1. Clinical Trial Results. org Relationship Between Adherence to Evidence- Based Pharmacotherapy and Long-term Mortality After Acute Myocardial Infarction Jeppe N. Rasmussen, MD; Alice Chong, BSc; David A. Alter, MD, PhD, FRCPC Published in JAMA January 2007 Relationship Between Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After Acute Myocardial Infarction

2. Clinical Trial Results. org The extent to which drug adherence may affect survival remains unclear, in part because mortality differences may be attributable to “healthy adherer” behavioral attributes more so than to pharmacologic benefits.The extent to which drug adherence may affect survival remains unclear, in part because mortality differences may be attributable to “healthy adherer” behavioral attributes more so than to pharmacologic benefits. Although it is known that adherence to evidence-based pharmacotherapy predicts better survival, no population outcome study has attempted to differentiate whether these associations are attributable to the drug’s biological responsiveness (herein termed drug effect) or to the adoption of healthier lifestyles that often accompany adherent behaviors (herein termed healthy adherer effect).Although it is known that adherence to evidence-based pharmacotherapy predicts better survival, no population outcome study has attempted to differentiate whether these associations are attributable to the drug’s biological responsiveness (herein termed drug effect) or to the adoption of healthier lifestyles that often accompany adherent behaviors (herein termed healthy adherer effect). The extent to which drug adherence may affect survival remains unclear, in part because mortality differences may be attributable to “healthy adherer” behavioral attributes more so than to pharmacologic benefits.The extent to which drug adherence may affect survival remains unclear, in part because mortality differences may be attributable to “healthy adherer” behavioral attributes more so than to pharmacologic benefits. Although it is known that adherence to evidence-based pharmacotherapy predicts better survival, no population outcome study has attempted to differentiate whether these associations are attributable to the drug’s biological responsiveness (herein termed drug effect) or to the adoption of healthier lifestyles that often accompany adherent behaviors (herein termed healthy adherer effect).Although it is known that adherence to evidence-based pharmacotherapy predicts better survival, no population outcome study has attempted to differentiate whether these associations are attributable to the drug’s biological responsiveness (herein termed drug effect) or to the adoption of healthier lifestyles that often accompany adherent behaviors (herein termed healthy adherer effect). Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186 Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Background

3. Clinical Trial Results. org The objective of this study was to explore the relationship between drug adherence and mortality in survivors of acute myocardial infarction (AMI) focused on seniors aged 65 years or older because:The objective of this study was to explore the relationship between drug adherence and mortality in survivors of acute myocardial infarction (AMI) focused on seniors aged 65 years or older because: –Elderly are more vulnerable with higher CV risk and propensity for premature drug discontinuation due to complexities in medical regimens, tolerance, and concerns about adverse effects –In Canada, medications are free for patients ≥65, thus affordability factors should not affect adherence –Administrative data allows for tracking, monitoring, and surveillance of all medication prescriptions in Ontario allowing adherence rates to be determined with precision using prescription refill data The objective of this study was to explore the relationship between drug adherence and mortality in survivors of acute myocardial infarction (AMI) focused on seniors aged 65 years or older because:The objective of this study was to explore the relationship between drug adherence and mortality in survivors of acute myocardial infarction (AMI) focused on seniors aged 65 years or older because: –Elderly are more vulnerable with higher CV risk and propensity for premature drug discontinuation due to complexities in medical regimens, tolerance, and concerns about adverse effects –In Canada, medications are free for patients ≥65, thus affordability factors should not affect adherence –Administrative data allows for tracking, monitoring, and surveillance of all medication prescriptions in Ontario allowing adherence rates to be determined with precision using prescription refill data Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Background Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186

4. Clinical Trial Results. org Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186 31,455 patients > 66 years surviving at least 1 year and 3 months after hospitalization with AMI between April 1, 1999 and May 1, 2003. Excluding patients who had been hospitalized with an AMI in the year before the index admission. Population-based. Observational. Longitudinal. Median follow-up 2.4 years. All patients had to fill at least 1 of 3 medications. They were divided into 3 categories according to proportion of days covered (PDC): High Adherence (High, >80% days), Intermediate Adherence (Intermediate, 40-79% days), and Low Adherence (Low, 80% days), Intermediate Adherence (Intermediate, 40-79% days), and Low Adherence (Low, <40% days) 31,455 patients > 66 years surviving at least 1 year and 3 months after hospitalization with AMI between April 1, 1999 and May 1, 2003. Excluding patients who had been hospitalized with an AMI in the year before the index admission. Population-based. Observational. Longitudinal. Median follow-up 2.4 years. All patients had to fill at least 1 of 3 medications. They were divided into 3 categories according to proportion of days covered (PDC): High Adherence (High, >80% days), Intermediate Adherence (Intermediate, 40-79% days), and Low Adherence (Low, 80% days), Intermediate Adherence (Intermediate, 40-79% days), and Low Adherence (Low, <40% days) Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Study Design Statins (Recommended in secondary prevention after MI-class 1 level of evidence) Statins β-blockers (Recommended in secondary prevention after MI-class 1 level of evidence) β-blockers (Recommended in secondary prevention after MI-class 1 level of evidence) Calcium channel blockers (Not recommended as first-choice drug in secondary prevention-class 2 level of evidence) Calcium channel blockers (Not recommended as first-choice drug in secondary prevention-class 2 level of evidence) High Intermediate Low High Intermediate Low High Intermediate Low 2.4 years follow-up  Primary Endpoint: Long-term mortality

5. Clinical Trial Results. org Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186 Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Association of Pt. Characteristics with 1 Year Adherence Level Increasing age, psychiatric illness, and increasing numbers of recurrent admissions within the year following AMI remained as independent determinants of poorer adherence to both statins and beta-blockers (p<0.001); however, prior evidence-based medication use within 6 months preceding the index AMI hospitalization was associated with improved adherence to these therapies (p<0.001).Increasing age, psychiatric illness, and increasing numbers of recurrent admissions within the year following AMI remained as independent determinants of poorer adherence to both statins and beta-blockers (p<0.001); however, prior evidence-based medication use within 6 months preceding the index AMI hospitalization was associated with improved adherence to these therapies (p<0.001). Post-MI revascularization was associated with improved adherence to statins but higher discontinuation rates of beta-blockers and calcium channel blockers, which may have been partially attributable to lower symptom burden among those who had successful revascularization.Post-MI revascularization was associated with improved adherence to statins but higher discontinuation rates of beta-blockers and calcium channel blockers, which may have been partially attributable to lower symptom burden among those who had successful revascularization. Increasing age, psychiatric illness, and increasing numbers of recurrent admissions within the year following AMI remained as independent determinants of poorer adherence to both statins and beta-blockers (p<0.001); however, prior evidence-based medication use within 6 months preceding the index AMI hospitalization was associated with improved adherence to these therapies (p<0.001).Increasing age, psychiatric illness, and increasing numbers of recurrent admissions within the year following AMI remained as independent determinants of poorer adherence to both statins and beta-blockers (p<0.001); however, prior evidence-based medication use within 6 months preceding the index AMI hospitalization was associated with improved adherence to these therapies (p<0.001). Post-MI revascularization was associated with improved adherence to statins but higher discontinuation rates of beta-blockers and calcium channel blockers, which may have been partially attributable to lower symptom burden among those who had successful revascularization.Post-MI revascularization was associated with improved adherence to statins but higher discontinuation rates of beta-blockers and calcium channel blockers, which may have been partially attributable to lower symptom burden among those who had successful revascularization.

6. Clinical Trial Results. org After adjustment for baseline characteristics, the risk of mortality was 12% higher for patients with intermediate adherence (p=0.03) and 25% higher among patients with poor adherence (p=0.001) as compared with high adherence statin users.After adjustment for baseline characteristics, the risk of mortality was 12% higher for patients with intermediate adherence (p=0.03) and 25% higher among patients with poor adherence (p=0.001) as compared with high adherence statin users. Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186 Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Primary Endpoint Kaplan-Meier estimates of long-term mortality for statins according to adherence Patients Surviving (%) Patients Surviving (%)

7. Clinical Trial Results. org There was a directional association between adherence with β- blockers and long-term mortality.There was a directional association between adherence with β- blockers and long-term mortality. The magnitude of association between adherence and mortality was smaller with β-blockers than it was with statins.The magnitude of association between adherence and mortality was smaller with β-blockers than it was with statins. Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186 Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Primary Endpoint Kaplan-Meier estimates of long-term mortality for β-blockers according to adherence Patients Surviving (%) Patients Surviving (%)

8. Clinical Trial Results. org There was no relationship between calcium channel blocker adherence and long-term mortality.There was no relationship between calcium channel blocker adherence and long-term mortality. Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186 Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Primary Endpoint Kaplan-Meier estimates of long-term mortality for calcium channel blockers according to adherence Patients Surviving (%) Patients Surviving (%)

9. Clinical Trial Results. org Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Limitations The study does not reflect relationship of adherence to mortality for other secondary prevention pharmacotherapies such as over the counter medications (e.g. aspirin).The study does not reflect relationship of adherence to mortality for other secondary prevention pharmacotherapies such as over the counter medications (e.g. aspirin). LV function was not adjusted for, but many factors, including comorbidity, risk severity, and concomitant and preexisting use of evidence-based therapies.LV function was not adjusted for, but many factors, including comorbidity, risk severity, and concomitant and preexisting use of evidence-based therapies. The study does not reflect relationship of adherence to mortality for other secondary prevention pharmacotherapies such as over the counter medications (e.g. aspirin).The study does not reflect relationship of adherence to mortality for other secondary prevention pharmacotherapies such as over the counter medications (e.g. aspirin). LV function was not adjusted for, but many factors, including comorbidity, risk severity, and concomitant and preexisting use of evidence-based therapies.LV function was not adjusted for, but many factors, including comorbidity, risk severity, and concomitant and preexisting use of evidence-based therapies. Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186

10. Clinical Trial Results. org Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Limitations Cont. Second, the data contain no information regarding potential adverse reactions, allergies or intolerance, all of which can potentially explain early discontinuation of therapy.Second, the data contain no information regarding potential adverse reactions, allergies or intolerance, all of which can potentially explain early discontinuation of therapy. However, the incidence of adverse drug reactions is relatively low, usually occurs early in therapy, and is unlikely to entirely account for non- adherence.However, the incidence of adverse drug reactions is relatively low, usually occurs early in therapy, and is unlikely to entirely account for non- adherence. Second, the data contain no information regarding potential adverse reactions, allergies or intolerance, all of which can potentially explain early discontinuation of therapy.Second, the data contain no information regarding potential adverse reactions, allergies or intolerance, all of which can potentially explain early discontinuation of therapy. However, the incidence of adverse drug reactions is relatively low, usually occurs early in therapy, and is unlikely to entirely account for non- adherence.However, the incidence of adverse drug reactions is relatively low, usually occurs early in therapy, and is unlikely to entirely account for non- adherence. Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186

11. Clinical Trial Results. org Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Limitations Cont. Third, the study used prescriptions to estimate adherence and had no information on actual medication adherence or other healthy lifestyle behaviors (i.e. smoking cessation, diet, and physical activity).Third, the study used prescriptions to estimate adherence and had no information on actual medication adherence or other healthy lifestyle behaviors (i.e. smoking cessation, diet, and physical activity). Nevertheless, this measure has been shown to correlate with pill counts, and is not subject to recall bias.Nevertheless, this measure has been shown to correlate with pill counts, and is not subject to recall bias. Third, the study used prescriptions to estimate adherence and had no information on actual medication adherence or other healthy lifestyle behaviors (i.e. smoking cessation, diet, and physical activity).Third, the study used prescriptions to estimate adherence and had no information on actual medication adherence or other healthy lifestyle behaviors (i.e. smoking cessation, diet, and physical activity). Nevertheless, this measure has been shown to correlate with pill counts, and is not subject to recall bias.Nevertheless, this measure has been shown to correlate with pill counts, and is not subject to recall bias. Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186

12. Clinical Trial Results. org Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Summary Adherence to evidence-based pharmacotherapy is associated with improved survival following AMI.Adherence to evidence-based pharmacotherapy is associated with improved survival following AMI. Specifically, for statins and β-blockers, adherence correlated with improved survival in a graded dose- response fashion.Specifically, for statins and β-blockers, adherence correlated with improved survival in a graded dose- response fashion. Conversely, adherence with calcium channel blockers, a drug-class with no proven post-MI survival advantages, was not associated with improved survival.Conversely, adherence with calcium channel blockers, a drug-class with no proven post-MI survival advantages, was not associated with improved survival. Adherence to evidence-based pharmacotherapy is associated with improved survival following AMI.Adherence to evidence-based pharmacotherapy is associated with improved survival following AMI. Specifically, for statins and β-blockers, adherence correlated with improved survival in a graded dose- response fashion.Specifically, for statins and β-blockers, adherence correlated with improved survival in a graded dose- response fashion. Conversely, adherence with calcium channel blockers, a drug-class with no proven post-MI survival advantages, was not associated with improved survival.Conversely, adherence with calcium channel blockers, a drug-class with no proven post-MI survival advantages, was not associated with improved survival. Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186

13. Clinical Trial Results. org Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Summary Cont. The long-term survival advantages associated with improved drug-adherence after AMI appear to be class-specific, suggesting that adherence outcome benefits are mediated by drug effects and do not merely reflect an epiphenomenon of “healthy adherer” behavioral attributes.The long-term survival advantages associated with improved drug-adherence after AMI appear to be class-specific, suggesting that adherence outcome benefits are mediated by drug effects and do not merely reflect an epiphenomenon of “healthy adherer” behavioral attributes. Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186