Assessing Applicability: Interactive Case Study Quiz C. Michael White, PharmD, FCP, FCCP Professor and Director University of Connecticut/Hartford Hospital Evidence-based Practice Center Speaker has no actual or potential conflicts of interest in relation to this activity

Interactive Case Quiz: Instructions Open this presentation as a slideshow. This will activate the hyperlinks. When you come to a decision slide, choose the red box corresponding to the correct choice. If you are correct, you will be directed forward in the case. If you are incorrect, you will be directed back to the decision slide to choose again. – – Click on forward hyperlinks (Red Boxes) to follow through case based on your responses – – Click on home hyperlink (Blue House Icon) to go back to the last correct step in the series

Cardiac Surgery We use two randomized clinical trials in this exercise. They are both concerned with the use of amiodarone to prevent postcardiac surgery atrial fibrillation. Cardiac surgery includes coronary artery bypass surgery and heart valve surgery. The first trial was conducted by Daoud et al., and the second is the Atrial Fibrillation Suppression Trial (AFIST). We will give some clinical facts about cardiac surgery and then summarize the pertinent methods and results of the trials. Using this information, we would like you to determine if the trials are efficacy or effectiveness trials and then do a thorough review of the AFIST trial for applicability using the PICOTS format.

Clinical Data on Cardiac Surgery 56% of patients receiving cardiac surgery are over the age of 65 years Without prophylaxis, 65% of patients undergoing cardiac surgery will develop atrial fibrillation Atrial fibrillation occurs two-thirds of the time on postoperative days 2 and 3 Beta-blockers are first-line prophylactic therapy in cardiac surgery – – With beta-blocker prophylaxis, 27 to 40% of patients receiving cardiac surgery still develop atrial fibrillation Bradycardia, heart block, and nausea can occur after surgery ; Maisel WH. Ann Intern Med 2001;135: ; Crystal E. Circulation 2002;106:75-80; Kowey PR. Am J Cardiol 1992;69:963-5.

Amiodarone Data Amiodarone is a class III antiarrhythmic agent used to treat or prevent ventricular and atrial arrhythmias Amiodarone is more effective than other antiarrhythmic agents at preventing atrial fibrillation recurrences in the noncardiac surgery population Amiodarone has the lowest proarrhythmic risk among the class III antiarrhythmic agents Amiodarone blocks liver metabolism through CYP1A2, 2D6, and 3A4, so it has many drug interactions Amiodarone can cause nausea, bradycardia, and heart block with short-term therapy and thyroid problems, liver dysfunction, and pulmonary fibrosis with long-term therapy Amiodarone is usually loaded with doses of 800 to 1,600 mg daily (in divided doses because of nausea) for 1 to 3 weeks and then the dose is reduced to 400 mg daily White CM. Applied Therapeutics. Williams & Wilkins ; Farthing K. Facts and Comparisons 2003.

Review Slide: Efficacy vs. Effectiveness Seven criteria used – – Five of seven indicative of effectiveness trial Enrolled primary care population Less stringent eligibility criteria Assessment of health-related outcomes Long study duration, clinically relevant treatment modalities Assessment of adverse events Adequate sample size to assess minimally important difference for a patient perspective Intention to treat analysis

Effectiveness of Efficacy We include the salient methods sections of four clinical trials evaluating the impact of prophylactic amiodarone in cardiothoracic surgery Using the seven-criteria scale, determine if each trial is an effectiveness or efficacy trial – – Appropriate parts of the methods section are given in order to score the trials

Case Example 1: Daoud Trial Methods Patients included in randomized control trial at University of Michigan and Harper Hospital The purpose was to assess use of amiodarone to prevent atrial fibrillation after cardiac surgery Subjects had to be >18 years old with cardiac surgery scheduled >6 days after identification and be in normal sinus rhythm 373 patients screened and 124 subjects randomized to receive oral amiodarone or placebo for >6 days before cardiac surgery through hospital discharge – – Mean preop loading period was 13+7 days Follow-up until 7 days postdischarge ITT principle used Significant reductions in atrial fibrillation noted Adverse effects not determined Dauod EG. N Engl J Med :

Participation Quiz: Question 1 Given the methodology and demographics reported on the previous slide, what would you say about this trial? It is an efficacy trial with a score of 2 of 7. It is an efficacy trial with a score of 4 of 7. It is an effectiveness trial with a score of 6 of 7.

Efficacy Study—2 of 7? Although a score below 5 would be defined as an efficacy trial, the correct score is 4 of 7 as determined below. This was not a primary care population, the eligibility criteria were strict (patients are relatively healthy if they could wait a minimum of 7 days from diagnostic cardiac catheterization to cardiothoracic surgery), and there was no assessment of adverse events. They did assess health-related outcomes (atrial fibrillation, morbidity, mortality) (+1), the study duration was adequate for a problem that occurs on postoperative days 2 and 3 and resolves on its own and the treatment modalities were clinically relevant (+1), the study has adequate number of patients to assess minimally important difference (+1), and intention to treat analysis was used (+1). [Click on Blue Box to Go Back]

Efficacy Study—4 of 7? Good job, this is correct. The score is 4 of 7 as determined below. This was not a primary care population, the eligibility criteria were strict (patients are relatively healthy if they could wait a minimum of 7 days from diagnostic cardiac catheterization to cardiothoracic surgery), and there was no assessment of adverse events. They did assess health-related outcomes (atrial fibrillation, morbidity, mortality) (+1), the study duration was adequate for a problem that occurs on postoperative days 2 and 3 and resolves on its own and the treatment modalities were clinically relevant (+1), the study has adequate number of patients to assess minimally important difference (+1), and intention to treat analysis was used (+1). [SELECT RED BOX]

Effectiveness Study—6 of 7? Although a score above 5 would be defined as an effectiveness trial, the correct score is 4 of 7 as determined below. This was not a primary care population, the eligibility criteria were strict (patients are relatively healthy if they could wait a minimum of 7 days from diagnostic cardiac catheterization to cardiothoracic surgery), and there was no assessment of adverse events. They did assess health-related outcomes (atrial fibrillation, morbidity, mortality) (+1), the study duration was adequate for a problem that occurs on postoperative days 2 and 3 and resolves on its own and the treatment modalities were clinically relevant (+1), the study has adequate number of patients to assess minimally important difference (+1), and intention to treat analysis was used (+1). [Click on Blue Box to Go Back]

Case Example 2: AFIST Trial Patients included in randomized control trial at Hartford Hospital, a community hospital The purpose was to assess use of amiodarone to prevent atrial fibrillation after cardiac surgery – – Ventricular arrhythmias and stroke also assessed Subjects had to be >60 years old with cardiac surgery scheduled >1 day after identification and be in normal sinus rhythm 220 subjects randomized to receive oral amiodarone or placebo for >6 days before cardiac surgery through hospital discharge – – Beta-blockers used in 70% of participants Power calculation suggested 200 patients needed Follow-up until 30 days post surgery ITT principle used Adverse effects determined via chart and by patient interview on postoperative days 2 and 3 Giri S. Lancet :830-6.

Key Demographics— AFIST Trial CharacteristicPlaceboAmiodarone Age (years) Men74%78% EthnicityNot Known Run-In PeriodNone Giri S. Lancet 2001;357:830-6.

Key Results—AFIST Trial CharacteristicPlaceboAmiodaroneP-Value Atrial Fibrillation 38%23%0.01 Ventricular Fibrillation 7%2%0.04 Stroke 5%2%0.16 Heart Block 2%0.8%0.27 Permanent Pacemaker 2% 0.35 Nausea 16%27%0.06 Giri S. Lancet 2001;357:830-6.

Participation Quiz: Question 2 Given the methodology and demographics reported on the previous slide, what would you say about this trial? It is an efficacy trial with a score of 2 of 7. It is an efficacy trial with a score of 4 of 7. It is an effectiveness trial with a score of 6 of 7.

Efficacy Study—2 of 7? Although a score below 5 would be defined as an efficacy trial, the correct score is 6 of 7 as determined below. This was not a primary care population. This trial did use less stringent eligibility criteria by allowing those with 5 days or 1 day from cardiac catheterization to cardiothoracic surgery to participate (+1), they assessed health-related outcomes (atrial fibrillation, stroke, ventricular arrhythmias) (+1), the study duration was adequate for a problem that occurs on postoperative days 2 and 3 and resolves on its own and the treatment modalities were clinically relevant (+1), there was assessment for adverse events (+1), the study has adequate number of patients to assess minimally important difference (+1), and intention to treat analysis was used (+1). [Click on Blue Box to Go Back]

Efficacy Study—4 of 7? Although a score below 5 would be defined as an efficacy trial, the correct score is 6 of 7 as determined below. This was not a primary care population. This trial did use less stringent eligibility criteria by allowing those with 5 days or 1 day from cardiac catheterization to cardiothoracic surgery to participate (+1), they assessed health-related outcomes (atrial fibrillation, stroke, ventricular arrhythmias) (+1), the study duration was adequate for a problem that occurs on postoperative days 2 and 3 and resolves on its own and the treatment modalities were clinically relevant (+1), there was assessment for adverse events (+1), the study has adequate number of patients to assess minimally important difference (+1), and intention to treat analysis was used (+1). [Click on Blue Box to Go Back]

Effectiveness Study—6 of 7? Good job! The correct score is 6 of 7 as determined below. This was not a primary care population. This trial did use less stringent eligibility criteria by allowing those with 5 days or 1 day from cardiac catheterization to cardiothoracic surgery to participate (+1), they assessed health-related outcomes (atrial fibrillation, stroke, ventricular arrhythmias) (+1), the study duration was adequate for a problem that occurs on postoperative days 2 and 3 and resolves on its own and the treatment modalities were clinically relevant (+1), there was assessment for adverse events (+1), the study has adequate number of patients to assess minimally important difference (+1), and intention to treat analysis was used (+1). [SELECT RED BOX]

Determining Applicability: AFIST Trial Review the clinical information on cardiac surgery and amiodarone Evaluate the full summarized methods and results of the AFIST trial, evaluate the applicability based on the PICOTS Place a (+) for factors that in AFIST that improve applicability and (-) for factors that cannot be determined or negatively affect applicability – – Then click on the link to see how we scored those factors (self-assessment) Remember that applicability is a general construct and cannot be determined based on an aggregate score

Clinical Data on Cardiac Surgery 56% of patients receiving cardiac surgery are over the age of 65 years Without prophylaxis, 65% of patients undergoing cardiac surgery will develop atrial fibrillation Atrial fibrillation occurs two-thirds of the time on postoperative days 2 and 3 Beta-blockers are first line prophylactic therapy in cardiac surgery – – With beta-blocker prophylaxis, 27 to 40% of patients receiving cardiac surgery still develop atrial fibrillation Bradycardia, heart block, and nausea can occur after surgery ; Maisel WH. Ann Intern Med : ; Crystal E. Circulation : ; Kowey PR. Am J Cardiol :963-5.

Amiodarone Data Amiodarone is a class III antiarrhythmic agent used to treat or prevent ventricular and atrial arrhythmias Amiodarone is more effective than other antiarrhythmic agents at preventing atrial fibrillation recurrences in the noncardiac surgery population Amiodarone has the lowest proarrhythmic risk among the class III antiarrhythmic agents Amiodarone blocks liver metabolism through CYP1A2, 2D6, and 3A4 so it has many drug interactions Amiodarone can cause nausea, bradycardia, and heart block with short-term therapy and thyroid problems, liver dysfunction, and pulmonary fibrosis with long-term therapy Amiodarone is usually loaded with doses of 800 to 1,600 mg daily (in divided doses because of nausea) for 1 to 3 weeks and then the dose is reduced to 400 mg daily White CM. Applied therapeutics. Williams & Wilkins 2008; Farthing K. Facts and comparisons 2003.

AFIST Trial Patients included in randomized control trial at Hartford Hospital, a community hospital The purpose was to assess use of amiodarone to prevent atrial fibrillation after cardiac surgery – – Ventricular arrhythmias and stroke also assessed Subjects had to be >60 years old with cardiac surgery scheduled >1 day after identification and be in normal sinus rhythm 220 subjects randomized to receive oral amiodarone or placebo for >6 days before cardiac surgery through hospital discharge – – Beta-blockers used in 70% of participants Power calculation suggested 200 patients needed ITT principle used Adverse effects determined via chart and by patient interview on postoperative days 2 and 3

Key Demographics: AFIST Trial CharacteristicPlaceboAmiodarone Age (years) Men74%78% EthnicityNot Known Run-In PeriodNone

Key Results: AFIST Trial CharacteristicPlaceboAmiodaroneP-Value Atrial Fibrillation 38%23%0.01 Ventricular Fibrillation 7%2%0.04 Stroke 5%2%0.16 Heart Block 2%0.8%0.27 Permanent Pacemaker 2% 0.35 Nausea 16%27%0.06

AFIST Trial: Population and Applicability (I) Data to Evaluate Eligibility criteria, proportion of screened individuals enrolled Demographics: age, gender, race, ethnicity Severity or stage of illness (referral or primary care population) Run-in period Event rates in treatment and control groups [How Would You Rate AFIST? Click Red Button to See How We Rated It]

AFIST Trial: Population and Applicability (II) Data to ExtractAFIST Trial Eligibility criteria, proportion of screened individuals enrolled Eligibility criteria lenient (+), exclusion rate unknown (-) Demographics: age, gender, race, ethnicity Age similar to general population with cardiac surgery (+), recruited both males and females with adequate female representation (+), no information on race or ethnicity (-) Severity or stage of illness (referral or primary care population) While this is a specialty population, it represents the general population of people who receive cardiac surgery (+) Run-in periodThere was no run-in period (+) Event rates in treatment and control groups Atrial fibrillation events rates similar to a general population with cardiac surgery

Intervention and Applicability (I) Data to Evaluate Medication dose, schedule, duration Adherence interventions Co-interventions [How Would You Rate AFIST? Click Red Button to See How We Rated It]

Intervention and Applicability (II) Data to AbstractAFIST Trial Medication dose, schedule, duration The dosing regimen is similar to that seen in practice for treating arrhythmias (+) Adherence interventions Patients monitored by their own cardiologists as if they were not in the study (+) Co-interventions Beta-blockers already found to reduce atrial fibrillation risk; both intervention and control group have high beta-blocker utilization (+)

Comparator, Outcomes, and Applicability (I) Data to Abstract Medication dose, schedule, duration (if applicable) Comparator chosen versus others available (if applicable) Outcomes (benefits AND HARMS) and how they were defined [How Would You Rate AFIST? Click Red Button to See How We Rated It]

Comparator, Outcomes, and Applicability (II) Data to AbstractAFIST Trial Medication dose, schedule, duration (if applicable) Placebo control (+) but high baseline utilization of beta- blockers Comparator chosen versus others available (if applicable) Placebo control (+) adequate since high baseline beta-blocker use in amiodarone and placebo group Outcomes (benefits AND HARMS) and how they were defined Health outcomes (Benefits: atrial fibrillation, ventricular fibrillation, stroke. Harms: nausea, heart block, permanent pacemaker [+] using standard definitions [+])

Timing, Setting, and Applicability Data to Abstract Timing of followup/outcome measures Geographic setting Clinical setting [How Would You Rate AFIST? Click Red Button to See How We Rated It]

Timing, Setting, and Applicability Data to AbstractAFIST Trial Timing of followup/outcome measures Since 2/3 of post-operative artial fibrillation occurs on days 2 and 3 and the other adverse events occur on proximity to it, the follow-up time of 30 days is adequate (+) Geographic setting Settings is in a community hospital in the United States (+); however, it is a single center trial in New England (-) Clinical setting Level of care similar to that in the community (+)

AFIST Trial: Overall Assessment It looks like the AFIST trial is applicable to patients receiving cardiac surgery in the United States. Allowing clinicians to hold experimental therapy or discontinue it and to treat adverse events due to either the surgery or experimental therapy and the use of an older population more reminiscent of the general population are especially noteworthy for improving applicability. Important limitations is that the benefits and harms were not broken out for men and women, that the ethnic contribution to the study population is unknown, and that it is a single center study. Although the applicability is strong for institutions routinely using prophylactic beta-blockers in cardiac surgery, its applicability for institutions not using beta-blockers is reduced.