Daily self-reported behavioural efficacy records on hypertension digital therapeutics as digital metrics associated with the reduction in morning home blood pressure: post-hoc analysis of HERB-DH1 trial.

Digital therapeutics for hypertension, proven effective in the HERB-DH1 trial, enable patients to record and track their daily actions and achievements to improve their lifestyles using an app. However, the association between recording daily behaviours and blood pressure (BP) reduction has not yet been investigated. We conducted a post-hoc analysis to investigate the relationship between them in the HERB-DH1 trial. We defined the counts of daily records of antihypertensive behaviour taken by the patient into the app as daily self-reported behavioural efficacy records (SER). SER was categorised into quartiles, and the trend of changes from baseline to week 12 in morning home systolic blood pressure (SBP), salt intake checklist score, and body weight was assessed. A total of 156 patients with hypertension were included in the analysis. A higher total count of SER was associated with greater SBP reduction (P for trend: 0.049). Patients with a higher SER for salt intake and weight reduction showed reductions in SBP (P for trend: 0.034 and 0.027, respectively). Furthermore, patients with higher salt intake SER exhibited a decrease in the salt intake checklist scores, and patients with greater weight reduction SER experienced a reduction in body weight (P for trend: 0.001 and 0.007, respectively). SER during digital therapeutics is associated with a reduction in morning home SBP in patients with hypertension. Enhancing patients' intrinsic motivation and self-efficacy, as evaluated by the SER, can play an important role in reducing BP by promoting lifestyle improvement. Daily self-reported behavioural efficacy records (SER) defined as the number of patient's app inputs of recall of day-by-day activity of behaviours at the end of the day, is partially affected by self-efficacy and affinity of app, resulting in the effectiveness of digital therapeutics.

Home blood pressure-lowering effect of digital therapeutics in hypertension: impact of body weight and salt intake.

Lifestyle modifications, including body weight reduction and salt restriction, help reduce blood pressure (BP). This study investigated the effects of body mass index (BMI) and salt intake on home BP reductions in unmedicated patients with hypertension receiving guideline-based lifestyle modification from doctors (control group) or with the addition of a digital therapeutics intervention. Data from the HERB Digital Hypertension 1 (HERB-DH1) pivotal trial were analyzed. Home BP was measured for 7 days before each study visit (baseline, and 4/8/12 weeks). Body weight was measured at each visit and salt intake questionnaire was answered at baseline and 12 weeks. This analysis included 302 patients with sufficient home BP monitoring data (digital therapeutics: 156; control group: 146). The reduction in morning home SBP from baseline to 12 weeks was significantly greater in the digital therapeutics vs. control group for patients with baseline BMI ≥ 25 kg/m2 and higher salt intake group (self-reported salt intake score ≥ 14) (-5.1 mmHg, p < 0.01). Patients in the digital therapeutics group who experienced a reduction in BMI and an improvement in salt intake score during the 12-week study also had a significantly greater reduction in morning home SBP compared with patients in the control group (-7.2 mmHg, p < 0.01). The digital therapeutic intervention reduced home BP the most in unmedicated patients with hypertension with high baseline BMI and salt intake score. Those with improvements in both BMI and salt intake during the digital therapeutics intervention achieved the greatest reduction in home BP vs. control.Clinical trial registration: Japan Registry of Clinical Trials (jRCT2032190148).

Concept, study design, and baseline blood pressure control status of the nationwide prospective HI-JAMP study using multisensor ABPM.

The Home-Activity Information and Communication Technology (ICT)-based Japan Ambulatory Blood Pressure Monitoring Prospective (HI-JAMP) study is a nationwide general practitioner-based cohort of medicated hypertensive patients that began in 2017. The primary objective of this study is to clarify which blood pressure (BP) measure is the best predictor of cardiovascular disease: office, home, or ambulatory BP. To this end, we used a newly developed ICT-based multisensor ambulatory BP monitoring (IMS-ABPM) device (TM-2441; A&D Company), which can also be used for home BP monitoring and is equipped with a high-sensitivity actigraph, a thermometer, and a barometer. This is the first study to evaluate three hemodynamic properties under resting home and active ambulatory conditions using the same device: (1) BP variability; (2) trigger-specific BP sensitivity to physical activity, temperature, and atmospheric pressure; and (3) central hemodynamics. A total of 2754 patients were enrolled, and 2731 patients with the required number of ambulatory BP readings (at least 6 daytime and 3 nighttime readings) were included in the final analysis. The overall patient group showed worse control of morning and nighttime BPs compared to office and daytime BPs, and the control rate was also poor among patients with a higher number of antihypertensive drugs. In conclusion, the baseline data of the HI-JAMP study demonstrated that morning home and nighttime BP remain difficult to control even among patients taking two or more hypertensive agents. By simultaneously considering office, home, and ambulatory BPs, the HI-JAMP study will contribute to the development of hypertension management strategies and new BP indices.

Inconsistent Control Status of Office, Home, and Ambulatory Blood Pressure All Taken Using the Same Device: The HI-JAMP Study Baseline Data.

BACKGROUND: Inconsistencies between the office and out-of-office blood pressure (BP) values (described as white-coat hypertension or masked hypertension) may be attributable in part to differences in the BP monitoring devices used. METHODS: We studied consistency in the classification of BP control (well-controlled BP vs. uncontrolled BP) among office, home, and ambulatory BPs by using a validated "all-in-one" BP monitoring device. In the nationwide, general practitioner-based multicenter HI-JAMP study, 2,322 hypertensive patients treated with antihypertensive drugs underwent office BP measurements and 24-hour ambulatory BP monitoring (ABPM), consecutively followed by 5-day home BP monitoring (HBPM), for a total of seven BP measurement days. RESULTS: Using the thresholds of the JSH2019 and ESC2018 guidelines, the patients with consistent classification of well-controlled status in the office (<140 mmHg) and home systolic BP (SBP) (<135 mmHg) (n = 970) also tended to have well-controlled 24-hour SBP (<130 mmHg) (n = 808, 83.3%). The patients with the consistent classification of uncontrolled status in office and home SBP (n = 579) also tended to have uncontrolled 24-hour SBP (n = 444, 80.9%). Among the patients with inconsistent classifications of office and home BP control (n = 803), 46.1% had inconsistent ABPM-vs.-HBPM out-of-office BP control status. When the 2017 ACC/AHA thresholds were applied as an alternative, the results were essentially the same. CONCLUSIONS: The combined assessment of the office and home BP is useful in clinical practice. Especially for patients whose office BP classification and home BP classification conflict, the complementary clinical use of both HBPM and ABPM might be recommended.

The first software as medical device of evidence-based hypertension digital therapeutics for clinical practice.

In 2021, the open-label randomized HERB-Digital Hypertension 1 (HERB-DH1) trial showed for the first time that hypertension digital therapeutics (a hypertension treatment app) successfully reduced blood pressure (BP) in patients with hypertension. Patients in the digital therapeutics group who used the app and home BP monitoring (HBPM) showed significant and persistent decreases in office, home and ambulatory BP values compared with the control group (who were under physician management using HBPM and lifestyle modifications). The results of the pivotal study led to the first global approval of this app for the treatment of hypertension in Japan in 2022, including medical insurance reimbursement. As a result, this hypertension app is expected to become widely used in the clinical management of all stages of hypertension. The most important remaining research issues include the identification of patients likely to respond to this therapeutic approach and the development of clinical efficacy indices. In addition, guidelines for the appropriate use of hypertension apps in the treatment of hypertension are needed. Next steps include the development and research of digital tools to facilitate the behavioral modifications required to prevent hypertension.

Digital Therapeutics in Hypertension: Evidence and Perspectives.

Digital therapeutics refers to the use of evidence-based therapeutic interventions driven by high-quality software programs to treat, manage, or prevent a medical condition. This approach is being increasingly investigated for the management of hypertension, a common condition that is the leading preventable cardiovascular disease risk factor worldwide. Digital interventions can help facilitate uptake of important guideline-recommended lifestyle modifications, reinforce home blood pressure monitoring, decrease therapeutic inertia, and improve medication adherence. However, current studies are only of moderate quality, and are highly heterogeneous in the interventions evaluated, comparator used, and results obtained. Therefore, additional studies are needed, focusing on the development of universally applicable and consistent digital therapeutic strategies designed with health care professional input and evaluation of these interventions in robust clinical trials with objective end points. Hopefully, the momentum for digital therapeutics triggered by the coronavirus disease 2019 pandemic can be utilized to maximize advancements in this field and drive widespread implementation.

Efficacy of a digital therapeutics system in the management of essential hypertension: the HERB-DH1 pivotal trial.

AIMS: Digital therapeutics is a new approach to facilitate the non-pharmacological treatment of hypertension using software programmes such as smartphone applications and/or device algorithms. Based on promising findings from a small pilot trial, the HERB Digital Hypertension 1 (HERB-DH1) pivotal trial investigated the efficacy of digital therapeutics in patients with hypertension not receiving antihypertensive medication. METHODS AND RESULTS: This prospective, open-label, randomized controlled study was performed at 12 sites in Japan. Patients with hypertension [office systolic blood pressure (SBP) 140 to <180 mmHg and 24 h SBP ≥130 mmHg] were randomly assigned 1:1 to the digital therapeutics group (HERB system + standard lifestyle modification) or control group (standard lifestyle modification alone). The primary efficacy endpoint was the mean change in 24 h ambulatory SBP from baseline to 12 weeks; key secondary efficacy endpoints were mean changes in office and home blood pressure (BP) from baseline to 12 weeks. All analyses were conducted in the full analysis set population. Between December 2019 and June 2020, 390 patients were randomly assigned to the digital therapeutics group (n = 199) or control (n = 191) group. Between-group differences in 24-h ambulatory, home, and office SBPs at 12 weeks were -2.4 (95% confidence interval -4.5 to -0.3), -4.3 (-6.7 to -1.9), and -3.6 (-6.2 to -1.0) mmHg, respectively. No major programme-related safety events occurred up to 24 weeks. CONCLUSION: The HERB-DH1 pivotal study showed the superiority of digital therapeutics compared with standard lifestyle modification alone to reduce 24-h ambulatory, home, and office BPs in the absence of antihypertensive medications.

Digital therapeutics for essential hypertension using a smartphone application: A randomized, open-label, multicenter pilot study.

Hypertension is the most considerable but treatable risk factor for cardiovascular disease. Although physicians prescribe multiple antihypertensive drugs and promote lifestyle modifications, the real-world blood pressure (BP) control rate remains poor. To improve BP target achievement, we developed a novel digital therapeutic-the HERB software system -to manage hypertension. Here, we performed a randomized pilot study to assess the safety and efficacy of the HERB system for hypertension. We recruited 146 patients with essential hypertension from March 2018 to March 2019. We allocated eligible patients to the intervention group (HERB system + standard lifestyle modification) or control group (standard lifestyle modification alone). The primary outcome was the mean change from baseline to 24 weeks in 24-hour systolic BP (SBP) measured by ambulatory blood pressure monitoring (ABPM). The baseline characteristics in each group were well balanced; the mean age was approx. 57 years, and 67% were male. In the primary end point at 24 weeks, HERB intervention did not lower the mean change of 24-hour SBP by ABPM compared with the controls (adjusted difference: -0.66 mmHg; p = .78). In an exploratory analysis focusing on antihypertensive drug-naïve patients aged <65, the effects of the HERB intervention were significantly greater than the control for reducing 24-hour SBP by ABPM at 16 weeks (adjusted difference: -7.6 mmHg; p = .013; and morning home SBP at 24 weeks (adjusted difference - 6.0 mmHg; p = .012). Thus, the HERB intervention did not achieve a primary efficacy end point. However, we observed that antihypertensive drug-naïve adult hypertensive patients aged <65 years could be a potential HERB system-effective target for further investigations of the efficacy of the system.

Effects of luseogliflozin on arterial properties in patients with type 2 diabetes mellitus: The multicenter, exploratory LUSCAR study.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the occurrence of cardiovascular and renal complications in patients with type 2 diabetes mellitus (T2DM) and represent guideline-recommended therapy in this indication. However, precise mechanisms underlying the beneficial cardiovascular effects of SGLT2 inhibitors are not fully understood. This study investigated the effects of the SGLT2 inhibitor, luseogliflozin, on arterial properties and home blood pressure (BP) in patients with T2DM. This multicenter, single-arm study enrolled adults with T2DM, glycosylated hemoglobin (HbA1c) 6.5%-8.9% in the previous 4 weeks, and an indication for new/additional antidiabetic therapy. Luseogliflozin 2.5 mg/d was given for 12 weeks. Primary outcome was change in cardio-ankle vascular index (CAVI) from baseline to Week 4 and Week 12. Home and office BP, BP variability, and metabolic parameters were secondary endpoints. Forty-seven patients (mean age 63.5 ± 10.7 years) treated with luseogliflozin were included in the full analysis set. CAVI did not change significantly from baseline (mean [95% confidence interval] 8.67 [8.37-8.97]) to Week 12 (8.64 [8.38-8.91]; P = .750), but there were significant reductions from baseline in morning home BP, HbA1c, body weight, body mass index, and serum uric acid levels during luseogliflozin therapy. The reduction in morning home systolic BP was ≥ 5 mm Hg and was independent of baseline BP and BP control status. In conclusion, there was no change in arterial stiffness (based on CAVI) during treatment with luseogliflozin, but changes in BP and metabolic parameters were consistent with the known beneficial effects of SGLT2 inhibitors in T2DM.

A multicenter clinical trial to assess the efficacy of the digital therapeutics for essential hypertension: Rationale and design of the HERB-DH1 trial.

Digital therapeutics is a new approach to treat hypertension via using software programs such as smartphone apps and/or device algorithms. We develop a HERB system-new interactive smartphone app (HERB Mobile) with web-based patient management console (HERB Console)-to lower blood pressure (BP) based on an algorithm that helps users to promote lifestyle modifications in conjunction with medically validated non-pharmacological interventions. The app can assess the personalities, behavior characteristics, and hypertension determinants of each patient with hypertension to provide adequate guidance. To demonstrate the efficacy of the system, we designed a randomized, controlled, multicenter, open-label trial "HERB-DH1 (HERB digital hypertension 1)" to assess the efficacy of HERB system in patients with essential hypertension. The authors allocate patients to the intervention group (HERB system + standard lifestyle modification) or to the control group (standard lifestyle modification alone). In the intervention group, we provide the HERB Mobile for patients and the HERB Console for their primary physicians for 24 weeks. Both groups are instructed for standard lifestyle modifications based on the current recommendations in the Japanese Society of Hypertension 2019 guideline. The primary outcome is the mean change from baseline to 12 weeks in 24-hour systolic BP measured by ambulatory BP monitoring. We started this study in December of 2019, and the trial results will be expected in early 2021. We believe that this trial enables us to verify the efficacy of the HERB system in patients with essential hypertension.

Salt Intake and Risk of Disaster Hypertension Among Evacuees in a Shelter After the Great East Japan Earthquake.

This study investigated the association between salt intake and risk of disaster hypertension. We analyzed the data of surveys evaluating the health condition of evacuees in shelters after the Great East Japan Earthquake on April 30 and May 5, 2011. Among 272 subjects who completed the basic health condition questionnaire and underwent a medical examination, 158 (58%) had disaster hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg). Average estimated sodium intake assessed by spot urine was significantly associated with disaster hypertension (odds ratio per 1 g/d, 1.16; 95% CI, 1.05-1.30). When we defined the high risk factors for salt-sensitive hypertension as older age (≥65 years), obesity (body mass index, ≥25 kg/m2), chronic kidney disease, and diabetes mellitus, estimated sodium intake was found to be a risk factor for disaster hypertension in the total group (odds ratio per 1 g/d, 1.27; 95% CI, 1.12-1.43) and even in the group without prevalent hypertension before disaster (n=146; odds ratio per 1 g/d, 1.46; 95% CI, 1.19-1.79). There was an interaction between estimated sodium intake and disaster hypertension according to the presence or absence of high risk of salt-sensitive hypertension in the group without prevalent hypertension (P=0.03). Disaster hypertension conferred a risk of microalbuminuria (odds ratio, 3.00; 95% CI, 1.71-5.26; P<0.001). We conclude that increased estimated sodium intake was associated with disaster hypertension in evacuees after disaster. This association was noted in the population with high risk of salt-sensitive hypertension and without prevalent hypertension before natural disaster. Additionally, disaster hypertension was associated with subclinical organ damage.

Patterns of drug treatment in patients with osteoarthritis and chronic low back pain in Japan: a retrospective database study.

Purpose: Musculoskeletal diseases, including osteoarthritis (OA) and low back pain (LBP), are the leading causes of years lived with disability, and are associated with lowered quality-of-life, lost productivity, and increased healthcare costs. However, information publicly available regarding the Japanese real-world usage of prescription medications is limited. This study aimed to describe the clinical characteristics of patients with OA and chronic LBP (CLBP), and to investigate the patterns of medications and opioid use in Japanese real-world settings. Materials and methods: A retrospective study was conducted using a Japanese administrative claims database between 2013 and 2017. The outcomes were patient characteristics and prescription medications, and they were evaluated separately for OA and CLBP. Results: The mean age of 118,996 patients with OA and 256,402 patients with CLBP was 68.8±13.1 years and 64.8±16.4 years, respectively. Approximately 90% of patients with OA and CLBP were prescribed non-steroidal anti-inflammatory drugs (NSAIDs). Other prescriptions included hyaluronate injection (35.6%), acetaminophen (21.4%), and steroid injection (20.0%) in patients with OA, and pregabalin (39.0%) and acetaminophen (22.4%) in patients with CLBP. Weak opioids were prescribed to 10.7% and 20.6% of patients with OA and CLBP, respectively. The prescription of COX-2 inhibitors (OA: +6.5%; CLBP: +6.7%) and acetaminophen (OA: +16.4%; CLBP: +14.4%) increased between 2013 and 2017. The first commonly prescribed medication among patients with OA and CLBP were NSAIDs; hyaluronate injection (patients with OA) and pregabalin (patients with CLBP) were also common first-line medications. Acetaminophen, steroid injection (patients with OA), and weak opioids were prescribed more in the later phases of treatment. Conclusion: Most patients were prescribed limited classes of pain drugs, with NSAIDs being the most common pain medication in Japan for patients with OA and CLBP. Opioid prescription was uncommon, and were weak opioids when prescribed.

Stem cell therapy: is there a future for reconstruction of large bone defects?

Large bone defects caused by fracture, non-union and bone tumor excision has been a major clinical problem. Autogenous bone grafting and Ilizarov method are commonly performed to treat them. However, bone grafting has limitation in volume of available bone, and Ilizarov method requires long periods of time to treat. Accordingly, there is need for stem cell therapy for bone repair and/or regeneration. Mesenchymal stem cells (MSCs) hold the ability to differentiate into osteoblasts and are available from a wide variety of sources. The route of "intramembranous ossification (direct bone formation)" by transplantation of undifferentiated MSCs has been tested but it did not demonstrate the success initially envisaged. Recently another approach has been examined being the transplantation of "MSCs pre-differentiated in vitro into cartilage-forming chondrocytes" into bone defect, in brief, representing the route of "endochondral ossification (indirect bone formation)". It's a paradigm shift of Stem Cell Therapy for bone regeneration. We have already reported on the healing of large femur defects in rats by transplantation of "MSCs pre-differentiated in vitro into cartilage-forming chondrocytes". We named the cells as Mesenchymal Stem Cell-Derived Chondrocytes (MSC-DCs). The success of reconstruction of a massive 15-mm femur defect (approximately 50% of the rat femur shaft length) provides a sound foundation for potential clinical application of this technique. We believe our results may offer a new avenue of reconstruction of large bone defect, especially in view of the their high reproducibility and the excellent biomechanical strength of repaired femora.

Bone regeneration in a massive rat femur defect through endochondral ossification achieved with chondrogenically differentiated MSCs in a degradable scaffold.

Mesenchymal stem cells (MSCs) are multipotent cells capable of proliferating and differentiating into several lineages. In regenerative medicine, their potential as a resource for tissue-replacement therapy is receiving much attention. However, transplanting MSCs to repair larger bone defects in animal models has so far proved disappointing. Here we report on the healing of both critical-sized (5 mm) and massive (15 mm) full-thickness femur defects in rats by implanting a uniquely fabricated PLGA scaffold seeded with MSCs pre-differentiated in vitro into cartilage-forming chondrocytes (MSC-DCs). This strategy closely mimics endochondral ossification, the process by which long bones develop in nature. It is thought that because the transplanted MSC-DCs induced natural bone formation, the defect size was not critical to the outcome. Crucially, after 8 weeks the mean biomechanical strength of femora with the massive 15 mm implant reached 75% that of a normal rat femur, while in the case of 5 mm implants there was no significant difference. Successful healing was also highly reproducible, with bone union occurring in all treated animals examined radiologically 8 or 16 weeks after surgery.

Establishment of reproducible, critical-sized, femoral segmental bone defects in rats.

Development of new treatment methodologies for bone nonunion requires validated experimental models for their application into tissue engineering approaches. Critical-sized bone defect (CSBD) models identify the smallest size at which tissue defects fail to completely heal during the experimental period. The purpose of this study was to systematically determine a CSBD in rat femurs using external fixation. Thirty Fischer 344 rats were equally divided into six groups. Bone defects of 1, 2, 3, 4, 5, and 6 mm were created in the diaphysis of the femur, before external fixation. Defects were evaluated radiographically at weekly intervals and histologically at the predefined healing period of 8 weeks. Defects of 4 mm or more failed to achieve union in our model. Nonunions were characterized by the absence of a bridging callus and filling of the defect with fibrous and muscle tissue. Radiographically, bone ends in nonunions were rounded up to 4 weeks postsurgery. Our systematic approach for identification of a CSBD in rat femurs, revealed that externally fixed defects of 4 mm and larger, failed to heal within the 8-week time frame.

Kinetics of left ventricular rotation during exercise and its relation to exercise tolerance in atrial fibrillation: assessment by two-dimensional speckle tracking echocardiography.

BACKGROUND: Left ventricular (LV) rotation plays an important role in cardiac function both at rest and during exercise in sinus rhythm. The kinetics of rotation during exercise and the relation between exercise tolerance and rotation-related parameters in patients with atrial fibrillation (AF) are unknown. METHODS: Twenty-nine patients (age 62 ± 13 years, 6 females) with AF and preserved LV ejection fraction (LVEF) were studied using two-dimensional speckle tracking echocardiography at rest and during exercise with a supine bicycle ergometer (20 W, 10 min). We measured the systolic rotation (Rot) and the peak rotation rate in systole and early diastole (eRotR) at the apical and basal levels of the LV. All patients underwent cardiopulmonary exercise testing to obtain their percent achieved of the predicted peak oxygen consumption (% peak VO2) value. RESULTS: During exercise, apical Rot-related indices were significantly increased only in the preserved % peak VO2 group. In contrast, E/e' was significantly elevated only in the reduced % peak VO2 group. Multivariable stepwise regression analysis showed that apical ΔRot was independently associated with % peak VO2 (ß = 0.72; p < 0.01). Apical ΔeRotR, which could not be selected as an independent predictor of % peak VO2, had a good linear correlation with apical ΔRot (r = 0.81, p < 0.01). CONCLUSIONS: The augmentation of apical rotation in response to exercise may coincide with an increase of the apical derotation rate, and apical rotation reserve may reflect exercise tolerance in patients with AF and preserved LVEF.