This is the first study analyzing the influence of PDC-rates in guideline recommended medication after AMI on health care expenditures with longitudinal real-world data. It seems that the absolute mean PDC-rate (inter-individual effect) only has minimal influence, while a deviation from this mean (intra-individual effect) has a large impact on health care expenditures. These results were quite robust in sensitivity analyses. Two different effects may partly explain this phenomenon. First, health care expenditures in the first year after AMI were much higher than in the consecutive years, and the deviation from the mean PDC-rate in the first year is most of the time positive, as the PDC-rates were highest in the first year after AMI. Second, a positive deviation of PDC-rates might be the reason for reverse causation, as it could be an indicator for worsening of the health status of a patient, leading to higher adherence of guideline-recommended medication. We adjusted for both effects by including the year after AMI and a time varying comorbidity index into the regression analysis.
Previously published literature from clinical trials led to the assumption that differences between sexes might exist regarding effectiveness of β-blockers (37–39), and ACE inhibitors (40–42). Interestingly, mean PDC-rate as well as deviations from mean PDC-rate for both men and women were significant in anti-platelet agents. For statins the intra-individual effect (deviation from the mean PDC-rate) became significant only in female. Significant differences between deviations from the mean were seen in ACE inhibitors in females, and β-blockers in males, which is in line with the findings of the clinical trials. For ACE inhibitors a deviation from the mean PDC-rate seems to be connected to a higher increase in costs in females compared to males. With respect to β-blockers an increasing negative deviation is associated with increasing costs while an increasing positive deviation is associated with increasing costs, which could be found in both sexes, but is more pronounced in male.
Overall, observed mean PDC-rates were lower than expected, given a threshold for adherence of 80% in most publications (48–52). Only the mean for statins was above 80% in men. Especially for anti-platelet agents PDC-rates were low in both sexes, ranging from 46.42% in males in the first year after AMI to 25.41% in females in the third year. The quite moderate declines from year 1 to 3 in β-blockers are interesting, as the guidelines (9, 10) recommend β-blockers after AMI only for up to two years.
Comparison with literature
Only three studies (28–30) were published so far measuring the influence of adherence of one (28, 29) or two (30) guideline-recommended medications after AMI on health care expenditures.
In a retrospective claims data analysis of a large US health insurer Bansilal et al. (30) measured the influence of statins and ACE-inhibitors adherence on hospitalization costs in a follow-up period up to three years, which was measured with PDC-rates (> 80% fully adherent; 40–79% partially adherent; and < 40% non-adherent). Full adherence to statins and ACE inhibitors was associated with reduced per-patient annual hospitalization costs for AMI and for revascularization procedures compared with partial and non-adherence.
Sun et al. (28) analyzed in a large US national pharmacy-benefit database the influence of adherence, which was measured with medication possession ratio (MPR) (> 80% fully adherent; 40–79% partially adherent; and < 40% non-adherent), in a 1-year follow-up period, to renin-angiotensin system agents (ACE inhibitors or angiotensin receptor blockers) on costs. They found that partially adherent and the fully adherent groups had significantly lower cardiovascular-related and total health care costs than the non-adherent group.
Summaria et al. (29) measured in an Italian retrospective observational study of administrative database (not further specified), the influence of statin adherence on health care expenditures in a follow-up period up to 3-years, using MPR (> 80%; 50–79%, 25–50%, < 25%). They found mean health care expenditures to increase from the non-adherent to the fully adherent group.
By focusing on PDCs (30) and MPRs (28, 29) previous studies used measures of adherence that were quite similar, yet with varying adherence thresholds, except for the fully adherent group (which was > 80% in all studies). The results of the two US studies (28, 30) indicate cost savings, while the only European (Italian) study (29) reported the highest health care expenditures in the fully adherent group.
Our results are not directly comparable, as we used a longitudinal approach considering all four guideline-recommended medications simultaneously. In addition, we chose an inter- (mean PDC-rate over the complete period) and intra-individual (deviation of the mean PDC-rate of a person in the observed year) approach to measure the influence of adherence on health care expenditures. Nevertheless, the findings of our analysis are to some degree in line with earlier findings, as we found no influence of statins but a significant negative influence of higher PDC-rates in ACE-inhibitors on health care expenditures in women.
So far, there are no previous observational studies based on German data that would allow comparing our results regarding health care expenditures. Comparison is possible only with respect to adherence to guideline-recommended medication and its development over time (18, 25, 53). In this regard, our findings are quite similar to their observations.
In the Cologne Infarction Model (KIM) Reuter and colleagues (25) measured self-reported adherence of 610 consecutive patients with ST-elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI) at hospital discharge and after a median follow-up period of 36 months. Respective proportions of adherence for ASS, statins, β-blockers, ACE-inhibitors or angiotensin-receptor blockers were at hospital discharge between 90.8 and 97.6% and at follow-up between 79.2% and 90.8%.
Amann et al. (53) measured self-reported adherence in 1,667 AMI patients from the MONICA/KORA cohort in a survey at hospital discharge and at a mean follow-up time of 6.1 years. The proportion of patients taking antiplatelet agents, β-blockers, statins, and renin-angiotensin-aldosterone system blockers were at hospital discharge between 83.6% and 97.5% and at follow-up between 79.3% and 90.9%.
Mangiapane et al. (18) analyzed prescriptions in a sample of 30,028 AMI patients insured at Techniker Krankenkasse. They found that prescription rates declined from 82% in β-blockers, 73% in statins, 69% in ACE inhibitors, and 66% in platelet aggregation inhibitors at hospital discharge to 36% in β-blockers, 17% in statins, 31% in ACE inhibitors, and 10% in platelet aggregation inhibitors after a follow-up of 5-years. Although different methods for determining adherence were used (self-reported adherence (25, 53), treatment persistence (18), and yearly PDC-rates in our study), the findings indicate a general decline in guideline recommended medication intake over time after AMI. The decline appears to be even more pronounced when the data basis are claims data rather than self-reported data.
Some potential limitations of this study should be considered while interpreting the results.
For β-blockers, national guidelines (54) recommend intake only for 1 up to 2 years after the AMI; we measured the mean PDC-rate over the complete 3-year follow-up period, which might underestimate the positive impact of adherence to β-blockers.
Pharmacy dispensing data were used as a measure of PDC-rates, which does not allow definite judgment as to whether patients had actually taken the paid for and collected medication. However, pharmacy refill records have been found to be highly correlated with electronic adherence monitoring, and the act of refilling a medication has been argued to reflect the patient’s active decision to continue with therapy (55). Furthermore, the number of days that needed to be covered with prescribed medication was reduced by the number of hospital days in the follow-up period because medication was presumably provided by the hospital during hospitalization. This means that a higher percentage of time spent in hospital, which increases costs, also increases the mean PDC-rate and positive deviation from mean PDC-rate.
Adherence to anti-platelet agents may be underestimated, as Aspirin 100 mg has a co-payment of 100% and is available over the counter. Although physicians can still prescribe aspirin after AMI, its removal from reimbursement had a clear effect on prescription incidence, which dropped from 72% in 2003 to 57% in 2004 (18). An ongoing prescription of anti-platelet agents might identify high-risk patients, as the physician makes sure, with the inclusion of Aspirin 100 mg on the prescription, the patient has not to additionally order it in the pharmacy. Therefore, our finding that a higher PDC-rate in anti-platelet agents causes higher health care expenditures should be interpreted with caution.
We did not exclude persons who were never prescribed any of the four medications as other studies measuring adherence or persistence did (29, 30). We wanted to measure adherence to guideline recommended medication, which are the same for every patient after AMI, except for contraindications, which we could not capture in a retrospective claims data analysis. Therefore, the findings might not be directly comparable.
Our study population was enrolled in the DMP CAD at index AMI, which is voluntary, and therefore we could not exclude a self-selection effect of patients leading to an overestimation of PDC rates. However, the DMP CAD might include the more severe cases, as a diagnosed CAD, which is an inclusion criterion for the DMP, existed before AMI.
Finally, as individual socioeconomic status is usually not sufficiently reflected in routine data, we incorporated an area deprivation index for Bavaria (BIMD 2010) as a proxy. Nevertheless, this procedure is a standard approach in corresponding studies utilizing claims or register data and the index used is a well-established and recognized tool to address such limitations (46).
Aside from these aspects, to the best of our knowledge this is the first study considering the influence of all four guideline recommended medications on health care expenditures, which likely gives a more realistic picture of the effectiveness of adherence to guideline-recommended medications after AMI because positive correlation of adherence to other guideline-recommended medications is accounted for (53). If this effect is not considered, the positive impact of one type of medication might be overestimated, as the positive impact of adherence to another type of medication is attributed to the medication under scrutiny.
Additionally, our sample size was large enough to stratify the analysis for sex, as there is evidence that there are differences in effectiveness of ACE-inhibitors and β-blockers between females and males. To what extend these differences influence health care expenditures were not investigated to date.
Furthermore, the generalized additive mixed model incorporates a longitudinal design which seems to be more appropriate than a cross sectional design, as it also controls for individual changes over time.
In addition, a relatively long period of 4 years was available for every patient, which means that information from the year before AMI could be considered in the analyses, such as medication stocks that patients had before the AMI, leading to a more realistic estimate of the PDC-rate.