWeaverWD, et al. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. Circulation2003; 108: 1184–1190.
