Risk of Renal, CV and Mortality Outcomes in Hypertension
Risk of Renal, CV and Mortality Outcomes in Hypertension
In this study, we found that the risk for cardiovascular, renal, and all-cause mortality outcomes were increased in individuals with cRH and uRH compared with those with non-RH. The resistant hypertension population as a whole had a greater risk for IHE, CHF, CVA, and ESRD compared with those with non-RH. There was a modest 6% increased mortality risk as well. The uRH subpopulation of resistant hypertension, which had the highest blood pressures, demonstrated the greatest risk for the outcomes studied. The uRH population compared with their counterparts with cRH experienced over a 20% increased risk for CVA and ESRD, underscoring the importance of blood pressure control. Within non-RH, cRH, and uRH, there was a consistently increased risk for ESRD in men, Hispanics, and those with comorbidities of CKD, DM, ischemic heart disease, and cerebrovascular disease. Older age was observed to have a lower risk for ESRD across all hypertension groups and was likely related to the competing risk of death, which has been well described. Similarly, the obesity paradox was observed in our cohort, which has also been described. Overall, our findings were drawn from a cohort of patients with hypertension who had relatively high blood pressure control rates in which the mean blood pressure was 132/75 mm Hg.
Our study cohort and findings represent real-world outcomes and comparisons among a relatively large and diverse population of resistant and nonresistant hypertension. Compared with observations from more homogeneous populations from Europe, China, or the United States Veterans administration, our population was more representative. We also believe that our findings have generalizability in observing these different hypertension populations compared with more controlled (artificial) environments such as clinical trials. Our clinical practice environment with a standardized approach minimizes some of the limitations with past observations such as fragmented data, fragmented populations, and heterogeneous practice patterns. The observations from our study were derived from a single integrated health system in which all hypertensive individuals were exposed to a comparable treatment environment including medications. Kaiser Permanente Southern California (KPSC) has a relatively homogeneous hypertension management program. Nevertheless, the comparative outcomes reported represent findings from a real-world clinical practice environment in which decisions are made based on provider perceptions. We also feel that the mixture of size, diversity, and length of follow-up in our cohort is a strength of our study.
Resistant hypertension represents an outlier among the general hypertension population. Clinically, they are more difficult to treat and control than non-RH. Although imperfect, we used an operational definition of resistant hypertension that is based on the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), the American Heart Association, and the European Society of Hypertension/European Society of Cardiology guidelines. The criteria using three medicines have been used to define and study resistant hypertension for over 30 years. The majority (up to 85%) of hypertensive individuals are treated with one or two medicines. We have previously shown that treated hypertensive individuals within KPSC averaged 1.97 antihypertensive medicines and others have described similar numbers. Thus, patients prescribed three or more medicines are outliers of the hypertension population and represent a different subpopulation such as what we are attempting to describe. We did not require the use of a diuretic as defining criteria, because we were primarily interested in identifying those with difficult-to-treat hypertension. A subset of patients who may have been intolerant of diuretics but required three or more medications were also included in our resistant hypertension study cohort. Overall, 97% of the resistant hypertension population (cRH and uRH) were on a diuretic. Within resistant hypertension, we also wanted to account for the effects of blood pressure and blood pressure control. Although we did not fully evaluate the effects of blood pressure across different ranges, we did further subcategorize resistant hypertension as controlled and uncontrolled based on the systolic blood pressure 140 mm Hg systolic blood pressure cutoff.
Blood pressure is an important component within resistant hypertension just as it is for general hypertension. Recently, the blood pressure goals and targets have come into question, as aggressive blood pressures have not translated into improved outcomes. However, the data and national guidelines continue to support minimum targets of blood pressures under 150 mm Hg systolic and perhaps lower for stroke risk reduction. Within our study, the 14% higher risk of CVA in resistant hypertension was no longer observed when resistant hypertension was controlled.
The resistant hypertension population is presumed to have an adverse physiology, which is prone to worsened outcomes. Among the general hypertension population, there are very few comparative studies on resistant hypertension compared with non-RH. Thus, measureable risks and prognosis are not well known. A short-term study on incidence of resistant hypertension suggested that individuals with resistant hypertension had a 47% higher risk of cardiovascular events. Two studies that evaluated hypertensive patients identified with coronary artery disease found that patients with resistant hypertension experienced worsened cardiovascular and mortality events compared with those with non-RH. Among CKD patients, those with resistant hypertension have been reported to experience a two-fold greater risk for both cardiovascular events and ESRD compared with those without resistant hypertension. Overall, there are even fewer studies that have evaluated CKD and ESRD outcomes in resistant hypertension. Our findings within a large diverse general hypertension population further demonstrate that individuals with resistant hypertension are at a greater risk for renal failure in addition to cardiovascular outcomes and mortality.
In our study, we sought to further categorize resistant hypertension on the basis of blood pressure control and presumed response to medications. Our assumption was that those with difficult-to-control blood pressures but who eventually attained control (<140/90 mm Hg) may be different from those whose blood pressures were not controlled (cRH vs. uRH). We found similar risks for IHE, CHF, and mortality in cRH and uRH. However, our findings do suggest that CVA and ESRD risk may be reduced by controlling blood pressure in uRH. Somewhat unexpectedly, we observed that the cRH had a greater number of adverse events compared with uRH (Table 2). This may speak to the fact that the cRH population represented the sickest population with the most comorbidities including CKD, DM, IHD, and CVA (Table 1). The lowest blood pressure was in the cRH cohort (123/67 mm Hg) and may be reflective of a weakened physiologic state. One example is the fact that the adjusted risk for CHF was greater in cRH vs. uRH, suggestive of inotropic compromise and inability to maintain higher blood pressures. In addition, the greater burden of comorbidities, particularly vascular disease, through the years may result in irreversible remodeling of the vascular beds. Thus, they may require relatively higher blood pressures to maintain systemic perfusion and adequate delivery of nutrients throughout the body. To that end, the cRH population may have been overtreated, whereas uRH patients had blood pressures conducive to better perfusion. Potential overtreatment of hypertension and the existence of a U-shaped curve for blood pressure has been observed in populations with CKD and cardiovascular disease. The question of where the ideal blood pressures should be, especially in those with chronic disease burdens, remains largely unanswered.
Few comparisons have been made between controlled and uncontrolled subpopulations of resistant hypertension, as was performed in our study. The subpopulation of those with uRH is even less understood. This population, which is difficult to treat and in whom blood pressure is never controlled, may represent a different biological phenotype. In our study, we used a lower threshold of three or more antihypertensive medicines to define uRH. Using this definition, we found that 7.9% of the hypertensive cohort had uRH, and these individuals were prone to worsened outcomes, particularly CVA compared with cRH. The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study used a more rigid definition of uRH of five or more medicines without control and found a rate of 0.5% among hypertensive individuals.
The prognosis and comparative outcomes in resistant hypertension deserve better understanding. Determining the risks and survival in these subpopulations can help shape treatment strategies of the hypertension itself and also comorbidities. Medication classes and the rationale behind their use may have to be more defined in order to account for the greater risk of certain outcomes in the resistant hypertension population. Comorbidities such as hyperlipidemia or DM may need to be managed more aggressively. Conversely, if survival is shorter in resistant hypertension, then we may need to consider certain comorbidities with poor prognoses as competing outcomes.
The relevance of current national hypertension guidelines may need to be reconsidered among resistant hypertension in order to achieve better blood pressure control. The resistant hypertension population may benefit from more individualized care rather than broad recommendations. For instance, the black population was overrepresented in our RH cohort compared with non-RH. Although KPSC uses a JNC-based medication treatment guideline, the efficacy of diuretics and calcium-channel blockers in the black population has been well described. Greater emphasis on these medications in blacks may lower the proportion of resistant hypertension in this group. Another example is to assess the physiology of hypertension by patients' response to treatment. A study on resistant hypertension that treated after classifying uncontrolled blood pressures as either volume or vasoconstrictive hypertension led to management strategies that achieved greater blood pressure reduction.
There are several potential limitations to our study that may confound the findings. We identified the study cohort from a 2-year window and followed up individuals up to 5 years. In contrast to real-world phenomenon where blood pressures vary over time, we somewhat arbitrarily identified a cohort as resistant hypertension. The assumption was that once individuals were identified as resistant hypertension they would remain so throughout the observation period. Conversely, those with non-RH may have gone on to develop resistant hypertension. We also did not have information on the duration of hypertension. Due to our definition, the resistant hypertension population would have had to had some duration of follow up to have medicine titrated to at least three medicines and thus introducing an immortal time bias. Non-RH individuals could have been identified based on only two visits. Therefore, the resistant hypertension population was more likely to have pre-existing vascular damage that may not have been identified at the start of the observation period compared with the non-RH population. By studying hypertension categories, we are somewhat trivializing the impact of blood pressure on our outcomes studied, as the stepwise risk of cardiovascular outcomes with higher blood pressures has been well described. In addition, we cannot account for heterogeneous practice patterns. Certain patients may be deemed sicker by clinicians and received more comprehensive care such as in our cRH population. They may have been seen more frequently and also had better health maintenance care. The fact that there was only a modest (6%) mortality risk in the resistant hypertension population compared with the general hypertension population may further suggest this confounding.
Discussion
In this study, we found that the risk for cardiovascular, renal, and all-cause mortality outcomes were increased in individuals with cRH and uRH compared with those with non-RH. The resistant hypertension population as a whole had a greater risk for IHE, CHF, CVA, and ESRD compared with those with non-RH. There was a modest 6% increased mortality risk as well. The uRH subpopulation of resistant hypertension, which had the highest blood pressures, demonstrated the greatest risk for the outcomes studied. The uRH population compared with their counterparts with cRH experienced over a 20% increased risk for CVA and ESRD, underscoring the importance of blood pressure control. Within non-RH, cRH, and uRH, there was a consistently increased risk for ESRD in men, Hispanics, and those with comorbidities of CKD, DM, ischemic heart disease, and cerebrovascular disease. Older age was observed to have a lower risk for ESRD across all hypertension groups and was likely related to the competing risk of death, which has been well described. Similarly, the obesity paradox was observed in our cohort, which has also been described. Overall, our findings were drawn from a cohort of patients with hypertension who had relatively high blood pressure control rates in which the mean blood pressure was 132/75 mm Hg.
Our study cohort and findings represent real-world outcomes and comparisons among a relatively large and diverse population of resistant and nonresistant hypertension. Compared with observations from more homogeneous populations from Europe, China, or the United States Veterans administration, our population was more representative. We also believe that our findings have generalizability in observing these different hypertension populations compared with more controlled (artificial) environments such as clinical trials. Our clinical practice environment with a standardized approach minimizes some of the limitations with past observations such as fragmented data, fragmented populations, and heterogeneous practice patterns. The observations from our study were derived from a single integrated health system in which all hypertensive individuals were exposed to a comparable treatment environment including medications. Kaiser Permanente Southern California (KPSC) has a relatively homogeneous hypertension management program. Nevertheless, the comparative outcomes reported represent findings from a real-world clinical practice environment in which decisions are made based on provider perceptions. We also feel that the mixture of size, diversity, and length of follow-up in our cohort is a strength of our study.
Resistant hypertension represents an outlier among the general hypertension population. Clinically, they are more difficult to treat and control than non-RH. Although imperfect, we used an operational definition of resistant hypertension that is based on the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), the American Heart Association, and the European Society of Hypertension/European Society of Cardiology guidelines. The criteria using three medicines have been used to define and study resistant hypertension for over 30 years. The majority (up to 85%) of hypertensive individuals are treated with one or two medicines. We have previously shown that treated hypertensive individuals within KPSC averaged 1.97 antihypertensive medicines and others have described similar numbers. Thus, patients prescribed three or more medicines are outliers of the hypertension population and represent a different subpopulation such as what we are attempting to describe. We did not require the use of a diuretic as defining criteria, because we were primarily interested in identifying those with difficult-to-treat hypertension. A subset of patients who may have been intolerant of diuretics but required three or more medications were also included in our resistant hypertension study cohort. Overall, 97% of the resistant hypertension population (cRH and uRH) were on a diuretic. Within resistant hypertension, we also wanted to account for the effects of blood pressure and blood pressure control. Although we did not fully evaluate the effects of blood pressure across different ranges, we did further subcategorize resistant hypertension as controlled and uncontrolled based on the systolic blood pressure 140 mm Hg systolic blood pressure cutoff.
Blood pressure is an important component within resistant hypertension just as it is for general hypertension. Recently, the blood pressure goals and targets have come into question, as aggressive blood pressures have not translated into improved outcomes. However, the data and national guidelines continue to support minimum targets of blood pressures under 150 mm Hg systolic and perhaps lower for stroke risk reduction. Within our study, the 14% higher risk of CVA in resistant hypertension was no longer observed when resistant hypertension was controlled.
The resistant hypertension population is presumed to have an adverse physiology, which is prone to worsened outcomes. Among the general hypertension population, there are very few comparative studies on resistant hypertension compared with non-RH. Thus, measureable risks and prognosis are not well known. A short-term study on incidence of resistant hypertension suggested that individuals with resistant hypertension had a 47% higher risk of cardiovascular events. Two studies that evaluated hypertensive patients identified with coronary artery disease found that patients with resistant hypertension experienced worsened cardiovascular and mortality events compared with those with non-RH. Among CKD patients, those with resistant hypertension have been reported to experience a two-fold greater risk for both cardiovascular events and ESRD compared with those without resistant hypertension. Overall, there are even fewer studies that have evaluated CKD and ESRD outcomes in resistant hypertension. Our findings within a large diverse general hypertension population further demonstrate that individuals with resistant hypertension are at a greater risk for renal failure in addition to cardiovascular outcomes and mortality.
In our study, we sought to further categorize resistant hypertension on the basis of blood pressure control and presumed response to medications. Our assumption was that those with difficult-to-control blood pressures but who eventually attained control (<140/90 mm Hg) may be different from those whose blood pressures were not controlled (cRH vs. uRH). We found similar risks for IHE, CHF, and mortality in cRH and uRH. However, our findings do suggest that CVA and ESRD risk may be reduced by controlling blood pressure in uRH. Somewhat unexpectedly, we observed that the cRH had a greater number of adverse events compared with uRH (Table 2). This may speak to the fact that the cRH population represented the sickest population with the most comorbidities including CKD, DM, IHD, and CVA (Table 1). The lowest blood pressure was in the cRH cohort (123/67 mm Hg) and may be reflective of a weakened physiologic state. One example is the fact that the adjusted risk for CHF was greater in cRH vs. uRH, suggestive of inotropic compromise and inability to maintain higher blood pressures. In addition, the greater burden of comorbidities, particularly vascular disease, through the years may result in irreversible remodeling of the vascular beds. Thus, they may require relatively higher blood pressures to maintain systemic perfusion and adequate delivery of nutrients throughout the body. To that end, the cRH population may have been overtreated, whereas uRH patients had blood pressures conducive to better perfusion. Potential overtreatment of hypertension and the existence of a U-shaped curve for blood pressure has been observed in populations with CKD and cardiovascular disease. The question of where the ideal blood pressures should be, especially in those with chronic disease burdens, remains largely unanswered.
Few comparisons have been made between controlled and uncontrolled subpopulations of resistant hypertension, as was performed in our study. The subpopulation of those with uRH is even less understood. This population, which is difficult to treat and in whom blood pressure is never controlled, may represent a different biological phenotype. In our study, we used a lower threshold of three or more antihypertensive medicines to define uRH. Using this definition, we found that 7.9% of the hypertensive cohort had uRH, and these individuals were prone to worsened outcomes, particularly CVA compared with cRH. The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study used a more rigid definition of uRH of five or more medicines without control and found a rate of 0.5% among hypertensive individuals.
The prognosis and comparative outcomes in resistant hypertension deserve better understanding. Determining the risks and survival in these subpopulations can help shape treatment strategies of the hypertension itself and also comorbidities. Medication classes and the rationale behind their use may have to be more defined in order to account for the greater risk of certain outcomes in the resistant hypertension population. Comorbidities such as hyperlipidemia or DM may need to be managed more aggressively. Conversely, if survival is shorter in resistant hypertension, then we may need to consider certain comorbidities with poor prognoses as competing outcomes.
The relevance of current national hypertension guidelines may need to be reconsidered among resistant hypertension in order to achieve better blood pressure control. The resistant hypertension population may benefit from more individualized care rather than broad recommendations. For instance, the black population was overrepresented in our RH cohort compared with non-RH. Although KPSC uses a JNC-based medication treatment guideline, the efficacy of diuretics and calcium-channel blockers in the black population has been well described. Greater emphasis on these medications in blacks may lower the proportion of resistant hypertension in this group. Another example is to assess the physiology of hypertension by patients' response to treatment. A study on resistant hypertension that treated after classifying uncontrolled blood pressures as either volume or vasoconstrictive hypertension led to management strategies that achieved greater blood pressure reduction.
Potential Limitations
There are several potential limitations to our study that may confound the findings. We identified the study cohort from a 2-year window and followed up individuals up to 5 years. In contrast to real-world phenomenon where blood pressures vary over time, we somewhat arbitrarily identified a cohort as resistant hypertension. The assumption was that once individuals were identified as resistant hypertension they would remain so throughout the observation period. Conversely, those with non-RH may have gone on to develop resistant hypertension. We also did not have information on the duration of hypertension. Due to our definition, the resistant hypertension population would have had to had some duration of follow up to have medicine titrated to at least three medicines and thus introducing an immortal time bias. Non-RH individuals could have been identified based on only two visits. Therefore, the resistant hypertension population was more likely to have pre-existing vascular damage that may not have been identified at the start of the observation period compared with the non-RH population. By studying hypertension categories, we are somewhat trivializing the impact of blood pressure on our outcomes studied, as the stepwise risk of cardiovascular outcomes with higher blood pressures has been well described. In addition, we cannot account for heterogeneous practice patterns. Certain patients may be deemed sicker by clinicians and received more comprehensive care such as in our cRH population. They may have been seen more frequently and also had better health maintenance care. The fact that there was only a modest (6%) mortality risk in the resistant hypertension population compared with the general hypertension population may further suggest this confounding.
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