Effect of Drug Monitoring on Adherence and Blood Pressure: A Multicenter Randomized Clinical Trial.

BACKGROUND: Drug concentration in blood or urine is an acknowledged method to detect non-adherence. Observational studies suggest that informing patients about low or absent serum drug levels improves blood pressure (BP). We performed a multicenter randomized clinical trial to test the hypothesis that therapeutic drug monitoring (TDM) could improve drug adherence and BP in patients with uncontrolled hypertension and reduced adherence to antihypertensive drugs. METHODS: Patients were ≥18 years on stable treatment with at least two antihypertensive agents. We planned to randomize 80 non-adherent patients with a systolic daytime ambulatory BP (ABPM) ≥135 mmHg to TDM-intervention or not. The control group and the study-personnel who measured BP remained uninformed about serum drug measurements throughout. All patients and physicians were blinded for BPs. Lifestyle advice and detailed information on disease process and importance of BP treatment were given to both groups. RESULTS: From 2017 to 2022, we randomized 46 diagnosed non-adherent from a total of 606 patients with uncontrolled hypertension. The TDM-group had a 6.7 (±14.5) mmHg reduction from 147.9 (±10.3) to 141.1 (±14.1) mmHg, and the control group experienced a 7.3 (±13.2) mmHg reduction from 147.1 (±9.2) to 139.1 (±17.4) mmHg, p=0.9 between groups. Adherence improved in both groups, 73% in the TDM group and 59% in the control group became adherent at three months, p=0.51. CONCLUSIONS: In our prospective multicenter clinical trial of uncontrolled and non-adherent hypertensive patients, we found no additional effect of therapeutic drug monitoring (TDM) on blood pressure and drug adherence compared with standard care.

Medical Measures in Hypertensives Considered Resistant.

BACKGROUND: Patients with resistant hypertension are the group of hypertensive patients with the highest cardiovascular risk. METHODS: All rules and guidelines for treatment of hypertension should be followed strictly to obtain blood pressure (BP) control in resistant hypertension. The mainstay of treatment of hypertension, also for resistant hypertension, is pharmacological treatment, which should be tailored to each patient's specific phenotype. Therefore, it is pivotal to assess nonadherence to pharmacological treatment as this remains the most challenging problem to investigate and manage in the setting of resistant hypertension. RESULTS: Once adherence has been confirmed, patients must be thoroughly worked-up for secondary causes of hypertension. Until such possible specific causes have been clarified, the diagnosis is apparent treatment-resistant hypertension (TRH). Surprisingly few patients remain with true TRH when the various secondary causes and adherence problems have been detected and resolved. Refractory hypertension is a term used to characterize the treatment resistance in hypertensive patients using ≥5 antihypertensive drugs. All pressor mechanisms may then need blockage before their BPs are reasonably controlled. CONCLUSIONS: Patients with resistant hypertension need careful and sustained follow-up and review of their medications and dosages at each term since medication adherence is a very dynamic process.

Accuracy and User Acceptability of 24-hour Ambulatory Blood Pressure Monitoring by a Prototype Cuffless Multi-Sensor Device Compared to a Conventional Oscillometric Device.

OBJECTIVE: 24-hour ambulatory blood pressure monitoring (24ABPM) is state of the art in out-of-office blood pressure (BP) monitoring. Due to discomfort and technical limitations related to cuff-based 24ABPM devices, methods for non-invasive and continuous estimation of BP without the need for a cuff have gained interest. The main aims of the present study were to compare accuracy of a pulse arrival time (PAT) based BP-model and user acceptability of a prototype cuffless multi-sensor device (cuffless device), developed by Aidee Health AS, with a conventional cuff-based oscillometric device (ReferenceBP) during 24ABPM. METHODS: Ninety-five normotensive and hypertensive adults underwent simultaneous 24ABPM with the cuffless device on the chest and a conventional cuff-based oscillometric device on the non-dominant arm. PAT was calculated using the electrocardiogram (ECG) and photoplethysmography (PPG) sensors incorporated in the chest-worn device. The cuffless device recorded continuously, while ReferenceBP measurements were taken every 20 minutes during daytime and every 30 minutes during nighttime. Two-minute PAT-based BP predictions corresponding to the ReferenceBP measurements were compared with ReferenceBP measurements using paired t-tests, bias, and limits of agreement. RESULTS: Mean (SD) of ReferenceBP compared to PAT-based daytime and nighttime systolic BP (SBP) were 129.7 (13.8) mmHg versus 133.6 (20.9) mmHg and 113.1 (16.5) mmHg versus 131.9 (23.4) mmHg. Ninety-five % limits of agreements were [-26.7, 34.6 mmHg] and [-20.9, 58.4 mmHg] for daytime and nighttime SBP respectively. The cuffless device was reported to be significantly more comfortable and less disturbing than the ReferenceBP device during 24ABPM. CONCLUSIONS: In the present study, we demonstrated that a general PAT-based BP model had unsatisfactory agreement with ambulatory BP during 24ABPM, especially during nighttime. If sufficient accuracy can be achieved, cuffless BP devices have promising potential for clinical assessment of BP due to the opportunities provided by continuous BP measurements during real-life conditions and high user acceptability.

What is the context?Hypertension is a major risk factor for cardiovascular and cerebrovascular end-organ damage, morbidity, and mortality world-wide.Accurate measurement of blood pressure is essential for the diagnosis and management of hypertension.What is new?Cuffless blood pressure devices that allow measurement of blood pressure without a pressure cuff is a promising and novel method of blood pressure estimation.The objective of this study is to assess whether pulse arrival time alone can be used to estimate blood pressure accurately during 24-hour ambulatory blood pressure monitoring, using a prototype cuffless device placed on the chest.Our analysis shows that a general model based on pulse arrival time overestimated ambulatory blood pressure, especially during nighttime.User acceptability was higher with the cuffless device compared to a conventional cuff-based oscillometric device during 24-hour ambulatory blood pressure monitoring.What is the impact?This study provides further evidence that accurate blood pressure estimations cannot be achieved by using pulse arrival time alone as a surrogate for blood pressure measurements.

Accuracy of non-invasive cuffless blood pressure in the intensive care unit: Promises and challenges.

Objective: Continuous non-invasive cuffless blood pressure (BP) monitoring may reduce adverse outcomes in hospitalized patients if accuracy is approved. We aimed to investigate accuracy of two different BP prediction models in critically ill intensive care unit (ICU) patients, using a prototype cuffless BP device based on electrocardiogram and photoplethysmography signals. We compared a pulse arrival time (PAT)-based BP model (generalized PAT-based model) derived from a general population cohort to more complex and individualized models (complex individualized models) utilizing other features of the BP sensor signals. Methods: Patients admitted to an ICU with indication of invasive BP monitoring were included. The first half of each patient's data was used to train a subject-specific machine learning model (complex individualized models). The second half was used to estimate BP and test accuracy of both the generalized PAT-based model and the complex individualized models. A total of 7,327 measurements of 15 s epochs were included in pairwise comparisons across 25 patients. Results: The generalized PAT-based model achieved a mean absolute error (SD of errors) of 7.6 (7.2) mmHg, 3.3 (3.1) mmHg and 4.6 (4.4) mmHg for systolic BP, diastolic BP and mean arterial pressure (MAP) respectively. Corresponding results for the complex individualized model were 6.5 (6.7) mmHg, 3.1 (3.0) mmHg and 4.0 (4.0) mmHg. Percentage of absolute errors within 10 mmHg for the generalized model were 77.6, 96.2, and 89.6% for systolic BP, diastolic BP and MAP, respectively. Corresponding results for the individualized model were 83.8, 96.2, and 94.2%. Accuracy was significantly improved when comparing the complex individualized models to the generalized PAT-based model in systolic BP and MAP, but not diastolic BP. Conclusion: A generalized PAT-based model, developed from a different population was not able to accurately track BP changes in critically ill ICU patients. Individually fitted models utilizing other cuffless BP sensor signals significantly improved accuracy, indicating that cuffless BP can be measured non-invasively, but the challenge toward generalizable models remains for future research to resolve.

Nonadherence by Serum Drug Analyses in Resistant Hypertension: 7-Year Follow-Up of Patients Considered Adherent by Directly Observed Therapy.

Background Measurement of serum concentrations of drugs is a novelty found useful in detecting poor drug adherence in patients taking ≥2 antihypertensive agents. Regarding patients with treatment-resistant hypertension, we previously based our assessment on directly observed therapy. The present study aimed to investigate whether serum drug measurements in patients with resistant hypertension offer additional information regarding drug adherence, beyond that of initial assessment with directly observed therapy. Methods and Results Nineteen patients assumed to have true treatment-resistant hypertension and adherence to antihypertensive drugs based on directly observed therapy were investigated repeatedly through 7 years. Serum concentrations of antihypertensive drugs were measured by ultra-high-performance liquid chromatography-tandem mass spectrometry from blood samples taken at baseline, 6-month, 3-year, and 7-year visits. Cytochrome P450 polymorphisms, self-reported adherence and beliefs about medicine were performed as supplement investigations. Seven patients (37%) were redefined as nonadherent based on their serum concentrations during follow-up. All patients reported high adherence to medications. Nonadherent patients expressed lower necessity and higher concerns regarding intake of antihypertensive medication (P=0.003). Cytochrome P450 polymorphisms affecting metabolism of antihypertensive drugs were found in 16 patients (84%), 21% were poor metabolizers, and none were ultra-rapid metabolizers. Six of 7 patients redefined as nonadherent had cytochrome P450 polymorphisms, however, not explaining the low serum drug concentrations measured in these patients. Conclusions Our data suggest that repeated measurements of serum concentrations of antihypertensive drugs revealed nonadherence in one-third of patients previously evaluated as adherent and treatment resistant by directly observed therapy, thereby improving the accuracy of adherence evaluation. Registration URL: https://www.clinicaltrials.gov; unique identifier: NCT01673516.

Blood pressure altering method affects correlation with pulse arrival time.

OBJECTIVE: Pulse arrival time (PAT) is a potential main feature in cuff-less blood pressure (BP) monitoring. However, the precise relationship between BP parameters and PAT under varying conditions lacks a complete understanding. We hypothesize that simple test protocols fail to demonstrate the complex relationship between PAT and both SBP and DBP. Therefore, this study aimed to investigate the correlation between PAT and BP during two exercise modalities with differing BP responses using an unobtrusive wearable device. METHODS: Seventy-five subjects, of which 43.7% had a prior diagnosis of hypertension, participated in an isometric and dynamic exercise test also including seated periods of rest prior to, in between and after. PAT was measured using a prototype wearable chest belt with a one-channel electrocardiogram and a photo-plethysmography sensor. Reference BP was measured auscultatory. RESULTS: Mean individual correlation between PAT and SBP was -0.82 ± 0.14 in the full protocol, -0.79 ± 0.27 during isometric exercise and -0.77 ± 0.19 during dynamic exercise. Corresponding correlation between PAT and DBP was 0.25 ± 0.35, -0.74 ± 0.23 and 0.39 ± 0.41. CONCLUSION: The results confirm PAT as a potential main feature to track changes in SBP. The relationship between DBP and PAT varied between exercise modalities, with the sign of the correlation changing from negative to positive between type of exercise modality. Thus, we hypothesize that simple test protocols fail to demonstrate the complex relationship between PAT and BP with emphasis on DBP.

Detection of Nonadherence to Antihypertensive Treatment by Measurements of Serum Drug Concentrations.

[Figure: see text].

Noninvasive Assessment of Ventricular-Arterial Coupling in Heart Failure.

The heart and the arterial system are anatomically and functionally linked together. Noninvasive assessment of ventricular-arterial coupling (VAC) can be done using different methods that are promising tools to assess individual hemodynamics and tailor treatment in patients with heart failure (HF). Moreover, different methods available can be appropriately used in different settings such as acute and chronic HF. VAC parameters also can add incremental value over the conventional risk factors in predicting cardiac outcome.

Changes in sympathetic nervous system activity after renal denervation: results from the randomised Oslo RDN study.

PURPOSE: Sympathetic nervous system (SNS) over-activity is associated with essential hypertension. Renal sympathetic denervation (RDN) possibly lowers office- and ambulatory blood pressure (BP) in patients with treatment-resistant hypertension (TRH). We aimed to assess the effect of RDN compared to drug adjustment on SNS activity among patients with TRH by measuring plasma catecholamines and heart rate variability (HRV) during stress tests. MATERIALS AND METHODS: Patients with TRH were randomised to RDN (n = 9) or Drug Adjustment (DA) (n = 10). We measured continuous HRV and beat-to-beat-BP using FinaPres® and obtained plasma catecholamines during standardised orthostatic- and cold-pressor stress tests (CPT) before- and six months after randomisation. RESULTS: CPT revealed no differences between groups at baseline in peak adrenaline concentration (69.3 pg/mL in the DA group vs. 70.0 pg/mL in the RDN group, p = 0.38) or adrenaline reactivity (Δ23.1 pg/mL in the DA group vs. Δ29.3 pg/mL in the RDN group, p = 0.40). After six months, adrenaline concentrations were statistically different between groups after one minute (66.9 pg/mL in the DA group vs. 55.3 pg/mL in the RDN group, p = 0.03), and six minutes (62.4 pg/mL in the DA group vs. 50.1 pg/mL in the RDN group, p = 0.03). There was a tendency of reduction in adrenaline reactivity after six months in the RDN group (Δ26.3 pg/mL at baseline vs. Δ12.8 pg/ml after six months, p = 0.08), while it increased in the DA group (Δ13.6 pg/mL at baseline vs. Δ19.9 pg/mL after six months, p = 0.53). We also found a difference in the Low Frequency band at baseline following the CPT (667µs2 in the DA group vs. 1628µs2 in the RDN group, p = 0.03) with a clear tendency of reduction in the RDN group to 743µs2 after six months (p = 0.07), compared to no change in the DA group (1052µs2,p = 0.39). CONCLUSION: Our data suggest that RDN reduces SNS activity after six months. This finding warrants investigation in a larger study. Clinical Trial Number registered at www.clinicaltrials.gov: NCT01673516.

The randomised Oslo study of renal denervation vs. Antihypertensive drug adjustments: efficacy and safety through 7 years of follow-up.

PURPOSE: The blood pressure (BP) lowering effect of renal sympathetic denervation (RDN) in treatment-resistant hypertension shows variation amongst the existing randomised studies. The long-term efficacy and safety of RDN require further investigation. For the first time, we report BP changes and safety up to 7 years after RDN, compared to drug adjustment in the randomised Oslo RDN study. MATERIALS AND METHODS: Patients with treatment-resistant hypertension, defined as daytime systolic ambulatory BP ≥135 mmHg after witnessed intake of ≥3 antihypertensive drugs including a diuretic, were randomised to either RDN (n = 9) or drug adjustment (n = 10). The initial primary endpoint was the change in office BP after 6 months. The RDN group had their drugs adjusted after 1 year using the same principles as the Drug Adjustment group. Both groups returned for long-term follow-up after 3 and 7 years. RESULTS: The decrease in office BP and ambulatory BP (ABPM) after 6 months did not persist, but gradually increased in both groups. From 6 months to 7 years follow-up, mean daytime systolic ABPM increased from 142 ± 10 to 145 ± 15 mmHg in the RDN group, and from 133 ± 11 to 137 ± 13 mmHg in the Drug Adjustment group, with the difference between them decreasing. In a mixed factor model, a significantly different variance was found between the groups in daytime systolic ABPM (p = .04) and diastolic ABPM (p = .01) as well as office diastolic BP (p<.01), but not in office systolic BP (p = .18). At long-term follow-up we unveiled no anatomical- or functional renal impairment in either group. CONCLUSIONS: BP changes up to 7 years show a tendency towards a smaller difference in BPs between the RDN and drug adjustment patients. Our data support RDN as a safe procedure, but it remains non-superior to intensive drug adjustment 7 years after the intervention.

Renal sympathetic denervation lowers systemic vascular resistance in true treatment-resistant hypertension.

PURPOSE: Renal sympathetic denervation (RDN) is again gaining interest as recent well-designed trials have demonstrated reduced ambulatory blood pressure (BP) after RDN. However, the hemodynamic mechanisms have not been elucidated. We aimed for the first time to investigate the effect of RDN on the "Hallmark of Hypertension" namely increased systemic vascular resistance index (SVRI). MATERIALS AND METHODS: We investigated SVRI change in patients with true treatment-resistant hypertension randomised to RDN (n = 9) or drug adjusted control (n = 9). Treatment-resistant hypertension was defined as office systolic BP ≥ 140 mmHg despite ≥ 3 antihypertensive drugs including a diuretic. True treatment-resistant hypertension was confirmed prior to inclusion with ambulatory daytime systolic BP ≥ 135 mmHg immediately after witnessed intake of antihypertensive drugs. Hemodynamic variables were recorded with thoracic impedance cardiography at baseline and at three and six months follow-up after RDN. This non-invasive method also guided further tailoring of drug treatment in the control group aiming to normalise hemodynamic variables and BP. RESULTS: From three to six months follow-up after RDN, SVRI decreased with a median of -611 dyn*s*m2/cm5 [IQR -949 to -267] (p < 0.01), while supine mean BP decreased with a median of -11 mmHg [IQR -21 to -3] (p = 0.02). In the same period, SVRI in the control group was reduced with -674 dyn*s*m2/cm5 [IQR -1,309 to -340] (p < 0.01), while supine mean BP decreased with -15 mmHg [IQR -29 to -6] (p = 0.01). Thus, hemodynamic variables and BP in the two groups normalised in parallel. CONCLUSION: Our data suggest that in patients with true treatment-resistant hypertension, renal sympathetic denervation lowers BP by reducing systemic vascular resistance of similar size as in the control group with careful individual selection of antihypertensive drugs and dose titration.

Management principles in patients with COVID-19: perspectives from a growing global experience with emphasis on cardiovascular surveillance.

The COVID-19, due to SARS-CoV-2, has uncovered many real-world issues when it comes to healthcare management and has led to a widespread mortality. Observations thus far from the reports of COVID-19 have indicated that certain risk groups for example, those with pre-existing cardiovascular (CV) disease, hypertension, diabetes, chronic kidney disease and tobacco use are prone to disease development and specifically development of severe disease and possible fatality. It is increasingly evident that many CV conditions occur frequently. These include myopericarditis, acute coronary syndromes, thrombosis, arrhythmias, hypertension and heart failure. Many professional organisations and societies related to cardiology have produced guidelines or recommendations on most of the above-mentioned aspects. Given these rapid developments, the aims of this review manuscript were to summarise and integrate recent publications with newly developed guidelines and with the first-hand experience of frontline physicians and to yield a pragmatic insight and approach to CV complications of COVID-19. We emphasise on a strategic tier-based approach for initial assessment and management of COVID-19, and then delve into focused areas within CV domains, and additionally highlighting the role of point-of-care ultrasound especially lung ultrasound, echocardiography and electrocardiography, in the management of these patients. We hope this paper will serve as a useful tool in the CV management of COVID-19 for clinicians practicing in both developing and developed countries.

Non-invasive hemodynamic monitoring as a guide to drug treatment of uncontrolled hypertensive patients: effects on home blood pressure in the BEAUTY study.

BACKGROUND: In the BEAUTY study we investigated whether utilizing non-invasive monitoring of hemodynamic parameters combined with a drug selection algorithm (integrated hemodynamic management-IHM) compared to conventional drug selection may improve home BP in patients with uncontrolled hypertension. METHODS: Uncontrolled (office systolic blood pressure (SBP) > 140 mmHg and ambulatory daytime SBP >135 mmHg while taking ≥2 antihypertensive drugs) essential hypertensive patients were referred to 5 European Hypertension Excellence Centers and, if eligible, were randomized into IHM-guided vs conventional treatment adjustment. Home blood pressure (BP) was taken with 2 repeated readings at 1-2 min intervals in the morning and in the evening (before drug intake and eating) during the week preceding the visit at the outpatient clinic after 5 min rest using a validated semi-automatic oscillometric arm cuff device and with a correct cuff bladder placement. Home blood pressure was measured in a sub-group of patients (n = 84) not significantly different from the other patients. RESULTS: Home SBP changed from 152.1+/-15.8 and 149.8+/-11.8 mmHg to 131.0 +/-11.1 and 139.6+/-12.8 mmHg in IHM group (n = 46) and Control group (n = 38), respectively, showing significantly greater reduction in IHM than in Control group (d= -10.9 mmHg, 95% CI -17.77, -4.02), p = 0.002. The reduction remained significant after multiple adjustments, particularly for baseline home SBP, recruiting center, age, sex and BMI (SBPIHM-Control= -9,63 mmHg, 95% CI -14.28, -5.11) mmHg, p < 0.0001). CONCLUSION: Drug selection algorithm based on non-invasive hemodynamic monitoring induced larger reduction in home BP compared to conventional drug selection in uncontrolled hypertensive patients referred to European Hypertension Excellence Centers. Although the main BEAUTY study was negative, these home BP measurements taken by patients themselves may suggest that the integrated hemodynamic monitoring is useful in patients with uncontrolled hypertension. This finding might depend on specific features of home BP measurements which could make it recommended BP measurement method for drug trials.

Blood pressure response to renal denervation is correlated with baseline blood pressure variability: a patient-level meta-analysis.

BACKGROUND: Sympathetic tone is one of the main determinants of blood pressure (BP) variability and treatment-resistant hypertension. The aim of our study was to assess changes in BP variability after renal denervation (RDN). In addition, on an exploratory basis, we investigated whether baseline BP variability predicted the BP changes after RDN. METHODS: We analyzed 24-h BP recordings obtained at baseline and 6 months after RDN in 167 treatment-resistant hypertension patients (40% women; age, 56.7 years; mean 24-h BP, 152/90 mmHg) recruited at 11 expert centers. BP variability was assessed by weighted SD [SD over time weighted for the time interval between consecutive readings (SDiw)], average real variability (ARV), coefficient of variation, and variability independent of the mean (VIM). RESULTS: Mean office and 24-h BP fell by 15.4/6.6 and 5.5/3.7 mmHg, respectively (P < 0.001). In multivariable-adjusted analyses, systolic/diastolic SDiw and VIM for 24-h SBP/DBP decreased by 1.18/0.63 mmHg (P ≤ 0.01) and 0.86/0.42 mmHg (P ≤ 0.05), respectively, whereas no significant changes in ARV or coefficient of variation occurred. Furthermore, baseline SDiw (P = 0.0006), ARV (P = 0.01), and VIM (P = 0.04) predicted the decrease in 24-h DBP but not 24-h SBP after RDN. CONCLUSION: RDN was associated with a decrease in BP variability independent of the BP level, suggesting that responders may derive benefits from the reduction in BP variability as well. Furthermore, baseline DBP variability estimates significantly correlated with mean DBP decrease after RDN. If confirmed in younger patients with less arterial damage, in the absence of the confounding effect of drugs and drug adherence, baseline BP variability may prove a good predictor of BP response to RDN.

The effects of baroreflex activation therapy on blood pressure and sympathetic function in patients with refractory hypertension: the rationale and design of the Nordic BAT study.

OBJECTIVE: To explore the effects of baroreflex activation therapy (BAT) on hypertension in patients with treatment resistant or refractory hypertension. METHODS: This investigator-initiated randomized, double-blind, 1:1 parallel-design clinical trial will include 100 patients with refractory hypertension from 6 tertiary referral hypertension centers in the Nordic countries. A Barostim Neo System will be implanted and after 1 month patients will be randomized to either BAT for 16 months or continuous pharmacotherapy (BAT off) for 8 months followed by BAT for 8 months. A second randomization will take place after 16 months to BAT or BAT off for 3 months. Eligible patients have a daytime systolic ambulatory blood pressure (ABPM) of ≥145 mm Hg, and/or a daytime diastolic ABPM of ≥95 mm Hg after witnessed drug intake (including ≥3 antihypertensive drugs, preferably including a diuretic). RESULTS: The primary end point is the reduction in 24-hour systolic ABPM by BAT at 8 months, as compared to pharmacotherapy. Secondary and tertiary endpoints are effects of BAT on home and office blood pressures, measures of indices of cardiac and vascular structure and function during follow-up, and safety. CONCLUSIONS: This academic initiative will increase the understanding of mechanisms and role of BAT in the refractory hypertension.

Results of a randomized controlled pilot trial of intravascular renal denervation for management of treatment-resistant hypertension.

OBJECTIVE: Previous trials of catheter-based renal-artery denervation (RDN) as treatment modality in resistant hypertension (rHT) generated unconvincing results. In the Investigator-Steered Project on Intravascular Denervation for Management of Treatment-Resistant Hypertension (INSPiRED; NCT01505010), we optimized selection and management of rHT patients. METHODS: With ethical clearance to randomize 18 patients, three Belgian hypertension centers screened 29 rHT patients on treatment with ≥3 drugs, of whom 17 after optimization of treatment (age <70 years; systolic/diastolic office blood pressure (BP) ≥ 140/90 mm Hg; 24-h BP ≥130/80 mm Hg; glomerular filtration rate [eGFR] ≥ 45 mL/min/1.73 m2; body mass index <40kg/m2) were randomized and 15 were analyzed 6 months later, while medical treatment was continued (n = 9) or combined with RDN by the EnligHTN™ multi-electrode system (n = 6). RESULTS: The baseline-adjusted between-group differences amounted to 19.5/10.4 mm Hg (change in control vs. intervention group, +7.6/+2.2 vs. -11.9/-8.2 mm Hg; P = .088) for office BP, 22.4/13.1 mm Hg (+0.7/+0.3 vs. -21.7/-12.8; mm Hg; P ≤ .049) for 24-h BP, the primary efficacy endpoint, and 2.5 mL/min/1.73 m2 (+1.5 vs. -1.1 mL/min/1.73 m2; P = .86) for eGFR, the primary safety endpoint. At 6 month, ECG voltages and the number of prescribed drugs (P ≤ .036) were lower in RDN patients, but quality of life and adherence, captured by questionnaire and urine analysis were similar in both groups. Changes in BP and adherence were unrelated. No major complications occurred. CONCLUSIONS: The INSPiRED pilot suggests that RDN with the EnligHTN™ system is effective and safe and generated insights useful for the design of future RDN trials.

Sham or no sham control: that is the question in trials of renal denervation for resistant hypertension. A systematic meta-analysis.

BACKGROUND: Studies of renal denervation (RDN) in patients with apparent treatment resistant hypertension have been hampered by a number of patient and physician related confounders on blood pressure (BP) including poor drug adherence. It remains uncertain whether RDN lowers BP. We aimed to investigate whether the use of sham control is essential in RDN studies or whether systematic use of 24-hour ambulatory BP provides enough information thereby making an invasive sham control redundant. METHODS: We meta-analyzed randomized controlled trials of the BP response to RDN on top of continued or optimized antihypertensive drugs in patients with resistant hypertension. On top of the randomized trials reviewed earlier, we additionally included three studies, one conducted in Spain (24 patients, RDN vs. spironolactone), one conducted in Denmark (69 patients, sham controlled) and one conducted in Netherlands (139 patients, RDN vs. continued treatment). We analyzed 24-hour ambulatory BP in 3 sham controlled studies vs. 7 no sham controlled studies. RESULTS: The updated meta-analysis of 10 studies showed 3.6 mmHg (p = .45) and 1.0 mmHg (p = .54) reductions in office and in 24-hour systolic BP, respectively. Meta-analysis of 24-hour systolic BP in the 3 sham-controlled studies showed a reduction of 2.18 mmHg (95% confidence intervals (CIs) -4.70 to 0.33 mmHg, n = 396 vs. 230, p = .07). For the 7 no sham controlled studies there was no difference in 24-hour systolic BP (+0.38 mmHg; 95% CIs -5.29 to 6.04 mmHg, n = 215 vs. 245, p = .90). The test for sub-group heterogeneity showed no significant interaction (p = .69). Removing one trial at a time produced confirmatory results. CONCLUSION: The overall meta-analysis of 10 randomized and controlled studies showed no significant effect on BP of RDN in resistant hypertension. Moreover, our analysis does not support the use of sham control but rather suggests extensive use of 24-hour ambulatory BP in studies of RDN in resistant hypertension.

Renal artery and parenchymal changes after renal denervation: assessment by magnetic resonance angiography.

OBJECTIVES: Relatively little is known about the incidence of long-term renal damage after renal denervation (RDN), a potential new treatment for hypertension. In this study the incidence of renal artery and parenchymal changes, assessed with contrast-enhanced magnetic resonance angiography (MRA) after RDN, is investigated. METHODS: This study is an initiative of ENCOReD, a collaboration of hypertension expert centres. Patients in whom an MRA was performed before and after RDN were included. Scans were evaluated by two independent, blinded radiologists. Primary outcome was the change in renal artery morphology and parenchyma. RESULTS: MRAs from 96 patients were analysed. Before RDN, 41 renal anomalies were observed, of which 29 mostly mild renal artery stenoses. After a median time of 366 days post RDN, MRA showed a new stenosis (25-49% lumen reduction) in two patients and progression of pre-existing lumen reduction in a single patient. No other renal changes were observed and renal function remained stable. CONCLUSIONS: We observed new or progressed renal artery stenosis in three out of 96 patients, after a median time of 12 months post RDN (3.1%). Procedural angiographies showed that ablations were applied near the observed stenosis in only one of the three patients. KEY POINTS: • The incidence of vascular changes 12 months post RDN was 3.1%. • No renal vascular or parenchymal changes other than stenoses were observed. • Ablations were applied near the stenosis in only one of three patients.

Apparent treatment-resistant hypertension - patient-physician relationship and ethical issues.

BACKGROUND: Poor drug adherence is a major cause of apparent treatment-resistant hypertension. As a consequence, several methods have been developed and attempted implemented in clinical practice to reveal non-adherence and to monitor drug adherence. There are, however, several hitherto unresolved ethical aspects regarding potential methods for drug monitoring in these patients. RESULTS: The most striking challenge is the balance between patient autonomy and the physician's desire for the patient to adhere to the prescribed therapy. Also, methods for monitoring must only be implemented in the treatment of well-informed and consenting patients. Major resources are used on non-adherent patients; how long the physician should encourage continuation of treatment is an important question. CONCLUSIONS: We believe that physicians should reflect and discuss these potential challenges, and that patient education, information and a solid patient-physician relationship are essential for achieving drug adherence. Methods for monitoring adherence represent, however, a useful and often necessary supplement.

Tertiary work-up of apparent treatment-resistant hypertension.

OBJECTIVE: Treatment-resistant hypertension (TRH) has regained attention with development of new methods for treatment. However, the prevalence of TRH varies considerably from primary to secondary and tertiary care. We aimed to assess the prevalence of true TRH in a population of patients with apparent TRH in a university hospital setting of tertiary work-up and also investigate reasons for poor BP control and evaluate how work-up can be performed in general practice and secondary care. METHODS: In this cohort study, we characterize a study population from Oslo Renal Denervation (RDN) Study. Patients (n = 83) were referred for RDN from secondary care. All patients underwent thorough medical investigation and 24-h ambulatory blood pressure measurements (24ABPM) after directly observed therapy (DOT). We then assessed reasons for lack of BP control. RESULTS: Fifty-three of 83 patients did not have true TRH. Main reasons for non-TRH were poor drug adherence (32%), secondary hypertension (30%) and white coat hypertension (15%). Forty-seven percent achieved blood pressure control after DOT with subsequent 24ABPM. There were otherwise no statistically significant differences in patient characteristics between the true TRH and the non-TRH group. CONCLUSION: Despite being a highly selected cohort referred for tertiary work-up of apparent TRH, BP control was achieved or secondary causes were identified in almost two thirds of the patients. Thorough investigation according to guidelines and DOT with subsequent 24ABPM is needed in work-up of apparent TRH.