Non-adherence to Antihypertensives Revealed
Non-adherence to Antihypertensives Revealed
Our results revealed that one in four hypertensive patients attending a specialist hypertension centre were partially or totally non-adherent to pharmacological BP lowering therapy on qualitative HP LC-MS/MS urine analysis. We also show that biochemically confirmed non-adherent hypertensive patients have higher BP (in particular DBP) than those who adhere to treatment. Furthermore, the data clearly demonstrate an association between the degree of non-adherence to antihypertensive treatment and clinic as well as 24 h daytime DBP values—the higher the numerical difference (or lower the ratio) between biochemically detected and prescribed medications, the higher the BP. Finally, we showed that almost one in four patients referred for renal denervation was completely non-adherent to prescribed BP lowering treatment.
Our study is one of the first to systematically use a robust detection method to report the prevalence of non-adherence to antihypertensive therapy among all new referrals to the specialist hypertension centre. Almost one in four of these patients showed some degree of non-adherence and one in 10 were completely non-adherent to BP lowering therapy. A majority of these patients in any secondary/tertiary care centre would routinely undergo many additional tests and procedures in search of the explanation for their apparent unresponsiveness to standard therapy prescribed by primary care. Our data suggest that in 20% of such patients, these investigations (along with follow-up appointments and exposure to unnecessary additional treatment) could be potentially avoided if HP LC-MS/MS urine analysis was used as a routine screening for non-adherence.
Based on a similar methodology, a recently published survey of 76 hypertensive patients with treatment resistance referred from primary care to an out-patient nephrology centre showed higher (≈50%) rate of non-adherence to BP lowering therapy. This difference may be explained by the different inclusion criteria between both studies. Indeed, Jung et al screened only patients with resistant hypertension while a majority of patients included in this study were consecutive, unselected referrals from primary care (Group A). The data from our investigation are based on a larger and clinically more diverse sample of hypertensive patients with a wider range of reasons for referral to the clinic. This better reflects the true clinical spectrum of patient population in a specialist hypertension centre. We should also note the apparent difference in the average number of prescribed antihypertensive medications between Jung et al and our study (five vs three). The higher number of BP lowering agents may also explain (at least to some extent) the higher rate of non-adherence in the study by Jung et al given that complex regime of prescribed medications is a recognised risk factor of non-adherent behaviour.
To the best of our knowledge, we are the first to report the rate of non-adherence to antihypertensive treatment among patients referred for renal denervation. What is striking about our findings in this group is their average rate of complete non-adherence. Although non-adherence is a recognised cause of resistant hypertension, the rates of true non-adherence to antihypertensive therapy were either not reported or reported suboptimally in clinical trials on this group of patients. The data collected in our audit suggest that as many as one in four patients referred for renal denervation would not have qualified for the procedure according to existing guidance on its use which excludes non-adherence to therapy. Of course, it could be argued that renal denervation could be the ideal treatment for persistently non-adherent patients given their lack of acceptance for regular administration of antihypertensive pills. However, at present we would not recommend that renal denervation is offered to non-adherent hypertensive patients. First, currently there is no evidence for the clinical benefits of this intervention in therapeutically non-adherent patients. Second, the existing data suggest that renal denervation may reduce the number of antihypertensive medications but unlikely to cure hypertension completely and as such may not be attractive enough option for patients who choose not to take any BP lowering medications (ie, all non-adherent patients in our renal denervation group). Third, in a substantial proportion of patients, non-adherence may be driven by fear of and/or certain beliefs around potential side effects of treatment. While stopping unwanted/unacceptable BP lowering medication is usually sufficient to eliminate these perceptions, renal denervation while generally safe is irreversible. Therefore, it may be difficult to convince such non-adherent patients and/or their managing clinicians to consider this mode of treatment.
Our study has several limitations. First, information on 24 h ambulatory BP lowering was not available for approximately 25% of included patients. The lower number of observations (and thus lower power to detect association) probably explains somewhat the weaker relationship between non-adherence to treatment and 24 h daytime BP values when compared with clinic BP measurements. Second, the group of patients referred for renal denervation was small. We also acknowledge several imperfections of the method used as a screening of adherence to treatment; that is, a single spot urine analysis may not fully account for periodicity (both personal and seasonal) of non-adherence to treatment. Furthermore, intuitively, one might expect some patients to better adhere to treatment on the day of clinic attendance (the so-called 'tooth brush effect'), given that poor BP control in clinic is likely to prompt further investigation and/or treatment escalation. Thus, the spot urine assay may underestimate chronic or intermittent non-adherence. However, this limitation applies to the majority of currently used adherence tests conducted in the clinic prior to appointments. Repeated urine tests could provide a better insight into patients' adherence to antihypertensive therapy. We also recognise the unavailability of indirect measures of adherence to antihypertensive treatment in this project. Further studies on utility and cost effectiveness of HP LC-MS/MS urine analysis should be conducted against indirect measures of adherence to inform future health policies and clinical practice. Finally, this analysis was conducted as an audit of adherence and we acknowledge the risks of potential bias from unmeasured confounders in an observational study.
However, biochemical screening for adherence to antihypertensive treatment using a spot urine sample has several major advantages. First, it is a completely non-invasive procedure that can be conducted by a healthcare assistant prior to routine clinical appointments. Unlike many other previously used methods of screening, the HP LC-MS/MS analysis provides a clear 'Yes/No' answer to a question on presence/absence of antihypertensive medications based on direct measurement of urine. Although the costs of HP LC-MS/MS analyser are not trivial (≈£150 000), many major clinical centres have access to such technology, a single urine test is relatively inexpensive (approximately £30) and the results can be provided quickly as sample processing takes about 3 h. Moreover, the frozen samples are stable when stored prior to biochemical analysis. Finally, HP LC-MS/MS is a recognised method with good to excellent sensitivity and specificity to detect many pharmacological agents in urine.
Discussion
Our results revealed that one in four hypertensive patients attending a specialist hypertension centre were partially or totally non-adherent to pharmacological BP lowering therapy on qualitative HP LC-MS/MS urine analysis. We also show that biochemically confirmed non-adherent hypertensive patients have higher BP (in particular DBP) than those who adhere to treatment. Furthermore, the data clearly demonstrate an association between the degree of non-adherence to antihypertensive treatment and clinic as well as 24 h daytime DBP values—the higher the numerical difference (or lower the ratio) between biochemically detected and prescribed medications, the higher the BP. Finally, we showed that almost one in four patients referred for renal denervation was completely non-adherent to prescribed BP lowering treatment.
Our study is one of the first to systematically use a robust detection method to report the prevalence of non-adherence to antihypertensive therapy among all new referrals to the specialist hypertension centre. Almost one in four of these patients showed some degree of non-adherence and one in 10 were completely non-adherent to BP lowering therapy. A majority of these patients in any secondary/tertiary care centre would routinely undergo many additional tests and procedures in search of the explanation for their apparent unresponsiveness to standard therapy prescribed by primary care. Our data suggest that in 20% of such patients, these investigations (along with follow-up appointments and exposure to unnecessary additional treatment) could be potentially avoided if HP LC-MS/MS urine analysis was used as a routine screening for non-adherence.
Based on a similar methodology, a recently published survey of 76 hypertensive patients with treatment resistance referred from primary care to an out-patient nephrology centre showed higher (≈50%) rate of non-adherence to BP lowering therapy. This difference may be explained by the different inclusion criteria between both studies. Indeed, Jung et al screened only patients with resistant hypertension while a majority of patients included in this study were consecutive, unselected referrals from primary care (Group A). The data from our investigation are based on a larger and clinically more diverse sample of hypertensive patients with a wider range of reasons for referral to the clinic. This better reflects the true clinical spectrum of patient population in a specialist hypertension centre. We should also note the apparent difference in the average number of prescribed antihypertensive medications between Jung et al and our study (five vs three). The higher number of BP lowering agents may also explain (at least to some extent) the higher rate of non-adherence in the study by Jung et al given that complex regime of prescribed medications is a recognised risk factor of non-adherent behaviour.
To the best of our knowledge, we are the first to report the rate of non-adherence to antihypertensive treatment among patients referred for renal denervation. What is striking about our findings in this group is their average rate of complete non-adherence. Although non-adherence is a recognised cause of resistant hypertension, the rates of true non-adherence to antihypertensive therapy were either not reported or reported suboptimally in clinical trials on this group of patients. The data collected in our audit suggest that as many as one in four patients referred for renal denervation would not have qualified for the procedure according to existing guidance on its use which excludes non-adherence to therapy. Of course, it could be argued that renal denervation could be the ideal treatment for persistently non-adherent patients given their lack of acceptance for regular administration of antihypertensive pills. However, at present we would not recommend that renal denervation is offered to non-adherent hypertensive patients. First, currently there is no evidence for the clinical benefits of this intervention in therapeutically non-adherent patients. Second, the existing data suggest that renal denervation may reduce the number of antihypertensive medications but unlikely to cure hypertension completely and as such may not be attractive enough option for patients who choose not to take any BP lowering medications (ie, all non-adherent patients in our renal denervation group). Third, in a substantial proportion of patients, non-adherence may be driven by fear of and/or certain beliefs around potential side effects of treatment. While stopping unwanted/unacceptable BP lowering medication is usually sufficient to eliminate these perceptions, renal denervation while generally safe is irreversible. Therefore, it may be difficult to convince such non-adherent patients and/or their managing clinicians to consider this mode of treatment.
Our study has several limitations. First, information on 24 h ambulatory BP lowering was not available for approximately 25% of included patients. The lower number of observations (and thus lower power to detect association) probably explains somewhat the weaker relationship between non-adherence to treatment and 24 h daytime BP values when compared with clinic BP measurements. Second, the group of patients referred for renal denervation was small. We also acknowledge several imperfections of the method used as a screening of adherence to treatment; that is, a single spot urine analysis may not fully account for periodicity (both personal and seasonal) of non-adherence to treatment. Furthermore, intuitively, one might expect some patients to better adhere to treatment on the day of clinic attendance (the so-called 'tooth brush effect'), given that poor BP control in clinic is likely to prompt further investigation and/or treatment escalation. Thus, the spot urine assay may underestimate chronic or intermittent non-adherence. However, this limitation applies to the majority of currently used adherence tests conducted in the clinic prior to appointments. Repeated urine tests could provide a better insight into patients' adherence to antihypertensive therapy. We also recognise the unavailability of indirect measures of adherence to antihypertensive treatment in this project. Further studies on utility and cost effectiveness of HP LC-MS/MS urine analysis should be conducted against indirect measures of adherence to inform future health policies and clinical practice. Finally, this analysis was conducted as an audit of adherence and we acknowledge the risks of potential bias from unmeasured confounders in an observational study.
However, biochemical screening for adherence to antihypertensive treatment using a spot urine sample has several major advantages. First, it is a completely non-invasive procedure that can be conducted by a healthcare assistant prior to routine clinical appointments. Unlike many other previously used methods of screening, the HP LC-MS/MS analysis provides a clear 'Yes/No' answer to a question on presence/absence of antihypertensive medications based on direct measurement of urine. Although the costs of HP LC-MS/MS analyser are not trivial (≈£150 000), many major clinical centres have access to such technology, a single urine test is relatively inexpensive (approximately £30) and the results can be provided quickly as sample processing takes about 3 h. Moreover, the frozen samples are stable when stored prior to biochemical analysis. Finally, HP LC-MS/MS is a recognised method with good to excellent sensitivity and specificity to detect many pharmacological agents in urine.
