Adherence to Antihypertensive Therapy Prior to Stroke
Adherence to Antihypertensive Therapy Prior to Stroke
In this large-scale, population-based linkage study, hypertensive patients who subsequently died or were hospitalized due to stroke had a lower adherence to antihypertensive medication already 2 years after receiving special reimbursement for continuous antihypertensive therapy than did the patients who did not experience stroke during the follow-up. Non-adherence to antihypertensive medication was associated with a 5.7-fold increased odds of fatal stroke during the year of death and a two-fold increased risk of non-fatal stroke. For those using agents acting on the renin–angiotensin system combined with diuretics and/or β-blockers, the corresponding OR was 7.5 for stroke death and 3.9 for hospitalization. Our dose–response analyses based on categories of high, intermediate, and low adherence to antihypertensive medication confirmed that the near- and long-term risk of fatal and non-fatal stroke increased at each step down the level of adherence.
To our knowledge, this is the first study to estimate trajectories of adherence to antihypertensive therapy prior to fatal or non-fatal incident stroke among hypertensive patients. Our findings are in agreement with previous investigations that have suggested a high adherence to antihypertensive therapy is associated with a lower risk of stroke or other cardiovascular events. An Italian study also found that, compared with patients with poor adherence, those with good (hazard ratio 0.69, P < 0.001) or excellent adherence (hazard ratio 0.53, P < 0.001) had a significantly lower risk for the combined outcome of all-cause death, fatal or non-fatal stroke, and fatal or non-fatal acute myocardial infarction even though separate analyses for the stroke outcomes showed no statistically significant differences between the adherence groups. An ecologic time-series study based on yearly official reports of stroke and coronary disease mortality and the use of antihypertensive medication in three Hungarian counties found a correlation between the use of high-ceiling diuretics or calcium channel blockers and decreased stroke mortality. Our analysis was unique, as none of these studies assessed adherence repeatedly over time at the individual level.
A major strength of our study was the large-scale population-based sample of Finns with an 80% oversample of deaths and linkage to comprehensive drug and hospitalization registration that allowed us to conduct a year-by-year analysis of adherence trajectories in relation to stroke events. The nationwide closed record system for both prescriptions and deaths meant that there was virtually no drop out or sample attrition during the follow-up. Information on hospitalization was essential to ensure that the patients were free of stroke and cardiovascular disease at baseline and thus were targets for primary rather than secondary prevention. We assessed stroke risk on the basis of records of non-fatal and fatal stroke, of which the latter, in particular, is a valid stroke outcome. For example, in a study of in-hospital deaths coded for participants in the Minnesota Heart Study, death certificates missed a proportion of stroke deaths, but deaths that were identified as stroke deaths were virtually all correct on the death certificates. The Finnish death register, which we used, has been ranked high with respect to reliability and accuracy in international comparisons. Therefore, bias due to coding error is an unlikely explanation for our results.
Our results have some limitations. First, although pharmacy refill records are objective measures and are collected routinely, they do not necessarily indicate whether the participants actually took the medications. It is possible that some of the participants characterized as adherents did not actually take their medication despite filling their prescriptions. Such misclassifications would lead to an overestimation of adherence but would bias the adherence–stroke relation only if they affect differently those who develop stroke vs. do not. Secondly, as the diagnosis of hypertension was based on health care records (more precisely eligibility to special reimbursement due to chronic hypertension) rather than a clinical examination at baseline, some imprecision in the inclusion of the participants is possible. While the participants were likely to be true hypertension cases, they did not include undiagnosed hypertensive individuals with a need for antihypertensive medication. However, this limitation is an unlikely source for major confounding in the association between adherence and stroke risk. Thirdly, data on such covariates as body mass index, smoking, alcohol consumption, and resting blood pressure were not available from the registers, and therefore analyses to identify subgroups particularly vulnerable to the harmful effects of non-adherence or patients with poorly controlled blood pressure despite adherence to drug therapy were precluded. Fourthly, the healthy user bias (i.e. the correlation between adherence and other behaviour-related risk factors) may artificially inflate associations between non-adherence and disease outcomes in observational studies on preventive medications, such as ours. However, this was an unlikely explanation for the accelerated decline in adherence that we observed 4 years before stroke death. Fifthly, the stringent exclusion criteria of our study population may have affected the assessment of the prevalence of adherence to medication. Further research to determine the generalizability of our findings is needed.
Given that randomization to different adherence groups is unethical, it is unlikely that trial evidence will be available on the effect of adherence to antihypertensive medication on fatal or non-fatal stroke events. Our findings from observational data show a lower adherence to antihypertensive medication already 9 years before a fatal or non-fatal stroke event among hypertensive patients; in the year of the stroke event, the association with non-adherence was the strongest. A dose–response relationship (the more non-adherent the greater the risk) was evident across the entire follow-up. These results emphasize the importance of hypertensive patients remaining adherent to antihypertensive therapy in order to minimize such serious complications as fatal and non-fatal stroke events.
Discussion
In this large-scale, population-based linkage study, hypertensive patients who subsequently died or were hospitalized due to stroke had a lower adherence to antihypertensive medication already 2 years after receiving special reimbursement for continuous antihypertensive therapy than did the patients who did not experience stroke during the follow-up. Non-adherence to antihypertensive medication was associated with a 5.7-fold increased odds of fatal stroke during the year of death and a two-fold increased risk of non-fatal stroke. For those using agents acting on the renin–angiotensin system combined with diuretics and/or β-blockers, the corresponding OR was 7.5 for stroke death and 3.9 for hospitalization. Our dose–response analyses based on categories of high, intermediate, and low adherence to antihypertensive medication confirmed that the near- and long-term risk of fatal and non-fatal stroke increased at each step down the level of adherence.
To our knowledge, this is the first study to estimate trajectories of adherence to antihypertensive therapy prior to fatal or non-fatal incident stroke among hypertensive patients. Our findings are in agreement with previous investigations that have suggested a high adherence to antihypertensive therapy is associated with a lower risk of stroke or other cardiovascular events. An Italian study also found that, compared with patients with poor adherence, those with good (hazard ratio 0.69, P < 0.001) or excellent adherence (hazard ratio 0.53, P < 0.001) had a significantly lower risk for the combined outcome of all-cause death, fatal or non-fatal stroke, and fatal or non-fatal acute myocardial infarction even though separate analyses for the stroke outcomes showed no statistically significant differences between the adherence groups. An ecologic time-series study based on yearly official reports of stroke and coronary disease mortality and the use of antihypertensive medication in three Hungarian counties found a correlation between the use of high-ceiling diuretics or calcium channel blockers and decreased stroke mortality. Our analysis was unique, as none of these studies assessed adherence repeatedly over time at the individual level.
A major strength of our study was the large-scale population-based sample of Finns with an 80% oversample of deaths and linkage to comprehensive drug and hospitalization registration that allowed us to conduct a year-by-year analysis of adherence trajectories in relation to stroke events. The nationwide closed record system for both prescriptions and deaths meant that there was virtually no drop out or sample attrition during the follow-up. Information on hospitalization was essential to ensure that the patients were free of stroke and cardiovascular disease at baseline and thus were targets for primary rather than secondary prevention. We assessed stroke risk on the basis of records of non-fatal and fatal stroke, of which the latter, in particular, is a valid stroke outcome. For example, in a study of in-hospital deaths coded for participants in the Minnesota Heart Study, death certificates missed a proportion of stroke deaths, but deaths that were identified as stroke deaths were virtually all correct on the death certificates. The Finnish death register, which we used, has been ranked high with respect to reliability and accuracy in international comparisons. Therefore, bias due to coding error is an unlikely explanation for our results.
Our results have some limitations. First, although pharmacy refill records are objective measures and are collected routinely, they do not necessarily indicate whether the participants actually took the medications. It is possible that some of the participants characterized as adherents did not actually take their medication despite filling their prescriptions. Such misclassifications would lead to an overestimation of adherence but would bias the adherence–stroke relation only if they affect differently those who develop stroke vs. do not. Secondly, as the diagnosis of hypertension was based on health care records (more precisely eligibility to special reimbursement due to chronic hypertension) rather than a clinical examination at baseline, some imprecision in the inclusion of the participants is possible. While the participants were likely to be true hypertension cases, they did not include undiagnosed hypertensive individuals with a need for antihypertensive medication. However, this limitation is an unlikely source for major confounding in the association between adherence and stroke risk. Thirdly, data on such covariates as body mass index, smoking, alcohol consumption, and resting blood pressure were not available from the registers, and therefore analyses to identify subgroups particularly vulnerable to the harmful effects of non-adherence or patients with poorly controlled blood pressure despite adherence to drug therapy were precluded. Fourthly, the healthy user bias (i.e. the correlation between adherence and other behaviour-related risk factors) may artificially inflate associations between non-adherence and disease outcomes in observational studies on preventive medications, such as ours. However, this was an unlikely explanation for the accelerated decline in adherence that we observed 4 years before stroke death. Fifthly, the stringent exclusion criteria of our study population may have affected the assessment of the prevalence of adherence to medication. Further research to determine the generalizability of our findings is needed.
Given that randomization to different adherence groups is unethical, it is unlikely that trial evidence will be available on the effect of adherence to antihypertensive medication on fatal or non-fatal stroke events. Our findings from observational data show a lower adherence to antihypertensive medication already 9 years before a fatal or non-fatal stroke event among hypertensive patients; in the year of the stroke event, the association with non-adherence was the strongest. A dose–response relationship (the more non-adherent the greater the risk) was evident across the entire follow-up. These results emphasize the importance of hypertensive patients remaining adherent to antihypertensive therapy in order to minimize such serious complications as fatal and non-fatal stroke events.
