“Do you take your drug?” Development of an UHPLC-MS/MS method to quantify antihypertensive drugs in human plasma, for the assessment of therapeutic adherence in patients with “resistant” hypertension

2017 ◽  
Vol 27 (1) ◽  
pp. e6
Author(s):  
V. Avataneo ◽  
A. De Nicolò ◽  
G. Bonifacio ◽  
F. Rabbia ◽  
E. Perlo ◽  
...  
Keyword(s):  
Drug Development ◽  
Human Plasma ◽  
Resistant Hypertension ◽  
Antihypertensive Drugs ◽  
Therapeutic Adherence

scholarly journals Improvement of Blood Pressure Control by Adherence Check in Patients With Apparent Treatment-Resistant Hypertension: A Case Series

2020 ◽  
Vol 13 ◽  
pp. 117954762090488
Author(s):  
Keiko Hosohata ◽  
Ayaka Inada ◽  
Saki Oyama ◽  
Takashi Doi ◽  
Iku Niinomi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Resistant Hypertension ◽  
Antihypertensive Drugs ◽  
Case Series ◽  
Pressure Control ◽  
Supporting Evidence ◽  
Treatment Resistant ◽  
Uncontrolled Blood Pressure ◽  
Important Challenge ◽  
Prescribed Medicines

Adherence to medications is an important challenge while treating chronic disease such as resistant hypertension, which is defined as uncontrolled blood pressure (BP) despite treatment with more than 3 antihypertensive drugs to achieve targets. It is possible that poor adherence is the most significant contributor to rates of pseudo-resistance among treated hypertensive patients. In this report, we describe 4 patients with apparent treatment-resistant hypertension, who received intervention to promote adherence by pharmacists who set the prescribed medicines in a weekly medication calendar and conducted a weekly pill count. The results showed that the intervention of pharmacists to medication adherence improved systolic BP in patients with apparent treatment-resistant hypertension; however, further controlled trials are required to strengthen supporting evidence.

scholarly journals Sex Differences in Spironolactone and the Active Metabolite Canrenone Concentrations and Adherence

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 137
Author(s):  
Laura E. J. Peeters ◽  
Leonardien K. Tjong ◽  
Wim J. R. Rietdijk ◽  
Teun van Gelder ◽  
Birgit C. P. Koch ◽  
...  
Keyword(s):  
Sex Differences ◽  
Resistant Hypertension ◽  
Active Metabolite ◽  
Drug Exposure ◽  
Antihypertensive Drugs ◽  
Controlled Trial ◽  
Linear Regression Models ◽  
Blood Concentrations ◽  
Males And Females ◽  
Post Hoc

We aim to investigate sex differences in blood concentrations of spironolactone and the active metabolite canrenone in resistant hypertension patients. Furthermore, sex differences in adherence for spironolactone and other antihypertensive drugs (AHDs) were studied. The patients in this post hoc study had all participated in a single-blind randomized controlled trial called RHYME-RCT (Dutch Trial Register, NL6736). Concentrations in blood of several AHDs were assessed in RHYME-RCT to investigate adherence to treatment. This allowed for a comparison of drug exposure to spironolactone and canrenone between males and females. In linear regression models, no statistically significant sex differences (N = 35) in spironolactone (B =−10.23, SE = 7.92, p = 0.206) or canrenone (B = 1.24, SE = 10.96, p = 0.911) concentrations after adjustment for dose and time between sampling and intake were found. Furthermore, no statistically significant differences in non-adherence to spironolactone were found between sexes (N = 54, male 15% vs. female 38%, p = 0.100), but non-adherence to spironolactone was associated with non-adherence to other AHDs (p ≤ 0.001). Spironolactone and canrenone concentrations were not different between males and females with resistant hypertension. Although not statistically significant, females were twice as likely to be non-adherent to spironolactone compared to males, and thereby also more likely to be non-adherent to other AHDs.

scholarly journals Resistant Hypertension: A Real Entity Requiring Special Treatment?

2016 ◽  
Vol 11 (1) ◽  
pp. 8
Author(s):  
Stefano Taddei ◽  
Rosa Maria Bruno ◽  
◽  
◽  
Keyword(s):  
Blood Pressure ◽  
Resistant Hypertension ◽  
Renal Denervation ◽  
Antihypertensive Drugs ◽  
Pressure Control ◽  
Clinical Situation ◽  
Special Treatment ◽  
Separate Clinical Entity ◽  
Real Entity ◽  
Definition Of

Resistant hypertension (RH) was defined many years ago as a clinical situation in which blood pressure remains uncontrolled despite concomitant intake of at least three antihypertensive drugs (one of them preferably being a diuretic) at full doses. This operative definition was aimed at identifying a subset of hypertensive patients requiring a more extensive clinical workup in order to achieve an adequate blood pressure control. An oversimplification of this picture led to consider RH as a separate clinical entity requiring special, expensive treatments, such as renal denervation and baroreceptor activating therapy. In this review we will discuss the utility and the shortcomings of the definition of RH and the possible consequences for treatment.

scholarly journals Renal Sympathetic Denervation for the Treatment of Difficult-to-Control or Resistant Hypertension

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Vasilios Papademetriou ◽  
Michalis Doumas ◽  
Konstantinos Tsioufis
Keyword(s):  
Resistant Hypertension ◽  
Antihypertensive Drugs ◽  
Sympathetic Denervation ◽  
Renal Sympathetic Denervation ◽  
Major Health Problem ◽  
Number Of Patients ◽  
Recovery Times ◽  
Potential Applications ◽  
Future Potential ◽  
Renal Sympathetic

Hypertension represents a major health problem with an appalling annual toll. Despite the plethora of antihypertensive drugs, hypertension remains resistant in a considerable number of patients, thus creating the need for alternative strategies, including interventional approaches. Recently, catheter-based renal sympathetic denervation has been shown to be fairly safe and effective in patients with resistant hypertension. Pathophysiology of kidney function, interaction and crosstalk between the kidney and the brain, justifies the use of renal sympathetic denervation in the treatment of hypertension. Data from older studies have shown that sympathectomy has effectively lowered blood pressure and prolonged life expectancy of hypertensive patients, but at considerable cost. Renal sympathetic denervation is devoid of the adverse effects of surgical sympathectomy, due to its localized nature, is minimally invasive, and provides short procedural and recovery times. This paper outlines the pathophysiological background for renal sympathetic denervation, describes the past and the present of this interventional approach, and considers several future potential applications.

Non-pharmacological methods in the treatment of resistant hypertension

Folia Medica ◽  
2012 ◽  
Vol 54 (2) ◽  
pp. 5-12 ◽  
Author(s):  
Kostadin N. Kichukov ◽  
Hristo V. Dimitrov ◽  
Lora K. Nikolova ◽  
Ivo S. Petrov ◽  
Maria P. Tokmakova
Keyword(s):  
Blood Pressure ◽  
Resistant Hypertension ◽  
Renal Denervation ◽  
Antihypertensive Drugs ◽  
Adult Population ◽  
Clinical Problem ◽  
Renal Sympathetic Denervation ◽  
Great Promise ◽  
Long Term Effects ◽  
Blood Pressure Targets

ABSTRACT INTRODUCTION: Arterial hypertension is the most common chronic cardiovascular disease affecting about 25% of the adult population. Meta-analyses have demonstrated a linear relationship between blood pressure and the risk of cardiovascular events. Resistant hypertension defined as failure to reach blood pressure targets despite treatment with three antihypertensive drugs including a diuretic represents a serious clinical problem. It has been estimated that it affects between 8.9% and 12.8% of all treated hypertensive subjects. In resistant hypertension the optimal blood pressure is illusive despite very well tailored therapy. OBJECTIVE: Management of resistant hypertension is exactly the fi eld where blood pressurecontrolling non-pharmacological methods fi t best. The present article aims at throwing light on these methods’ principles of action, on who the target patient groups are and the respective results. Two methods are especially reviewed here: the carotid barorefl ex stimulation and the transcatheter renal sympathetic denervation. Current results from the use of renal denervation suggest stable effi ciency of the method, the results becoming signifi cant 6 months after the procedure is applied and sustained for two years in the follow-up. As much as 90% of the treated patients respond to the procedure. The transcatheter renal denervation is associated with only 2.61% of procedural complications. The barorefl ex carotid stimulation, too, is known to produce a stable effect on blood pressure: the effect become obvious at 12 months in 88% of the treated subjects. The neurologic complications associated with the procedure are reported to occur in 4.4% of cases. CONCLUSION: The present review article clearly demonstrates that non-pharmacological methods for treatment of resistant hypertension show great promise despite some open questions concerning their long term effects and procedural safety.

scholarly journals Predictors of blood pressure response after renal denervation beyond pretreatment blood pressure

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
R Schmieder ◽  
C Delles ◽  
L Lauder ◽  
C Ott ◽  
M Boehm ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Resistant Hypertension ◽  
Renal Denervation ◽  
Antihypertensive Drugs ◽  
Blood Pressure Response ◽  
Methodological Approach ◽  
Large Degree ◽  
Initial Value ◽  
Study Population ◽  
Pre Treatment

Abstract Background The principle of initial value (Wilder's law of initial value) proposes that the “direction of response of body function to any agent depends to a large degree on the initial value of that function”. Indeed, in several trials on renal denervation (RDN), pre-treatment blood pressure (BP) has been consistently and repeatedly found to predict the decrease in BP after RDN. Efforts to discover further statistically significant and clinically meaningful predictors of BP response to RDN failed. Objective By use of a new methodological approach, we aimed to determine predictors of BP response after RDN in patients with resistant hypertension. Methods The study population comprised 266 patients with resistant hypertension (mean age 62 years, 34% females, mean BMI 30.5 kg/m2, 27% had coronary heart disease, 42% had diabetes mellitus and 61% had hypercholesterolaemia) who underwent radiofrequency RDN with the Symplicity catheter at the Universities of Homburg and Erlangen. Clinical data including 24h ambulatory BP (ABP) were obtained prior to, and 3, 6 and 12 months after RDN. The primary parameter of response was defined as change in 24-hour systolic ABP after 6 months from pre-treatment values. As expected, change in 24h systolic ABP correlated with pre-treatment 24h systolic ABP (r2 linear = 0.225, p<0.001), with change in 24h systolic ABP = 73.82 + 0.55 x pre-treatment 24h systolic ABP. To overcome the predominant role of the pre-treatment BP that may mask other factors, we calculated for each individual patient the “expected systolic ABP decrease” by applying this regression equation and the “excessive systolic ABP decrease” by subtracting the measured from expected change in 24h systolic ABP. We divided the study population into 2 groups (above [responders] and below [non-responders] of the median change in excessive 24h systolic ABP. Results Neither pre-treatment 24h systolic or diastolic ABP, nor office systolic or diastolic BP differed between the two groups (all p>0.20). Following RDN, 24h systolic ABP decreased in the responders by −23.3±16 vs non-responders +1.4±11 mmHg at 6 month, and 24h systolic ABP values were also significantly lower in responders at 3 and 12 months (all p<0.001), without difference in number of antihypertensive drugs between the groups. Of all clinical variables at baseline, office heart rate (65.6 vs 68.7±12 bpm, p=0.024) and HbA1c (6.07±0.88 vs. 6.37±1.23%, p=0.035) were lower in responders compared with non-responders. Finally, a multiple regression analysis confirmed that pre-treatment 24h systolic ABP (beta +0.565, p<0001), HbA1c (beta −0.167, p=0.004) and office HR (beta +0.106, p=0.057) were independent predictors of decrease in 24h systolic ABP. Conclusion In patients with resistant hypertension, lower HbA1c and office HR were identified as predictors of BP response in addition to pre-treatment BP. This finding may help to identify hypertensive patients who benefit most from RDN. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): Extramural grant provided vy Medtronic INc

scholarly journals Resistant hypertension and risk of adverse events in individuals with type 1 diabetes: A nationwide prospective study

2020 ◽  
Author(s):  
Raija Lithovius ◽  
Valma Harjutsalo ◽  
Stefan Mutter ◽  
Daniel Gordin ◽  
Carol Forsblom ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Prospective Study ◽  
Resistant Hypertension ◽  
Antihypertensive Drugs ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Nationally Representative ◽  
Reduced Kidney Function

<b>Objectives</b>. To estimate the risk of diabetic nephropathy (DN) progression, incident coronary heart disease (CHD) and stroke, and all-cause mortality associated with resistant hypertension (RH) in individuals with type 1 diabetes stratified by stages of DN, renal function and sex. <p><b> </b></p> <p><b>Research Design and Methods </b>This prospective study<b> </b>included a nationally representative cohort of individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study who had purchases of antihypertensive drugs at (±6 months) baseline visit (1995–2008). Individuals (N=1,103) were divided into three groups: (a) RH, (b) uncontrolled BP, but no RH and (c) controlled BP. DN progression, cardiovascular events and deaths were identified from the individuals’ healthcare records and national registries, until 31 December 2015.</p> <p> </p> <p><b>Results</b> At baseline 18.7% of the participants had RH, while 23.4% had controlled BP. After full adjustments for clinical confounders, RH was associated with increased risk of DN progression (HR 1.95 [95% CI 1.37, 2.79], <i>p</i>=0.0002), while no differences were observed in those with no RH<i> </i>(1.05 [0.76, 1.44], <i>p</i>=0.8), compared with those who had controlled BP. The risk of incident CHD, incident stroke and all-cause mortality was higher in individuals with RH compared with those who had controlled BP, but not beyond albuminuria and reduced kidney function. Notably, in those with normo- and microalbuminuria the risk of stroke remained higher in the RH compared to controlled BP group (3.49 [81.20, 10.15], <i>p</i>=0.02).<b> <br></b></p><p><b><br></b></p><p><b>Conclusion </b>Our findings highlight importance to identify and provide diagnostic and therapeutic counseling to these very high risk individuals with RH.</p>

scholarly journals Nonadherence in Hypertension: How to Develop and Implement Chemical Adherence Testing

Hypertension ◽  
2021 ◽  
Author(s):  
Dan Lane ◽  
Alexander Lawson ◽  
Angela Burns ◽  
Michel Azizi ◽  
Michel Burnier ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Resistant Hypertension ◽  
Antihypertensive Medication ◽  
Antihypertensive Drugs ◽  
Test Results ◽  
Sample Collection ◽  
Treatment Resistant ◽  
Blood Samples ◽  
Hypertensive Patients ◽  
Adherence Test

Nonadherence to antihypertensive medication is common, especially in those with apparent treatment-resistant hypertension (true treatment-resistant hypertension requires exclusion of nonadherence), and its routine detection is supported by clinical guidelines. Chemical adherence testing is a reliable and valid method to detect adherence, yet methods are unstandardized and are not ubiquitous. This article describes the principles of chemical adherence testing for hypertensive patients and provides a set of recommendations for centers wishing to develop the test. We recommend testing should be done in either of two instances: (1) in those who have resistant hypertension or (2) in those on 2 antihypertensives who have a less than 10 mm Hg drop in systolic blood pressure on addition of the second antihypertensive medication. Furthermore, we recommend that verbal consent is secured before undertaking the test, and the results should be discussed with the patient. Based on medications prescribed in United Kingdom, European Union, and United States, we list top 20 to 24 drugs that cover >95% of hypertension prescriptions which may be included in the testing panel. Information required to identify these medications on mass spectrometry platforms is likewise provided. We discuss issues related to ethics, sample collection, transport, stability, urine versus blood samples, qualitative versus quantitative testing, pharmacokinetics, instrumentation, validation, quality assurance, and gaps in knowledge. We consider how to best present, interpret, and discuss chemical adherence test results with the patient. In summary, this guidance should help clinicians and their laboratories in the development of chemical adherence testing of prescribed antihypertensive drugs.

scholarly journals Investigating the endothelin receptor antagonist aprocitentan in resistant hypertension: design and baseline characteristics of the PRECISION study

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
P Danaietash ◽  
P Verweij ◽  
J Wang ◽  
G Dresser ◽  
I Kantola ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Resistant Hypertension ◽  
Antihypertensive Drugs ◽  
Beta Blockers ◽  
Dose Finding ◽  
Antihypertensive Medications ◽  
Private Company ◽  
Double Blind ◽  
Ckd Stage ◽  
Precision Study

Abstract   The endothelin (ET) system plays an important role in hypertension, especially in volume and salt-dependent forms, which are common in patients with resistant hypertension (RHT). Therapies targeting the ET system may provide a new treatment option. A Phase 2 dose-finding study demonstrated an effect of the dual ET receptor antagonist aprocitentan monotherapy on blood pressure (BP) [1]. PRECISION is a randomized, parallel-group, Phase 3 study assessing the short-term effect of 2 doses of aprocitentan (12.5 mg and 25 mg) and its long-term sustained effect on BP. Following randomization, patients entered a 4-week, double-blind (DB), placebo-controlled part, followed by aprocitentan 25 mg for 32 weeks, and a 12-week, placebo-controlled, randomized withdrawal part (Figure 1). The primary endpoint is the change in systolic BP (SBP) from randomization to week 4 and the key secondary endpoint is the change in SBP from re-randomization to week 40. The study enrolled 1971 patients with RHT diagnosed according to the site's medical practice, from 193 centres worldwide. Entry criteria included sitting SBP [SiSBP] ≥140 mmHg, measured by unattended automated office BP (uAOBP, reducing the white coat effect), despite the use of ≥3 antihypertensive medications. During the screening period of 4 to 12 weeks, secondary causes of hypertension were excluded by the investigator and patients still having SiSBP ≥140 mmHg were switched from their individual antihypertensive drugs to a single-tablet, triple combination of valsartan 160 mg /amlodipine 5 or 10 mg /hydrochlorothiazide 25 mg o.d. (minimizing medical inertia and improving drug adherence) for at least 4 weeks before entering the placebo run-in (RI) period. The screening failure rate of 53% is indicative of the high incidence of apparent RHT within the hypertensive population. Patients continuing having SiSBP ≥140 mmHg on triple therapy (true RHT) then entered the 4-week, single-blind placebo RI period. Of these patients, 20% failed to be randomized, most frequently because of SiSBP &lt;140 mmHg, possibly due to a placebo effect. As of 12 March 2021, 860 patients were in the placebo RI period and 664 patients were randomized, 30% from North America, 62% from Europe, and 8% from Asia/Australia. Mean age was 61.8 years (standard deviation [SD]=10.8). 40% of patients were women, 11% were Black, 5% Asian, and 83% White. Mean body mass index (BMI) was 33.6 kg/m2 (SD=6.4) and mean estimated glomerular filtration rate (eGFR) was 76.8 mL/min/1.73 m2 (including 21% chronic kidney disease [CKD] stage 3–4 patients). Medical history included diabetes (54%), myocardial infarction (30%), stroke (23%), congestive heart failure (19%), and sleep apnoea (15%). In addition to the standardized antihypertensive medication, 59% of patients used beta-blockers. Mean baseline SiSBP/SiDBP was 153/88 mmHg. Results of the trial will be available in 2022. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): The PRECISION study is sponsored by Idorsia Pharmaceuticals Ltd.

scholarly journals Resistant hypertension and risk of adverse events in individuals with type 1 diabetes: A nationwide prospective study

2020 ◽  
Author(s):  
Raija Lithovius ◽  
Valma Harjutsalo ◽  
Stefan Mutter ◽  
Daniel Gordin ◽  
Carol Forsblom ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Prospective Study ◽  
Resistant Hypertension ◽  
Antihypertensive Drugs ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Nationally Representative ◽  
Reduced Kidney Function

<b>Objectives</b>. To estimate the risk of diabetic nephropathy (DN) progression, incident coronary heart disease (CHD) and stroke, and all-cause mortality associated with resistant hypertension (RH) in individuals with type 1 diabetes stratified by stages of DN, renal function and sex. <p><b> </b></p> <p><b>Research Design and Methods </b>This prospective study<b> </b>included a nationally representative cohort of individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study who had purchases of antihypertensive drugs at (±6 months) baseline visit (1995–2008). Individuals (N=1,103) were divided into three groups: (a) RH, (b) uncontrolled BP, but no RH and (c) controlled BP. DN progression, cardiovascular events and deaths were identified from the individuals’ healthcare records and national registries, until 31 December 2015.</p> <p> </p> <p><b>Results</b> At baseline 18.7% of the participants had RH, while 23.4% had controlled BP. After full adjustments for clinical confounders, RH was associated with increased risk of DN progression (HR 1.95 [95% CI 1.37, 2.79], <i>p</i>=0.0002), while no differences were observed in those with no RH<i> </i>(1.05 [0.76, 1.44], <i>p</i>=0.8), compared with those who had controlled BP. The risk of incident CHD, incident stroke and all-cause mortality was higher in individuals with RH compared with those who had controlled BP, but not beyond albuminuria and reduced kidney function. Notably, in those with normo- and microalbuminuria the risk of stroke remained higher in the RH compared to controlled BP group (3.49 [81.20, 10.15], <i>p</i>=0.02).<b> <br></b></p><p><b><br></b></p><p><b>Conclusion </b>Our findings highlight importance to identify and provide diagnostic and therapeutic counseling to these very high risk individuals with RH.</p>

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