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Relationship Between Adherence to Evidence-Relationship Between Adherence to Evidence-Based Pharmacotherapy and Long-term Based Pharmacotherapy and Long-term

Mortality After Acute Myocardial InfarctionMortality After Acute Myocardial Infarction

Relationship Between Adherence to Evidence-Relationship Between Adherence to Evidence-Based Pharmacotherapy and Long-term Based Pharmacotherapy and Long-term

Mortality After Acute Myocardial InfarctionMortality After Acute Myocardial Infarction

Jeppe N. Rasmussen, MD; Alice Chong, BSc; Jeppe N. Rasmussen, MD; Alice Chong, BSc;

David A. Alter, MD, PhD, FRCPCDavid A. Alter, MD, PhD, FRCPC

Published in JAMA Published in JAMA

January 2007January 2007

Relationship Between Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After Acute Myocardial Infarction

Relationship Between Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After Acute Myocardial Infarction


• The extent to which drug adherence may affect survival The extent to which drug adherence may affect survival remains unclear, in part because mortality differences remains unclear, in part because mortality differences may be attributable to “healthy adherer” behavioral may be attributable to “healthy adherer” behavioral attributes more so than to pharmacologic benefits.attributes more so than to pharmacologic benefits.

• Although it is known that adherence to evidence-based Although it is known that adherence to evidence-based pharmacotherapy predicts better survival, no population pharmacotherapy predicts better survival, no population outcome study has attempted to differentiate whether outcome study has attempted to differentiate whether these associations are attributable to the drug’s these associations are attributable to the drug’s biological responsiveness (herein termed biological responsiveness (herein termed drug effectdrug effect) or ) or to the adoption of healthier lifestyles that often to the adoption of healthier lifestyles that often accompany adherent behaviors (herein termed accompany adherent behaviors (herein termed healthy healthy adherer effectadherer effect).).

• The extent to which drug adherence may affect survival The extent to which drug adherence may affect survival remains unclear, in part because mortality differences remains unclear, in part because mortality differences may be attributable to “healthy adherer” behavioral may be attributable to “healthy adherer” behavioral attributes more so than to pharmacologic benefits.attributes more so than to pharmacologic benefits.

• Although it is known that adherence to evidence-based Although it is known that adherence to evidence-based pharmacotherapy predicts better survival, no population pharmacotherapy predicts better survival, no population outcome study has attempted to differentiate whether outcome study has attempted to differentiate whether these associations are attributable to the drug’s these associations are attributable to the drug’s biological responsiveness (herein termed biological responsiveness (herein termed drug effectdrug effect) or ) or to the adoption of healthier lifestyles that often to the adoption of healthier lifestyles that often accompany adherent behaviors (herein termed accompany adherent behaviors (herein termed healthy healthy adherer effectadherer effect).).

Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186 Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186

Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Background



• The objective of this study was to explore the relationship The objective of this study was to explore the relationship between drug adherence and mortality in survivors of acute between drug adherence and mortality in survivors of acute myocardial infarction (AMI) focused on seniors aged 65 myocardial infarction (AMI) focused on seniors aged 65 years or older because:years or older because:

– Elderly are more vulnerable with higher CV risk and Elderly are more vulnerable with higher CV risk and propensity for premature drug discontinuation due to propensity for premature drug discontinuation due to complexities in medical regimens, tolerance, and concerns complexities in medical regimens, tolerance, and concerns about adverse effectsabout adverse effects

– In Canada, medications are free for patients In Canada, medications are free for patients ≥65, thus ≥65, thus affordability factors should not affect adherenceaffordability factors should not affect adherence

– Administrative data allows for tracking, monitoring, and Administrative data allows for tracking, monitoring, and surveillance of all medication prescriptions in Ontario surveillance of all medication prescriptions in Ontario allowing adherence rates to be determined with precision allowing adherence rates to be determined with precision using prescription refill datausing prescription refill data

• The objective of this study was to explore the relationship The objective of this study was to explore the relationship between drug adherence and mortality in survivors of acute between drug adherence and mortality in survivors of acute myocardial infarction (AMI) focused on seniors aged 65 myocardial infarction (AMI) focused on seniors aged 65 years or older because:years or older because:

– Elderly are more vulnerable with higher CV risk and Elderly are more vulnerable with higher CV risk and propensity for premature drug discontinuation due to propensity for premature drug discontinuation due to complexities in medical regimens, tolerance, and concerns complexities in medical regimens, tolerance, and concerns about adverse effectsabout adverse effects

– In Canada, medications are free for patients In Canada, medications are free for patients ≥65, thus ≥65, thus affordability factors should not affect adherenceaffordability factors should not affect adherence

– Administrative data allows for tracking, monitoring, and Administrative data allows for tracking, monitoring, and surveillance of all medication prescriptions in Ontario surveillance of all medication prescriptions in Ontario allowing adherence rates to be determined with precision allowing adherence rates to be determined with precision using prescription refill datausing prescription refill data




Clinical Trial Results . orgClinical Trial Results . org Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186 Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186

31,455 patients 31,455 patients >> 66 years surviving at least 1 year and 3 months after hospitalization with 66 years surviving at least 1 year and 3 months after hospitalization with AMI between April 1, 1999 and May 1, 2003.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.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.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 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, covered (PDC): High Adherence (High, >>80% days), Intermediate Adherence (Intermediate, 40-79% days), and Low 80% days), Intermediate Adherence (Intermediate, 40-79% days), and Low

Adherence (Low, <40% days)Adherence (Low, <40% days)

31,455 patients 31,455 patients >> 66 years surviving at least 1 year and 3 months after hospitalization with 66 years surviving at least 1 year and 3 months after hospitalization with AMI between April 1, 1999 and May 1, 2003.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.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.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 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, covered (PDC): High Adherence (High, >>80% days), Intermediate Adherence (Intermediate, 40-79% days), and Low 80% days), Intermediate Adherence (Intermediate, 40-79% days), and Low

Adherence (Low, <40% days)Adherence (Low, <40% days)

Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Study DesignAdherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Study Design

StatinsStatins

(Recommended in secondary (Recommended in secondary prevention after MI-class 1 prevention after MI-class 1

level of evidence)level of evidence)

StatinsStatins



ββ-blockers-blockers



ββ-blockers-blockers



Calcium channel blockersCalcium channel blockers

(Not recommended as first-choice (Not recommended as first-choice drug in secondary prevention-drug in secondary prevention-

class 2 level of evidence)class 2 level of evidence)

Calcium channel blockersCalcium channel blockers

(Not recommended as first-choice (Not recommended as first-choice drug in secondary prevention-drug in secondary prevention-

class 2 level of evidence)class 2 level of evidence)

HighHigh IntermediateIntermediate LowLow



2.4 years follow-up 2.4 years follow-up

Primary Endpoint: Long-term mortalityPrimary Endpoint: Long-term mortality Primary Endpoint: Long-term mortalityPrimary Endpoint: Long-term mortality

Clinical Trial Results . orgClinical Trial Results . org Rasmussen et al., JAMA. 2007 Jan; 297(2):177-186 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

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 Increasing age, psychiatric illness, and increasing numbers of recurrent admissions within the year following AMI of recurrent admissions within the year following AMI remained as independent determinants of poorer remained as independent determinants of poorer adherence to both statins and beta-blockers (p<0.001); adherence to both statins and beta-blockers (p<0.001); however, prior evidence-based medication use within 6 however, prior evidence-based medication use within 6 months preceding the index AMI hospitalization was months preceding the index AMI hospitalization was associated with improved adherence to these therapies associated with improved adherence to these therapies (p<0.001).(p<0.001).

• Post-MI revascularization was associated with improved Post-MI revascularization was associated with improved adherence to statins but higher discontinuation rates of adherence to statins but higher discontinuation rates of beta-blockers and calcium channel blockers, which may beta-blockers and calcium channel blockers, which may have been partially attributable to lower symptom burden have been partially attributable to lower symptom burden among those who had successful revascularization.among those who had successful revascularization.

• Increasing age, psychiatric illness, and increasing numbers Increasing age, psychiatric illness, and increasing numbers of recurrent admissions within the year following AMI of recurrent admissions within the year following AMI remained as independent determinants of poorer remained as independent determinants of poorer adherence to both statins and beta-blockers (p<0.001); adherence to both statins and beta-blockers (p<0.001); however, prior evidence-based medication use within 6 however, prior evidence-based medication use within 6 months preceding the index AMI hospitalization was months preceding the index AMI hospitalization was associated with improved adherence to these therapies associated with improved adherence to these therapies (p<0.001).(p<0.001).

• Post-MI revascularization was associated with improved Post-MI revascularization was associated with improved adherence to statins but higher discontinuation rates of adherence to statins but higher discontinuation rates of beta-blockers and calcium channel blockers, which may beta-blockers and calcium channel blockers, which may have been partially attributable to lower symptom burden have been partially attributable to lower symptom burden among those who had successful revascularization.among those who had successful revascularization.


• After adjustment for After adjustment for baseline baseline characteristics, the characteristics, the risk of mortality was risk of mortality was 12% higher for 12% higher for patients with patients with intermediate intermediate adherence (p=0.03) adherence (p=0.03) and 25% higher and 25% higher among patients with among patients with poor adherence poor adherence (p=0.001) as compared (p=0.001) as compared with high adherence with high adherence statin users.statin users.


Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Primary Endpoint


Kaplan-Meier estimates of long-term mortality for statins Kaplan-Meier estimates of long-term mortality for statins according to adherenceaccording to adherence

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• There was a directional There was a directional association between association between adherence with adherence with ββ--blockers blockers and long-term and long-term mortality. mortality.

• The magnitude of The magnitude of association between association between adherence and adherence and mortality was smaller mortality was smaller with with ββ-blockers-blockers than it than it was with statins.was with statins.




Kaplan-Meier estimates of long-term mortality for Kaplan-Meier estimates of long-term mortality for ββ-blockers-blockers according to adherenceaccording to adherence

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• There was no There was no relationship relationship between calcium between calcium channel blocker channel blocker adherence and adherence and long-term mortality.long-term mortality.




Kaplan-Meier estimates of long-term mortality for calcium channel Kaplan-Meier estimates of long-term mortality for calcium channel blockers according to adherenceblockers according to adherence

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Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Limitations

Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Limitations

• The study does not reflect relationship of The study does not reflect relationship of adherence to mortality for other secondary adherence to mortality for other secondary prevention pharmacotherapies such as over prevention pharmacotherapies such as over the counter medications (e.g. aspirin).the counter medications (e.g. aspirin).

• LV function was not adjusted for, but many LV function was not adjusted for, but many factors, including comorbidity, risk severity, factors, including comorbidity, risk severity, and concomitant and preexisting use of and concomitant and preexisting use of evidence-based therapies.evidence-based therapies.

• The study does not reflect relationship of The study does not reflect relationship of adherence to mortality for other secondary adherence to mortality for other secondary prevention pharmacotherapies such as over prevention pharmacotherapies such as over the counter medications (e.g. aspirin).the counter medications (e.g. aspirin).

• LV function was not adjusted for, but many LV function was not adjusted for, but many factors, including comorbidity, risk severity, factors, including comorbidity, risk severity, and concomitant and preexisting use of and concomitant and preexisting use of evidence-based therapies.evidence-based therapies.



Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Limitations Cont.


• Second, the data contain no information Second, the data contain no information regarding potential adverse reactions, allergies or regarding potential adverse reactions, allergies or intolerance, all of which can potentially explain intolerance, all of which can potentially explain early discontinuation of therapy.early discontinuation of therapy.

• However, the incidence of adverse drug reactions However, the incidence of adverse drug reactions is relatively low, usually occurs early in therapy, is relatively low, usually occurs early in therapy, and is unlikely to entirely account for non-and is unlikely to entirely account for non-adherence.adherence.

• Second, the data contain no information Second, the data contain no information regarding potential adverse reactions, allergies or regarding potential adverse reactions, allergies or intolerance, all of which can potentially explain intolerance, all of which can potentially explain early discontinuation of therapy.early discontinuation of therapy.

• However, the incidence of adverse drug reactions However, the incidence of adverse drug reactions is relatively low, usually occurs early in therapy, is relatively low, usually occurs early in therapy, and is unlikely to entirely account for non-and is unlikely to entirely account for non-adherence.adherence.





• Third, the study used prescriptions to estimate Third, the study used prescriptions to estimate adherence and had no information on actual adherence and had no information on actual medication adherence or other healthy lifestyle medication adherence or other healthy lifestyle behaviors (i.e. smoking cessation, diet, and behaviors (i.e. smoking cessation, diet, and physical activity).physical activity).

• Nevertheless, this measure has been shown to Nevertheless, this measure has been shown to correlate with pill counts, and is not subject to recall correlate with pill counts, and is not subject to recall bias.bias.

• Third, the study used prescriptions to estimate Third, the study used prescriptions to estimate adherence and had no information on actual adherence and had no information on actual medication adherence or other healthy lifestyle medication adherence or other healthy lifestyle behaviors (i.e. smoking cessation, diet, and behaviors (i.e. smoking cessation, diet, and physical activity).physical activity).

• Nevertheless, this measure has been shown to Nevertheless, this measure has been shown to correlate with pill counts, and is not subject to recall correlate with pill counts, and is not subject to recall bias.bias.



Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Summary

Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Summary

• Adherence to evidence-based pharmacotherapy is Adherence to evidence-based pharmacotherapy is associated with improved survival following AMI.associated with improved survival following AMI.

• Specifically, for statins and Specifically, for statins and ββ-blockers, adherence -blockers, adherence correlated with improved survival in a graded dose- correlated with improved survival in a graded dose- response fashion.response fashion.

• Conversely, adherence with calcium channel blockers, a Conversely, adherence with calcium channel blockers, a drug-class with no proven post-MI survival advantages, drug-class with no proven post-MI survival advantages, was not associated with improved survival.was not associated with improved survival.

• Adherence to evidence-based pharmacotherapy is Adherence to evidence-based pharmacotherapy is associated with improved survival following AMI.associated with improved survival following AMI.

• Specifically, for statins and Specifically, for statins and ββ-blockers, adherence -blockers, adherence correlated with improved survival in a graded dose- correlated with improved survival in a graded dose- response fashion.response fashion.

• Conversely, adherence with calcium channel blockers, a Conversely, adherence with calcium channel blockers, a drug-class with no proven post-MI survival advantages, drug-class with no proven post-MI survival advantages, was not associated with improved survival.was not associated with improved survival.



Adherence to Evidence-Based Pharmacotherapy and Long-term Mortality After AMI: Summary Cont.Adherence to Evidence-Based Pharmacotherapy

and Long-term Mortality After AMI: Summary Cont.

• The long-term survival advantages associated with The long-term survival advantages associated with improved drug-adherence after AMI appear to be improved drug-adherence after AMI appear to be class-specific, suggesting that adherence outcome class-specific, suggesting that adherence outcome benefits are mediated by drug effects and do not benefits are mediated by drug effects and do not merely reflect an epiphenomenon of “healthy merely reflect an epiphenomenon of “healthy adherer” behavioral attributes.adherer” behavioral attributes.

• The long-term survival advantages associated with The long-term survival advantages associated with improved drug-adherence after AMI appear to be improved drug-adherence after AMI appear to be class-specific, suggesting that adherence outcome class-specific, suggesting that adherence outcome benefits are mediated by drug effects and do not benefits are mediated by drug effects and do not merely reflect an epiphenomenon of “healthy merely reflect an epiphenomenon of “healthy adherer” behavioral attributes.adherer” behavioral attributes.


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