Ignite Creation Date:
2024-05-06 @ 11:10 AM
Last Modification Date:
2024-10-26 @ 12:41 PM
Study NCT ID:
NCT03457168
Status:
RECRUITING
Last Update Posted:
2023-05-09
First Post:
2018-02-21
Brief Title:
Treatment of Hypertension During Sleep
Sponsor:
University of Vigo
Organization:
University of Vigo
Study Overview
Official Title:
A Prospective Randomized Open-label Clinical Trial on the Effects of Intensive Versus Conventional Control of Ambulatory-determined Asleep Systolic Blood Pressure Mean on Cardiovascular Metabolic and Renal Disease Risks
Status:
RECRUITING
Status Verified Date:
2023-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
THADEUS
Brief Summary:
On the basis of new evidence on the relationship between achieved office blood pressure BP measurements OBPM and the risk of cardiovascular disease CVD morbidity and mortality documented in the SPRINT trial the recent 2017 guidelines of the American College of Cardiology ACC and the American Heart Association AHA have established lower values of 13080 mmHg for clinic systolic BP SBPdiastolic BP DBP as new diagnostic thresholds for hypertension and therapeutic targets for treatment of all individuals aged 18 years regardless of age sex or concomitant complications including presence of diabetes chronic kidney disease CKD or history of past CVD event According to these guidelines the new proposed ambulatory BP measurment ABPM thresholds for diagnosis of hypertension in adults are 13080 and 11065 mmHg for the awake and asleep SBPDBP means respectively However the ACCAHA guidelines do not provide any scientific evidence documenting neither the equivalence between these ABPM thresholds and the 13080 mmHg cut-off values for OBPM nor the potential improved CVD event-free survival time of the proposed more intensive control of ambulatory BP
Results derived from observational prospective studies consistently document that therapeutic BP targets in hypertensive individuals ie persons at increased CVD risk should be established in terms of proper control of asleep BP To date no prospective randomized study has ever before evaluated which should be the adequate therapeutic ABPM target for most effective reduction of CVD risk Accordingly the Tratamiento de Hipertensión Arterial Durante el Sueño study THADEUS ie Treatment of Hypertension During Sleep has been designed to prospectively evaluate if intensive control of asleep SBP mean proposed by the new ACCAHA guidelines 110 mmHg in more effective than the so far its conventional control 120 mmHg to reduce CVD morbidity and mortality in hypertensive individuals
Results derived from observational prospective studies consistently document that therapeutic BP targets in hypertensive individuals ie persons at increased CVD risk should be established in terms of proper control of asleep BP To date no prospective randomized study has ever before evaluated which should be the adequate therapeutic ABPM target for most effective reduction of CVD risk Accordingly the Tratamiento de Hipertensión Arterial Durante el Sueño study THADEUS ie Treatment of Hypertension During Sleep has been designed to prospectively evaluate if intensive control of asleep SBP mean proposed by the new ACCAHA guidelines 110 mmHg in more effective than the so far its conventional control 120 mmHg to reduce CVD morbidity and mortality in hypertensive individuals
Detailed Description:
1 BACKGROUND AND RATIONALE OF THE STUDY
11 Clinic and ambulatory blood pressure for the diagnosis of hypertension
The diagnosis of hypertension and all clinical decisions regarding its treatment today are still mainly based only on a limited number of daytime office blood pressure BP measurements OBPM obtained in the clinic occasionally supplemented by wake-time self-assessments at home and work Those casual time-unspecified OBPM disregard the mostly predictable circadian variation in BP Various circadian rhythms may also significantly affect the pharmacokinetics and pharmacodynamics both beneficial and adverse effects of hypertension medications as extensively documented Most important numerous outcome trials and published meta-analyses substantiate the correlation between BP level and risk of target organ injury damage and cardiovascular disease CVD events is much stronger for parameters derived from around-the-clock ambulatory BP monitoring ABPM than it is for values derived from traditional daytime OBPM ABPM is a diagnostic tool with the added advantage that allows thorough description and quantification of all aspects of the 24h BP variation
On the basis of this substantial and indisputable evidence several international guidelines now propose ambulatory measurements as a requirement to confirm the office diagnosis of hypertension in adults On the contrary other guidelines despite recognizing greater prognostic value of ABPM than OBPM still recommended the use of the later for diagnosis of hypertension for historical reasons unjustified on the light of current available scientific evidence
12 Asleep BP mean as an independent prognostic marker of CVD risk
Specific features of the ABPM-determined 24h BP pattern have been explored as biomarkers or mediators of target tissue injury and triggers of and risk factors for CVD events -- angina pectoris myocardial infarction cardiac arrest sudden cardiac death pulmonary embolism -- and cerebrovascular events -- ischemic and hemorrhagic stroke Numerous studies consistently substantiate a strong association between the abnormal physiologic feature of blunted sleep-time relative BP decline non-dipperriser BP pattern and increased incidence of fatal and non-fatal CVD events not only in hypertensive persons but also in normotensive individuals27 Furthermore various independent prospective studies demonstrate CVD events are better predicted by the asleep than awake or 24h BP means
Overall such prospective ABPM studies demonstrate elevated sleep-time BP constitutes a significant CVD risk factor independent of the daytime OBPM or ambulatory awake and 24h BP means Nonetheless all previous investigations addressing the merit of ABPM for predicting CVD risk except the Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares study MAPEC ie Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events discussed below relied upon only a single low-reproducible study-inclusion baseline 24h ABPM assessment per participant Lack of systematic and multiple ABPM evaluations of participants over time in all previously reported long-term follow-up studies except MAPEC precluded the opportunity to explore the potential reduction in CVD risk associated with modification of prognostic parameters by hypertension therapy andor lifestyle changes ie either increase of sleep-time relative BP decline towards the more normal dipper pattern or more specifically reduction of asleep BP mean Incorporation of periodic at least annual ABPM studies of participants during follow-up as in the MAPEC study clearly establishes that i features of the 24h BP pattern change over time and ii therapeutic reduction of the asleep BP mean and increase of the sleep-time relative BP decline towards normal dipping lessen not only CVD risk but also progression towards new-onset type 2 diabetes and chronic kidney disease CKD
Potential reduction in CVD risk through modification of prognostic ABPM parameters by a time-specified hypertension-treatment strategy has so far been investigated only in the MAPEC study Cox regression survival analysis of each potential prognostic BP parameter analyzed individually indicates the hazard ratio HR of total CVD events is greater with progressively higher sleep-time SBP mean and lower sleep-time relative SBP decline ie more non-dipperriser BP patterning Moreover joint analysis of the multiple BP parameters potentially capable of contributing to CVD risk finds OBPM does not independently predict CVD morbidity and mortality when the outcomes model is adjusted by the asleep BP mean HR144 95CI 130-160 P0001 per SD elevation in asleep SBP mean HR109 097-123 P0123 per SD elevation in clinic SBP The best Cox regression fully adjusted model includes only the asleep SBP mean HR143 95CI 129-158 P0001 and sleep-time relative SBP decline HR088 078-098 P0023
13 Asleep BP mean as a therapeutic target for CVD risk reduction
Data from the MAPEC study in which participants were repeatedly assessed by periodic 48h ABPM also permitted prospective evaluation of the impact of changes in OBPM and ABPM during follow-up on CVD risk Progressive treatment-induced lowering of the awake asleep and 48h BP means but not daytime OBPM when each variable is analyzed individually reveals association with significant CVD risk reduction Most importantly Cox survival analysis with joint inclusion of asleep and awake BP means as potential predictors indicates progressive attenuation of asleep SBP mean is significantly associated with diminished CVD risk adjusted HR067 055-081 P0001 per SD decrease in asleep SBP mean while progressive lowering of awake SBP mean is not adjusted HR100 086-118 P0958 per SD decrease in awake SBP mean during follow-up Overall the best fully adjusted time-dependent Cox regression model includes only the progressive attenuation of the asleep SBP mean HR076 95CI 068-085 P0001 per SD decrease in asleep SBP mean and increase in the sleep-time relative SBP decline HR119 101-139 P0038 per SD decrease in sleep-time relative SBP decline during follow-up Thus a diminished asleep but not awake BP mean is a highly significant independent prognostic marker of reduced CVD morbidity and mortality risk and therefore constitutes a novel therapeutic target for increased event-free survival
Thus far apart from MAPEC the only prospective study in which participants are evaluated periodically by ABPM is the Hygia Project a research network primarily designed to extend the use of ABPM in primary care as a requirement for the diagnosis of hypertension evaluation of response to treatment and individualized assessment of CVD and other risks Presently the Hygia Project is composed of 40 clinical sites primary care centers involving 292 investigators properly trained to ABPM and all study procedures The study was designed to evaluate in the routine primary care clinical setting among other objectives the prognostic value of multiple ABPM-derived parameters mainly asleep BP mean and sleep-time relative BP decline with OBPM for the prediction of CVD morbidity and mortality new-onset diabetes and new-onset CKD The investigators so far prospectively evaluated 18078 individuals 9769 men8309 women 591143 meanSD years of age with baseline ambulatory BP ranging from normotension to hypertension At inclusion and at scheduled visits mainly annually during follow-up ambulatory BP was evaluated for 48 consecutive hours During the current 51-year median patient follow-up 2311 individuals had CVD events including 1209 experiencing the primary outcome composite of CVD death myocardial infarction coronary revascularization heart failure and stroke The asleep SBP mean was the most significant prognostic marker of the primary outcome HR129 95CI 122-135 per SD elevation P0001 independent of clinic 103 097-109 P0315 and awake SBP 102 094-110 P0682 Most important the progressive treatment-induced attenuation of asleep SBP was the most significant prognostic marker of event-free survival 075 95CI 069-082 per SD decrease P0001 independent of changes in office 107 097-117 P0176 or awake SBP mean 096 085-108 P0473 during follow-up Only the decrease in asleep SBP mean and increase in sleep-time relative SBP decline towards the more normal dipper BP pattern remained jointly and significantly associated with reduced CVD risk There was a highly significant decrease in risk of CVD outcome with progressively lower achieved asleep SBP mean in particular CVD event-rate was significantly lower in participants with achieved asleep SBP mean 105 mmHg at their final evaluation than those with achieves asleep SBP mean between 105 and 120 mmHg 335 vs 727 events per 1000 patientsyear respectively P0001 54 CVD risk reduction in the lower achieved asleep SBP mean of these two groups of hypertensive patients with controlled asleep SBP mean According to this prospective evaluation the asleep SBP mean but not the daytime OBPM or the awake ambulatory BP mean is the most significant and independent prognostic marker of CVD outcome
On the basis of new evidence on the relationship between achieved OBPM and the risk of CVD morbidity and mortality documented in the SPRINT trial the recent 2017 guidelines of the American College of Cardiology ACC and the American Heart Association AHA have established lower values of 13080 mmHg for clinic SBPDBP as new diagnostic thresholds for hypertension and therapeutic targets for treatment of all individuals aged 18 years regardless of age sex or concomitant complications including presence of diabetes CKD or history of past CVD event According to these guidelines the new proposed ABPM thresholds for diagnosis of hypertension in adults are 13080 and 11065 mmHg for the awake and asleep SBPDBP means respectively However the ACCAHA guidelines do not provide any scientific evidence documenting neither the equivalence between these ABPM thresholds and the 13080 mmHg cut-off values for OBPM nor the potential improved CVD event-free survival time of the proposed more intensive control of ambulatory BP
All the results described above including the main findings of the MAPEC and Hygia trials pertaining to the greater prognostic value of ABPM than OBPM are derived from observational prospective studies consistently documenting that therapeutic BP targets in hypertensive individuals ie persons at increased CVD risk should be established in terms of proper control of asleep BP To date no prospective randomized study has ever before evaluated which should be the adequate therapeutic ABPM target for most effective reduction of CVD risk Accordingly the Tratamiento de Hipertensión Arterial Durante el Sueño study THADEUS ie Treatment of Hypertension During Sleep has been designed to prospectively evaluate if the intensive control of asleep SBP mean proposed by the new ACCAHA guidelines 110 mmHg in more effective than the so far conventional control 120 mmHg to reduce CVD morbidity and mortality in hypertensive individuals
11 Clinic and ambulatory blood pressure for the diagnosis of hypertension
The diagnosis of hypertension and all clinical decisions regarding its treatment today are still mainly based only on a limited number of daytime office blood pressure BP measurements OBPM obtained in the clinic occasionally supplemented by wake-time self-assessments at home and work Those casual time-unspecified OBPM disregard the mostly predictable circadian variation in BP Various circadian rhythms may also significantly affect the pharmacokinetics and pharmacodynamics both beneficial and adverse effects of hypertension medications as extensively documented Most important numerous outcome trials and published meta-analyses substantiate the correlation between BP level and risk of target organ injury damage and cardiovascular disease CVD events is much stronger for parameters derived from around-the-clock ambulatory BP monitoring ABPM than it is for values derived from traditional daytime OBPM ABPM is a diagnostic tool with the added advantage that allows thorough description and quantification of all aspects of the 24h BP variation
On the basis of this substantial and indisputable evidence several international guidelines now propose ambulatory measurements as a requirement to confirm the office diagnosis of hypertension in adults On the contrary other guidelines despite recognizing greater prognostic value of ABPM than OBPM still recommended the use of the later for diagnosis of hypertension for historical reasons unjustified on the light of current available scientific evidence
12 Asleep BP mean as an independent prognostic marker of CVD risk
Specific features of the ABPM-determined 24h BP pattern have been explored as biomarkers or mediators of target tissue injury and triggers of and risk factors for CVD events -- angina pectoris myocardial infarction cardiac arrest sudden cardiac death pulmonary embolism -- and cerebrovascular events -- ischemic and hemorrhagic stroke Numerous studies consistently substantiate a strong association between the abnormal physiologic feature of blunted sleep-time relative BP decline non-dipperriser BP pattern and increased incidence of fatal and non-fatal CVD events not only in hypertensive persons but also in normotensive individuals27 Furthermore various independent prospective studies demonstrate CVD events are better predicted by the asleep than awake or 24h BP means
Overall such prospective ABPM studies demonstrate elevated sleep-time BP constitutes a significant CVD risk factor independent of the daytime OBPM or ambulatory awake and 24h BP means Nonetheless all previous investigations addressing the merit of ABPM for predicting CVD risk except the Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares study MAPEC ie Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events discussed below relied upon only a single low-reproducible study-inclusion baseline 24h ABPM assessment per participant Lack of systematic and multiple ABPM evaluations of participants over time in all previously reported long-term follow-up studies except MAPEC precluded the opportunity to explore the potential reduction in CVD risk associated with modification of prognostic parameters by hypertension therapy andor lifestyle changes ie either increase of sleep-time relative BP decline towards the more normal dipper pattern or more specifically reduction of asleep BP mean Incorporation of periodic at least annual ABPM studies of participants during follow-up as in the MAPEC study clearly establishes that i features of the 24h BP pattern change over time and ii therapeutic reduction of the asleep BP mean and increase of the sleep-time relative BP decline towards normal dipping lessen not only CVD risk but also progression towards new-onset type 2 diabetes and chronic kidney disease CKD
Potential reduction in CVD risk through modification of prognostic ABPM parameters by a time-specified hypertension-treatment strategy has so far been investigated only in the MAPEC study Cox regression survival analysis of each potential prognostic BP parameter analyzed individually indicates the hazard ratio HR of total CVD events is greater with progressively higher sleep-time SBP mean and lower sleep-time relative SBP decline ie more non-dipperriser BP patterning Moreover joint analysis of the multiple BP parameters potentially capable of contributing to CVD risk finds OBPM does not independently predict CVD morbidity and mortality when the outcomes model is adjusted by the asleep BP mean HR144 95CI 130-160 P0001 per SD elevation in asleep SBP mean HR109 097-123 P0123 per SD elevation in clinic SBP The best Cox regression fully adjusted model includes only the asleep SBP mean HR143 95CI 129-158 P0001 and sleep-time relative SBP decline HR088 078-098 P0023
13 Asleep BP mean as a therapeutic target for CVD risk reduction
Data from the MAPEC study in which participants were repeatedly assessed by periodic 48h ABPM also permitted prospective evaluation of the impact of changes in OBPM and ABPM during follow-up on CVD risk Progressive treatment-induced lowering of the awake asleep and 48h BP means but not daytime OBPM when each variable is analyzed individually reveals association with significant CVD risk reduction Most importantly Cox survival analysis with joint inclusion of asleep and awake BP means as potential predictors indicates progressive attenuation of asleep SBP mean is significantly associated with diminished CVD risk adjusted HR067 055-081 P0001 per SD decrease in asleep SBP mean while progressive lowering of awake SBP mean is not adjusted HR100 086-118 P0958 per SD decrease in awake SBP mean during follow-up Overall the best fully adjusted time-dependent Cox regression model includes only the progressive attenuation of the asleep SBP mean HR076 95CI 068-085 P0001 per SD decrease in asleep SBP mean and increase in the sleep-time relative SBP decline HR119 101-139 P0038 per SD decrease in sleep-time relative SBP decline during follow-up Thus a diminished asleep but not awake BP mean is a highly significant independent prognostic marker of reduced CVD morbidity and mortality risk and therefore constitutes a novel therapeutic target for increased event-free survival
Thus far apart from MAPEC the only prospective study in which participants are evaluated periodically by ABPM is the Hygia Project a research network primarily designed to extend the use of ABPM in primary care as a requirement for the diagnosis of hypertension evaluation of response to treatment and individualized assessment of CVD and other risks Presently the Hygia Project is composed of 40 clinical sites primary care centers involving 292 investigators properly trained to ABPM and all study procedures The study was designed to evaluate in the routine primary care clinical setting among other objectives the prognostic value of multiple ABPM-derived parameters mainly asleep BP mean and sleep-time relative BP decline with OBPM for the prediction of CVD morbidity and mortality new-onset diabetes and new-onset CKD The investigators so far prospectively evaluated 18078 individuals 9769 men8309 women 591143 meanSD years of age with baseline ambulatory BP ranging from normotension to hypertension At inclusion and at scheduled visits mainly annually during follow-up ambulatory BP was evaluated for 48 consecutive hours During the current 51-year median patient follow-up 2311 individuals had CVD events including 1209 experiencing the primary outcome composite of CVD death myocardial infarction coronary revascularization heart failure and stroke The asleep SBP mean was the most significant prognostic marker of the primary outcome HR129 95CI 122-135 per SD elevation P0001 independent of clinic 103 097-109 P0315 and awake SBP 102 094-110 P0682 Most important the progressive treatment-induced attenuation of asleep SBP was the most significant prognostic marker of event-free survival 075 95CI 069-082 per SD decrease P0001 independent of changes in office 107 097-117 P0176 or awake SBP mean 096 085-108 P0473 during follow-up Only the decrease in asleep SBP mean and increase in sleep-time relative SBP decline towards the more normal dipper BP pattern remained jointly and significantly associated with reduced CVD risk There was a highly significant decrease in risk of CVD outcome with progressively lower achieved asleep SBP mean in particular CVD event-rate was significantly lower in participants with achieved asleep SBP mean 105 mmHg at their final evaluation than those with achieves asleep SBP mean between 105 and 120 mmHg 335 vs 727 events per 1000 patientsyear respectively P0001 54 CVD risk reduction in the lower achieved asleep SBP mean of these two groups of hypertensive patients with controlled asleep SBP mean According to this prospective evaluation the asleep SBP mean but not the daytime OBPM or the awake ambulatory BP mean is the most significant and independent prognostic marker of CVD outcome
On the basis of new evidence on the relationship between achieved OBPM and the risk of CVD morbidity and mortality documented in the SPRINT trial the recent 2017 guidelines of the American College of Cardiology ACC and the American Heart Association AHA have established lower values of 13080 mmHg for clinic SBPDBP as new diagnostic thresholds for hypertension and therapeutic targets for treatment of all individuals aged 18 years regardless of age sex or concomitant complications including presence of diabetes CKD or history of past CVD event According to these guidelines the new proposed ABPM thresholds for diagnosis of hypertension in adults are 13080 and 11065 mmHg for the awake and asleep SBPDBP means respectively However the ACCAHA guidelines do not provide any scientific evidence documenting neither the equivalence between these ABPM thresholds and the 13080 mmHg cut-off values for OBPM nor the potential improved CVD event-free survival time of the proposed more intensive control of ambulatory BP
All the results described above including the main findings of the MAPEC and Hygia trials pertaining to the greater prognostic value of ABPM than OBPM are derived from observational prospective studies consistently documenting that therapeutic BP targets in hypertensive individuals ie persons at increased CVD risk should be established in terms of proper control of asleep BP To date no prospective randomized study has ever before evaluated which should be the adequate therapeutic ABPM target for most effective reduction of CVD risk Accordingly the Tratamiento de Hipertensión Arterial Durante el Sueño study THADEUS ie Treatment of Hypertension During Sleep has been designed to prospectively evaluate if the intensive control of asleep SBP mean proposed by the new ACCAHA guidelines 110 mmHg in more effective than the so far conventional control 120 mmHg to reduce CVD morbidity and mortality in hypertensive individuals
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2017470 | REGISTRY | State Committee of Ethics in Investigation of Galicia | None |
| 2017-001410-28 | EUDRACT_NUMBER | None | None |