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C. Michael Gibson, M. S. , M. D. Harvard Medical School State of the C. Michael Gibson, M. S. , M. D. Harvard Medical School State of the Art in the Adjudication of Cardiovascular Endpoints

Goal of Universal Definitions • “Endpoint definitions are necessary in clinical trials so that Goal of Universal Definitions • “Endpoint definitions are necessary in clinical trials so that events are clearly characterized by objective criteria and reported uniformly. • If uniformly defined, events in drug development programs or among different clinical trials may be analyzed more easily and trends and other safety signals may be identified. ” Draft Universal Definitions, October 20 th, 2010

Goal of Universal Definitions • In the conduct of non-inferiority trials, definitions with increased Goal of Universal Definitions • In the conduct of non-inferiority trials, definitions with increased specificity minimize bias towards showing noninferiority • The increased specificity of the new definitions requires careful design of e. CRFs and careful collection of source documents so sufficient information is available to permit adjudication • If source documents are not collected to adjudicate events, “true positive” events may not be adjudicated as such leading to lower event rates, and reduced power to demonstrate non-inferiority (or superiority as well)

FDA Standardized Definitions for CV Outcomes Trials • • July 2009 Initial Draft definitions FDA Standardized Definitions for CV Outcomes Trials • • July 2009 Initial Draft definitions issued Nov 2009 – Feb 2010 variety of working group meetings to discuss definitions March 2010 Revised draft definitions issued Completion of draft definitions Oct. 20, 2010 - definitions posted for 30 days for public comment Ultimate goal is a white paper (late 2010) CRF standardization possibly to complete mid-2011 Stakeholders: FDA, CDER, CPI, ACC, ACROs, CDISC, CTTI, HL 7, NHLBI, Ph. RMA, pharmaceutical industry Working group representatives: Cleveland Clinic, Columbia, Duke Cardiovascular Research Institute, HCRI, TIMI, Brigham & Women’s, St. Louis University, PERFUSE/Beth Israel, FDA neurology working group

Evolving Challenges in Adjudication • Event driven trials require the occurrence of a pre-specified Evolving Challenges in Adjudication • Event driven trials require the occurrence of a pre-specified number of adjudicated events • There is therefore a need for real time adjudication of events

Evolution of the CEC Process Old Method State of the Art Need for ongoing Evolution of the CEC Process Old Method State of the Art Need for ongoing adjudication in real time Absent Present Medium Paper Electronic Speed Slow / Intermittent Fast / Ongoing Meeting format Committee members physically present at same time (every few weeks or months) Committee members adjudicate events independently over internet, reach consensus on ongoing basis Prompt CEC member to inconsistencies & incomplete data Absent Present Requires manual entry of data from CEC meeting Yes No Ability to seamlessly review images from a case Absent Present

Classification of Causes of Death Cardiovascular • Death due to Acute MI (arrhythmia, CHF, Classification of Causes of Death Cardiovascular • Death due to Acute MI (arrhythmia, CHF, low output within 30 days of MI) • Sudden cardiac death (pt well previous day, dead in bed next day) • Death due to heart failure or cardiogenic shock (not in setting of MI or arrhythmia) • Death due to stroke • Death due to other cardiovascular cause (aneurysm, peripheral dz, patient found dead at home, undetermined causes) Non-Cardiovascular • Non-cardiovascular death (subdivided into cancer and non-malignant causes such as sepsis, organ failure, trauma, drug overdose) Undetermined Discouraged, due to a lack of information Draft Universal Definitions, October 20 th, 2010

MI Definitions • In general, the diagnosis of MI requires the combination of: – MI Definitions • In general, the diagnosis of MI requires the combination of: – Evidence of myocardial necrosis (either changes in cardiac biomarkers or post-mortem pathological findings); and – Supporting information derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery imaging For cardiac biomarkers, laboratories should report an upper reference limit (URL). If the 99 th percentile of the upper reference limit (URL) from the respective laboratory performing the assay is not available, then the URL for myocardial necrosis from the laboratory should be used. If the 99 th percentile of the URL or the URL for myocardial necrosis is not available, the MI decision limit for the particular laboratory should be used as the URL. Draft Universal Definitions, October 20 th, 2010

Myocardial Infarction Issues: • Type of MI important: CEC adjudicates type of MI (spontaneous, Myocardial Infarction Issues: • Type of MI important: CEC adjudicates type of MI (spontaneous, demand, CABG, periprocedural) • Size of MI important: Cardiologist often unconcerned with higher rates of small MIs • Timing of MI important: Is benefit early in treatment course after loading dose, or late in course during maintenance dose • Multiple MIs important: Does the drug reduce second and third events during maintenance dose phase

Common Classification Schemes for MI Categories • By Electrocardiographic Features: ST-Elevation MI (STEMI), Non-ST-Elevation Common Classification Schemes for MI Categories • By Electrocardiographic Features: ST-Elevation MI (STEMI), Non-ST-Elevation MI (NSTEMI), Unknown • By the Universal MI Definition: Type 1, Type 2, Type 3, Type 4 a, 4 b, Type 5 Types of MI Treatment A Treatment B Number of patients (N=) MI Type 1 n, % MI Type 2 n, % MI Type 3 n, % MI Type 4 n, % MI Type 5 n, % Total number n, % N=total number of patients; n= number of patients with a particular MI Draft Universal Definitions, October 20 th, 2010

Classification of the Different Types of Myocardial Infarction According to Multiples of the 99 Classification of the Different Types of Myocardial Infarction According to Multiples of the 99 th Percentile URL of the Applied Cardiac Biomarker Multiple MI Type 1 (Spontaneous) MI Type 2 (Secondary) MI Type 3 (Sudden death) MI Type 4 (PCI) MI Type 5 (CABG) Total Number 1 -2 X 2 -3 X 3 -5 X 5 -10 X > 10 X Total Number Draft Universal Definitions, October 20 th, 2010

Myocardial Infarction Issues: Silent MI Questions • What is incidence of Silent MI? • Myocardial Infarction Issues: Silent MI Questions • What is incidence of Silent MI? • What is prognosis of Silent MI vs. Symptomatic MI? • Can incidence of Silent MI be modified by therapy? • Would it be scientifically important/interesting • Can inclusion of silent MIs in the endpoint shorten the duration of a trial?

Criteria for Silent MI or Prior MI (with or without Symptoms) No evidence of Criteria for Silent MI or Prior MI (with or without Symptoms) No evidence of acute MI AND any one of the following criteria: 1. Appearance of new persistent pathological Q waves. A confirmatory ECG is recommended if there have been no clinical symptoms or history of myocardial infarction. 2. Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause 3. Pathological findings of a healed or healing myocardial infarction

Unrecognized Myocardial Infarction Study Patients # MI % silent 12, 866 460 25 Framingham Unrecognized Myocardial Infarction Study Patients # MI % silent 12, 866 460 25 Framingham (1990) 5070 363 30 CVS (1990) 5888 901 22 9141 13, 000 237 641 35 33 MRFIT (1987) Rekjavik (1995 -8) - Men - Women

Silent MI in FIELD Study 9597 Pts with DM Overall Incidence 4. 1% Clinical Silent MI in FIELD Study 9597 Pts with DM Overall Incidence 4. 1% Clinical MI 2. 7% Silent MI 36. 8% were silent Burgess DC. EHJ. 2009

BARI 2 D 2368 pts with angiographically proven CAD 279 - 1 st MIs BARI 2 D 2368 pts with angiographically proven CAD 279 - 1 st MIs (12. 4% at 5 yrs) 243 - Non-fatal 1 st MIs MI Type N (%) HR 169 (69. 5) 3 yr Cardiac Mortality 16. 1% Type I sympt Silent 23 (9. 4) 10. 7% 4. 8 Peri-PCI No MI 51 (21. 0) 9. 6% 2. 4% 3. 4 - 8. 2 Chaitman BR. Circulation. 2009; 120: 2529 -2540

Treatment Effect on MI Type Burgess DC. EHJ. 2009 Treatment Effect on MI Type Burgess DC. EHJ. 2009

Impact Of Including Silent MI As Part Of The MI Endpoint Assume An Event Impact Of Including Silent MI As Part Of The MI Endpoint Assume An Event Driven Trial With Approximately 1000 Events: Rate of Silent MI # Additional MI 10% 52 Months saved to accrue # endpoints 3. 7 20% 104 7. 4 30% 156 11. 1 40% 208 14. 8 Shortening a trial’s timeline by 7 to 11 months could significantly reduce costs

Operational Issues in Assessing Silent MI • Timepoints – Most logical times to collect Operational Issues in Assessing Silent MI • Timepoints – Most logical times to collect the ECGs are at baseline and at the end of the study. – Unless the anticipated rate of silent MI is known, it may not help that much in speeding up trial as the ECG adjudication happens after the last visit, and you would not know until the end of the trial if you are on target with respect to the event rate. – An assessment of silent MIs halfway through the trial may help in estimating the rate of silent MIs at the end of the trial to assure you are on target.

Hospitalization for Unstable Angina: FDA 2009 FDA 2010 Yes, at least 10 min Yes, Hospitalization for Unstable Angina: FDA 2009 FDA 2010 Yes, at least 10 min Yes, but no time duration Hospitalization Yes but w/in 24 hrs ECG changes, evidence of myocardial ischemia, angiographic evidence ≥ 70%, lesion, or revascularization Yes No biomarker elevation No evidence of AMI Symptoms Biomarkers

Unstable Angina Requiring Hospitalization Symptoms of myocardial ischemia at rest (chest pain or equivalent) Unstable Angina Requiring Hospitalization Symptoms of myocardial ischemia at rest (chest pain or equivalent) or an accelerating pattern of angina with frequent episodes associated with progressively decreased exercise capacity AND Prompting an unscheduled visit to a healthcare facility and hospitalization (including chest pain observation units) within 24 hours of the most recent symptoms AND At least one of the following: a. New or worsening ST or T wave changes on resting ECG b. Definite evidence of myocardial ischemia on myocardial scintigraphy (clear reversible perfusion defect), stress echocardiography (reversible wall motion abnormality) c. Angiographic evidence of ≥ 70% lesion and/or thrombus d. Need for coronary revascularization procedure (PCI or CABG) during the same hospital stay. Draft Universal Definitions, October 20 th, 2010

Unstable Angina Requiring Hospitalization: Caveats Escalation of pharmacotherapy for ischemia, such as intravenous nitrates Unstable Angina Requiring Hospitalization: Caveats Escalation of pharmacotherapy for ischemia, such as intravenous nitrates or increasing dosages of β-blockers, should be considered supportive of the diagnosis of unstable angina. However, a typical presentation and admission to the hospital with escalation of pharmacotherapy, without any of the additional findings listed under category 3, would be insufficient alone to support classification as hospitalization for unstable angina. Planned rehospitalization for performance of an elective revascularization in the absence of symptoms at rest prompting admission should not be considered a hospitalization for unstable angina. For example, a patient with stable exertional angina whose admission for coronary angiography and PCI is prompted by a positive outpatient stress test should not be considered a hospitalization for unstable angina. Draft Universal Definitions, October 20 th, 2010

Stroke Definitions Stroke is defined as an acute episode of neurological dysfunction caused by Stroke Definitions Stroke is defined as an acute episode of neurological dysfunction caused by focal or global brain, spinal cord, or retinal vascular injury. Classification: A. Ischemic Stroke Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by an infarction of central nervous system tissue. Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke. B. Hemorrhagic Stroke Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal dysfunction caused by a nontraumatic intraparenchymal, intraventricular, or subarachnoid hemorrhage. C. Undetermined Stroke Undetermined stroke is defined as a stroke with insufficient information to allow categorization as A or B. Draft Universal Definitions, October 20 th, 2010

TIA Definitions “The distinction between a Transient Ischemic Attack and an Ischemic Stroke is TIA Definitions “The distinction between a Transient Ischemic Attack and an Ischemic Stroke is the presence of infarction, not the transience of the symptoms. ” Transient Ischemic Attack Transient ischemic attack (TIA) is defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. Draft Universal Definitions, October 20 th, 2010

Scale Disability 0 No symptoms at all 1 No significant disability despite symptoms; able Scale Disability 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6 Dead Draft Universal Definitions, October 20 th, 2010

Stroke Definitions Old Definitions New Definitions Role of Imaging Required to classify event Not Stroke Definitions Old Definitions New Definitions Role of Imaging Required to classify event Not required to diagnose as stroke, only required to sub-classify stroke. Supplementary to clinical diagnosis of stroke Sub-classification Ischemic, hemorrhagic, or undetermined if no imaging or autopsy Subdural bleed Counted as stroke Counted as intracranial bleed Epidural bleed Counted as stroke Counted as intracranial bleed TIA with imaging abnormality Classified as TIA Classified as stroke Micro-hemorrhage Not recognized Tracked as an event, not classified as a stroke

Heart Failure Requiring Hospitalization • Requires hospitalization defined as an admission to an inpatient Heart Failure Requiring Hospitalization • Requires hospitalization defined as an admission to an inpatient unit or a visit to an emergency department that results in at least a 24* hour stay (or a date change if the time of admission/discharge is not available). • * For studies with Class III/IV CHF, a stay shorter than 24 hours may be sufficient. AND Symptoms of heart failure (dyspnea, orthopnea, PND etc. ) AND Physical signs of heart failure (edema, rales, JVD, S 3, x ray, etc. ) AND Need for additional therapy (augmentation, inotropes, uptitration, mechanical intervention, ultrafiltration, dialysis, pacing, etc. ) AND No other cardiac etiology Draft Universal Definitions, October 20 th, 2010

BARC: Bleeding Academic Research Consortium BARC: Bleeding Academic Research Consortium

BARC Bleeding Definitions • Type 0: No Bleeding. • Type 1: Bleeding that is BARC Bleeding Definitions • Type 0: No Bleeding. • Type 1: Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a health care professional. Examples include but are not limited to bruising, hematoma, nosebleeds, and hemorrhoidal bleeding.

BARC Minor (Type 2) Bleeding • Type 2: Any overt sign of hemorrhage (e. BARC Minor (Type 2) Bleeding • Type 2: Any overt sign of hemorrhage (e. g. , more bleeding than would be expected for a clinical circumstance; including bleeding found by imaging alone) that does not meet criteria for Type 3 BARC bleeding, Type 4 BARC bleeding (CABG-related), or Type 5 BARC bleeding (fatal bleeding) that is actionable. The bleeding must require diagnostic studies, hospitalization or treatment by a health care professional. In particular, the bleeding must meet at least one of the following criteria: 1) Requiring intervention: defined as a health care professional-guided medical or surgical treatment to stop or treat bleeding including temporarily or permanently discontinuing or changing the dose of a medication or study drug. Examples include but are not limited to surgical repair, coiling, compression, drainage or cautery of a bleeding site, reversal of vitamin K antagonism, protamine administration, local lidocaine administration to reduce oozing or a reduction in the dose of or a temporary/permanent cessation of antiplatelet or antithrombin therapy; 2) Leading to hospitalization or an increased level of care: defined as leading to or prolonging hospitalization or transfer to a hospital unit capable of providing a higher level of care; and 3) Prompting evaluation: defined as leading to an unscheduled visit to a healthcare professional and diagnostic testing (laboratory or imaging). Examples include but are not limited to hematocrit testing, hemoccult testing, endoscopy, colonoscopy, computed tomography scanning or urinalysis.

BARC Major (Type 3) Bleeding • • • Type 3: Elements of the definition BARC Major (Type 3) Bleeding • • • Type 3: Elements of the definition should include clinical, laboratory, and imaging data; physician response to bleeding; and site specific parameters. In order to curb the influence of physician judgment and decision-making, hemodynamic compromise and transfusion are included in the definition. It is subcategorized in: a. BARC Type 3 a Bleeding Intracranial hemorrhage (does not include microbleeds; does include intraspinal). Subcategories; Confirmed by autopsy or imaging or LP Intra-ocular compromising vision (even temporarily) Overt bleeding plus hemoglobin drop > 5 g/d. L (provided hemoglobin drop is related to bleed) Tamponade Bleeding requiring surgical or percutaneous intervention for control (exclude dental/nose/skin/hemorrhoids) or inotropes BARC Type 3 b Bleeding Any transfusion with overt bleeding Overt bleeding plus hemoglobin drop 3 to 5 g /d. L

BARC CABG (Type 4) Bleeding • 1) BARC CABG-related bleeding definitions must include the BARC CABG (Type 4) Bleeding • 1) BARC CABG-related bleeding definitions must include the same criteria for fatal bleeding, intracranial hemorrhage, need for intervention to control bleeding and the number of transfusions as for BARC non-CABG related bleeding, • 2) specific criteria for the amount of chest tube drainage need to be included, • 3) If bleeding is not defined as BARC Type 3, it will not be counted as an event, • 4) Specific time intervals will need to apply for CABG-related events: up to 48 hours for transfusions and intracranial bleeding, (how many? ) hours for ‘excessive’ chest tube drainage. It is appropriate that there will be no time window for the occurrence of fatal bleeding.

BARC Fatal (TYPE 5) Bleeding Type 5: Fatal Bleeding. Fatal bleeding is bleeding that BARC Fatal (TYPE 5) Bleeding Type 5: Fatal Bleeding. Fatal bleeding is bleeding that directly causes death with no other explainable cause. BARC Fatal Bleeding is categorized as either definite or probable as follows: • 1) Definite fatal bleeding is bleeding that is directly observed or confirmed on autopsy or imaging. • 2) Probable fatal bleeding is bleeding that is clinically suspicious as the cause of death, but the bleeding is not directly observed and there is no autopsy or confirmatory imaging. The site of fatal bleeding is specified as intracranial, GI, retroperitoneal, pulmonary, pericardial, GU, or other.

Where Can I Go to Comment on the Definitions? • http: //www. cdisc. org/therapeutic Where Can I Go to Comment on the Definitions? • http: //www. cdisc. org/therapeutic is accepting comments through Monday, January 31 st, 2011

Impact of New Definitions on Clinical Trials • Specificity: Rigorous definitions and CEC process Impact of New Definitions on Clinical Trials • Specificity: Rigorous definitions and CEC process will increase specificity in classification of events, & minimize bias in determining non-inferiority • Sensitivity: The following will increase the number of events – Sensitive MI definitions so that unstable angina cases may be reclassified as MI – Potential to include “silent MIs” in endpoints – Reclassification of prior TIAs as strokes if there is an imaging abnormality • Net Impact: Ascertainment of more events will lead to realistic sample sizes and feasible timelines