Protocol Number K16. Version 1.2 September 29 th, Study promoted by Fondazione per il Tuo cuore - HCF Onlus

Transcription

1 Protocol Number K16 Version 1.2 September 29 th, 2015 Study promoted by Fondazione per il Tuo cuore - HCF Onlus

2 TABLE OF CONTENTS Signature Page for Chairman and Co-Chairman of the study... 3 Signature Page for Principal Investigator... 4 LIST OF ABBREVIATION... 5 SUMMARY... 6 BACKGROUND AND RATIONALE... 8 STUDY DESIGN AND METHODS... 9 SPECIFIC AIMS OF THE STUDY... 9 SELECTION OF STUDY POPULATION Data Collection in ER Data collection in Cardiology Inclusion criteria Exclusion criteria OUTCOME VARIABLES Primary Outcome variables Secondary Outcome variables Safety variables Health Economic variables DATA COLLECTION Management in ER Admission to the Cardiology Ward Follow-up data STATISTICAL CONSIDERATIONS AND SAMPLE SIZE PUBLICATION POLICY MONITORING PROCEDURES FOR DATA COLLECTION IN CARDIOLOGY 14 STUDY ORGANIZATION Steering Committee Executive Committee ETHICAL ISSUES Protection of Human Subject ER Admissions Cardiology Admissions REFERENCES

3 Signature Page for Chairman and Co-Chairman of the study BLITZ Atrial Fibrillation Protocol Approved by: Michele Massimo Gulizia September 29, 2015 (Chairman) Signature date Furio Colivicchi September 29, 2015 (Co-Chairman) Signature date 3

4 Signature Page for Principal Investigator BLITZ Atrial Fibrillation Protocol I have read this protocol and I agree to conduct this study in accordance with all stipulations of the protocol and in accordance with the current regulations. (Principal Investigator) Signature date 4

5 LIST OF ABBREVIATION ACC AF AFFIRM trial AHA CRF ER ESC FIRE study HRS American College of Cardiology Atrial Fibrillation Atrial Fibrillation Follow-Up Investigation of Rhythm Management Trial American Heart Association Case Report Form Emergency Room European Society of Cardiology atrial FIbrillation and atrial flutter REgistry study Heart Rhythm Society 5

6 SUMMARY Project Title Sponsor Principal Investigator Rationale and aims of the study Study Design, Participating Centers and population BLITZ Atrial Fibrillation Fondazione per il Tuo cuore HCF Onlus Dr. Michele Massimo Gulizia Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a significant related morbidity and mortality. Management strategies for AF have made many advances over the last decade but despite the availability of guidelines, and the fact that guideline-adherent therapy seems to improve patients outcome, there is still a great heterogeneity in the management of AF and it remains unclear how often clinicians adhere to current guidelines. A survey of an updated AF management would enable a timely assessment of implementation of current International guidelines, allow monitoring of early management of AF when a patients is admitted in a Emergency Room (ER), evaluation of the implementation of catheter ablation techniques, new antithrombotic drugs and new antiarrhythmic agents, and would inform about outcomes related to different management of AF. The aims of the BLITZ AF survey are: - to evaluate the number of admissions to the ER of patients with AF and Atrial Flutter and the management in ER of AF; - to allow a comparison with the dataset from the previous FIRE study in terms of AF management; - to evaluate the clinical profile, diagnostic and therapeutic strategies for AF followed-up in the Cardiology wards and the appropriateness of treatments in relation to the current 2012 ESC guidelines; - to evaluate the rate of use of oral anticoagulation therapies and to describe the use of antiarrhythmic therapy; - to allow additional information on costs and health economics of this clinical condition in Italy; - to describe the routine practice of the cardiology centers in following-up AF patients within the 12 months after hospital discharge; - to evaluate, in a subset of centers representative of the Italian cardiology reality, 1-year survival, AF related events and need of hospitalization with their related causes within the 12 months after hospital discharge and AF related changes in quality of life. Multicentre, observational study. 200 Italian Hospitals fully representing the Italian cardiology reality in terms of geographical distribution and level of hospital technology. Data collection in ER: Data on AF and Atrial Flutter episodes in ER will be collected retrospectively by checking the records of ER without collection of any data that can allow to identify the patients. These data will be collected under the responsibility of the Cardiology Departments consecutively for 4 weeks. Data collection in Cardiology: Inclusion criteria All patients with AF, admitted to cardiology wards for an urgent or planned hospitalization. 6

7 All patients admitted in a Day Hospital regimen for treatment of AF The diagnosis of AF must be confirmed by ECG. Signed Patient Inform Consent. Exclusion criteria The qualifying episode of AF was not documented with an ECG. Age <18 years. Patients with AF as a complication of an acute coronary syndrome (within 1 week from symptoms onset). Patients with AF associated with cardiothoracic surgery (within 1 week from surgery). Concomitant participation in other studies that can modify the diagnostic and/or therapeutic treatments. Patients already enrolled in BLITZ-AF These data will be collected under the responsibility of the Cardiology Departments for 12 weeks consecutively. Outcome variables Primary outcome variables - Number of admissions to the ER and cardiology wards of patients with AF. - Rate and type of antiarrhythmic strategy. - Rate of use of oral antithrombotic strategies. Secondary outcome variables - Number of admission to the ER for atrial flutter - Rate of patients regularly followed up by the cardiology centers. - Rate of adherence to the 1A recommendations of current guidelines. Safety variables Complications of electrical, pharmacological cardioversion or catheter ablation. All embolic events. All Bleedings (major and minor). 1-year re-hospitalization rate for cardiovascular or noncardiovascular reasons. 1 year death and related causes. Statistical aspects For all patients and subgroups, data analysis will be mainly descriptive and will assess the degree of adhesion to guidelines recommendations. Multivariable analyses may be used to explore relationship between baseline covariates and post-baseline endpoints, as appropriate. Considering the explorative and observational nature of the current study, no formal sample size calculation has been performed. However, the current study is aiming at a sample of at least 3000 admissions in the ER of patients with AF and 2000 patients admitted in the cardiology wards to allow for a representative Italian cohort of patients with AF. 7

8 BACKGROUND AND RATIONALE Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, occurring in 1% 2% of the general population. 1,2 The prevalence of AF in a given population increases with age, the presence of cardiovascular risk factors, established heart disease or heart failure. An increasingly ageing population will contribute to the increasing prevalence of AF. Over six million Europeans suffer from this arrhythmia, and its prevalence is estimated to at least double in the next 50 years as the population ages. 3-5 AF may have various clinical presentations although in many subjects, AF is often totally asymptomatic. Also for this reason, for a long time AF was considered a benign arrhythmia, but it is well recognized now that AF has a significant morbidity and mortality, particularly from an increased risk of stroke and thromboembolism, heart failure, dementia and impaired quality of life. 6-9 Management strategies for AF have made many advances over the last decade. Broadly, they can be discussed in relation to strategies of thromboprophylaxis, rate or rhythm control and the management of associated co-morbidities. 10 Clearly, stroke prevention has greatly improved with oral anticoagulation, warfarin and more recently, the new oral anticoagulant drugs that overcome some of the limitations of warfarin. 11,12 Whilst large trials comparing rate versus rhythm control strategies have shown that both are noninferior, one post-hoc analysis from the AFFIRM trial has reported a benefit of sinus rhythm and warfarin, but this was offset by an increased mortality with antiarrhythmic drugs Despite the evidence from epidemiology, trials, and guidelines, there is still a great heterogeneity in the management of patients with AF, although guideline-adherent therapy seems to be able to improve patients outcomes. Despite the availability of guidelines, it remains unclear how often clinicians adhere to them. Given the advances in AF management and the availability of ESC and ACC/AHA/HRS guidelines, there is a need for the systematic collection of contemporary data regarding the management and treatment of AF in the European countries. 15,16 The Italian FIRE study was published nearly 15 years ago describing the management of AF in a broad and representative network of Italian clinical centers, and now a new registry is needed. 17 A survey of an updated AF management would enable a timely assessment of uptake of the current International guidelines, allow monitoring of early management of AF when a patients is admitted in a Emergency Room (ER), evaluation of the implementation of catheter ablation techniques, new antithrombotic drugs and new antiarrhythmic agents, and would also inform about outcomes related to different management of AF. 8

9 STUDY DESIGN AND METHODS The BLITZ AF study is a multicentre, observational study of patients with AF presenting to about 200 Italian Hospitals fully representing the Italian cardiology reality in terms of geographical distribution and level of hospital technology. The survey will be also focused on the contemporary diagnosis and management of patients with AF amongst ER health professionals and cardiologists at the time of enrolment, and provide important information on events and management changes over time. Standard management of patients will be the diagnostic and therapeutic interventions currently performed in each centre for patients with AF. Drug prescriptions and indications to perform diagnostic/therapeutic procedures will be completely left to participating physicians decision. No specific protocols or recommendations for evaluation, management, and/or treatment will be put forth during this observational study. However, current guidelines for the management of AF will be discussed during the Investigator meetings, and doctors participating in the registry, should be adherent to them. SPECIFIC AIMS OF THE STUDY The general objectives of the BLITZ AF survey on clinical epidemiology and medical management of AF are summarized as follows: - to assess the number of admissions of patients with AF and Atrial Flutter in the ER and the management in ER of AF, describing separately those admissions due specifically to AF and those in which AF is just a co-morbid condition; - to allow a comparison with the dataset from the previous FIRE study in terms of AF management; - to evaluate the clinical profile of patients with AF admitted to the cardiology wards; - to evaluate the diagnostic and therapeutic strategies for AF followed for each patient admitted in a Cardiology ward; - to allow additional information on costs and health economics of this clinical condition in Italy. More specifically: - to describe and evaluate the appropriateness of treatments in the different subsets of AF in relation to the current 2012 ESC guidelines on AF, as well as most recent guidelines on hypertension, heart failure, stable coronary disease and cardiovascular disease prevention; - to evaluate the rate of use of oral anticoagulation therapies, including Vitamin K antagonists and the new anticoagulant drugs (oral direct thrombin inhibitors or oral Factor Xa inhibitors); 9

10 - to describe the use of antiarrhythmic therapy; - to describe the routine practice of the cardiology centers in following AF patients within the 12 months after hospital discharge; - to evaluate, in a subset of centers representative of the Italian cardiology reality, 1- year survival, bleeding events, embolic events, need of hospitalization and other major clinical events with their related causes within the 12 months after hospital discharge and AF related changes in quality of life. SELECTION OF STUDY POPULATION Data Collection in ER Data on admission in ER of patients with AF and Atrial Flutter will be collected retrospectively by checking the records of ER without collection of any demographic information that can allow the identification of the patient. The diagnosis of AF must be confirmed by ECG. AF may be the primary or secondary diagnosis of ER admission. Data collection in Cardiology Inclusion criteria All patients with AF admitted to the participating cardiology wards for an urgent or planned hospitalization will be included. All patients admitted in a Day Hospital regimen for treatment of AF The diagnosis of AF must be confirmed by ECG. AF may be the primary or secondary diagnosis, i.e. the current admission / visit may be due to other reasons. Signed patient inform consent. Exclusion criteria The qualifying episode of AF was not documented with an ECG. Patients with AF as a complication of an acute coronary syndrome (within 1 week from symptoms onset). Patients with AF associated with cardiothoracic surgery (within 1 week from surgery). Age <18 years. Concomitant participation in other clinical studies that can modify the routine clinical practice diagnostic and/or therapeutic treatments. Patients already enrolled in BLITZ-AF 10

11 OUTCOME VARIABLES Primary Outcome variables - Number of admissions to the ER and cardiology wards of patients with AF, describing separately those admissions due specifically to AF and those in which AF is just a comorbid condition. - The rate of type of antiarrhythmic strategy (rhythm control, including catheter ablation, versus rate control). - The rate of use of oral antithrombotic strategies: antiplatelet agents, anticoagulation therapies with the Vitamin K antagonists or with the new oral anticoagulant (direct thrombin inhibitors or oral Factor Xa inhibitors). Secondary Outcome variables - Number of admissions to the ER of patients with atrial flutter - Rate of patients regularly followed up by the cardiology centers. - Rate of adherence to the 1A recommendations of current guidelines. Safety variables - Complications of electrical or pharmacological cardioversion. - Complications of AF catheter ablations. - All embolic events. - All Bleedings (major and minor). - 1 year re-hospitalization rate for cardiovascular or non-cardiovascular reasons. - 1 year death rate and related causes. Information at 1 Year follow-up will be collected in those patients who are routinely followed up by the recruiting centers and in all patients of the subset of centers in which the follow up visits at 1 year will be planned by protocol. Pharmacovigilance will be followed by the investigator according to the rules in force for the spontaneous reports (post-marketing). The investigator will inform the Competent Authority of all serious expected and unexpected adverse reactions that occurred during the conduction of the observational study. The documentation related to the above mentioned reactions will be sent also to the promoter. Health Economic variables Data on use of resources (drugs and diagnostic/therapeutic procedures) during the hospital phase will be collected in the patients admitted in the Cardiology ward. Information on the need of repeated hospitalizations (and related reasons) or ER accesses 11

12 will be collected during the follow-up period. EQ-5D will be used at discharge and 12 months as a standardized instrument for use as a measure of health outcome in the subset of centers in which the follow up visits are planned by protocol. DATA COLLECTION Management in ER A very simple CRF will be filled with respect to the information collected in the ER. - Admission diagnosis, - Type of AF, - Underlying heart disease, - Co-morbidities, - Type of antithrombotic and anti-arrhythmic management in the ER, - Need for admission and in the affirmative case, ward of admission. These data will be retrospectively collected for 4 weeks consecutively by checking the records of ER under the responsibility of the cardiology department. Admission to the Cardiology Ward A more detailed CRF will be filled in the case the patient is admitted in the Cardiology ward, including information on: - demographics, - clinical history, - type of AF, - most relevant laboratory measures, if performed and available (routine blood tests, renal function, thyroid function), - risk factors for cardiovascular diseases, - presence and severity of concomitant cardiac abnormalities, - other co-morbidities, - type of arrhythmic management, - type and dosage of antithrombotic management, - invasive or non-invasive diagnostic or therapeutic procedures, - other therapies prescribed during hospitalization and at discharge. These data will be prospectively collected under the responsibility of the cardiology department for 12 weeks consecutively. Weeks ER Cardiology 1-4 Fill CRF(retrospectively) Fill CRF(prospectively) 5-12 Fill CRF(prospectively) 12

13 Data will be collected using a web based system. Follow-up data For the patients admitted in the cardiology ward, information on the availability of a follow-up visit will be required after 1 year from hospital discharge. In the case the clinical visit at 1 year has been performed, information regarding survival status, bleeding events, other major clinical events, need of hospital and/or ER admissions, type of antithrombotic and anti-arrhythmic management of AF will be collected. In a subset of centers, representative of the Italian cardiology reality, the follow up visit at 1 year will be mandatorily performed, collecting the same type of clinical information. STATISTICAL CONSIDERATIONS AND SAMPLE SIZE All patients enrolled will be included in the analysis. Since this is an observational study, descriptive summaries will be presented for all the patients, and for subgroups of patients. Statistical tests may be carried out for exploratory purposes, as appropriate. Specific attention will be dedicated to the description of the management of AF. Multivariable analyses may be used to explore the relationships between baseline covariates and postbaseline endpoints, as appropriate. Based on the main objectives, data analysis will be mainly descriptive and will assess the degree of adhesion to guidelines recommendations. In addition, comparisons can be made between hospital types and geographical distribution. Ancillary analyses can be proposed, with the sanction of the Steering Committee, with appropriate access to the database. Considering the explorative and observational nature of the current study, no formal sample size calculation has been performed. However, the current study is aiming at a sample of at least 3000 patients admitted in the ER with AF and 2000 in the cardiology ward to allow for a representative Italian cohort of patients with AF. PUBLICATION POLICY The study will be published anyhow, independently from the final results. Manuscripts and abstracts will be prepared through cooperation between the Steering Committee and the ANMCO Research Centre. The Steering Committee agrees to provide manuscripts and abstracts to the financial supporter for review and comments. A period of 5 working days for presentational material and abstract(s) and 15 working days for a scientific journal submission will be required for the review. 13

14 MONITORING PROCEDURES FOR DATA COLLECTION IN CARDIOLOGY The study will be monitored to ensure overall quality of data. The Steering Committee of the study delegates the monitoring aspects to the monitoring group of the Coordinating Centre (ANMCO Research Centre). All centres participating in the study will be monitored according to monitoring procedures set out by HCF for observational studies. The investigator must maintain source documents for each patient in the study, including documentation of AF, notes containing demographic and medical information, copies of laboratory and clinical tests. The investigator must also keep the original informed consent form signed by the patient. The investigator must give the monitor access to all relevant source documents to confirm their consistency with the (e)crf entries. STUDY ORGANIZATION Steering Committee The Steering Committee acts as the Sponsor of the study, and has the full responsibility for planning, conduct, analysis, and publication of study protocol and results. Executive Committee The Executive Committee will be responsible for the formulation of the study protocol and to oversee its implementation. ETHICAL ISSUES Protection of Human Subject The survey is an observational study that does not dictate the manner in which patients are evaluated or treated for AF. Physicians may decide to evaluate and manage-patients with AF in any way they deem appropriate according to the local standard of care. ER Admissions Only information on number of Atrial Flutter and number and management of AF episodes will be collected, retrospectively and without collection of data that can allow to identify the patients. For this reason signed informed consent will not required. Cardiology Admissions For patients admitted in cardiology, a signed informed consent will be required as inclusion criteria. Patient data collected will be strictly anonymous. Only a code, gender, date of birth will identify patients. In order to maintain strict security, each investigator/study personnel will have a unique login and password to enter patient s information. There will be no storage of clinical data outside of the data collection instrument, which will be a secure, web-based form. The main database will be secured according to current standards to ensure both ethical and integrity requirements of the data. 14

15 REFERENCES 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 study. Circulation 2014;129: Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol 2001;37: Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmested Country, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114: Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285: Lip GY, Kakar P, Watson T. Atrial fibrillation--the growing epidemic. Heart 2007;93: Wolf PA, D Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham study. Stroke 1991;22: Boriani G, Laroche C, Diemberger E et al. Asymptomatic atrial fibrillation: clinical correlates, managememt and putcomes in the EORP-AF Pilot General Registry. Am J Med 2015;128: e2 8. Benjamin EJ, Wolf PA, D Agostino RB Silbershatz H, Kannel WB, Levy D. et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98: Thrall G, Lane D, Carrol D, Lip GY. Quality of life in patients with atrial fibrillation: a systematic review. Am J Med 2006;119:448.e Camm AJ, Lip GY, De Caterina R, et al focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33: Reeves MJ, Grau-Sepulveda MV, Fornarow GC, Olson DM, Smith EE, Schwamm LH. Are quality improvements in the Get With The Guidelines-Stroke Program related to better care or better data documentation? Circ Cardiovasc Qual Outcomes 2011;4: Granger CB, Armaganijan LV. Newer oral anticoagulants should be used as first line agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism. Circulation 2012;125:

16 13. Wyse DG, Waldo AL, Di Marco JP. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Eng J Med 2002;347: The AFFIRM Investigators. Relationship between sinus rhythm, treatment and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation 2004;109: Camm AJ, Lip GY, De Caterina R, et al.; ESC Committee for Practice Guidelines (CPG) focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33: January CT, Wann LS, Alpert JS, et al AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2014;130:e199 e Santini M, DE Ferrari GM, Pandozi C et al. Atrial fibrillation requiring urgent medical care. Approach and outcome in the various departments of admission. Data from the atrial Fibrillation/flutter Italian Registry (FIRE). Ital Heart J 2004;5: