Resistant Hypertension Management Trial

Patients will be recruited from vascular, cardiology and nephrology outpatient clinics of 11 hospitals including two university hospitals. Patients are eligible for participation if they fulfill the criteria of resistant hypertension, use at least two AHDs for which DBS-analysis are available, are 18 years or older and are able to provide informed consent. Due to the large population of people orginating from Turkey in Rotterdam, the patient information leaflet is made available in both the Dutch and Turkish language.
Resistant hypertension is defined as having an office BP of > 140 mmHg (systolic) and/or 90 mmHg (diastolic) or, if available, a 24-h ambulatory blood pressure measurement (24-h ABPM) daytime BP of > 135 mmHg and/or 85 mmHg despite a medication regimen of AHDs in the maximal tolerable dose of at least three AHDs from different drug classes, including a diuretic, or at least four AHDs from different drug classes. In Table 1 the minimal drug dose needed at time of the inclusion and the lower limit of detection of each included drug are shown. DBS analysis includes the following AHDs and active metabolites: enalapril and enalaprilate, perindopril and perindoprilate, irbesartan, valsartan, losartan and losartan-carboxylic acid (losartan-CA), hydrochlorothiazide, bumetanide, spironolactone and canrenone, amlodipine, barnidipine, nifedipine, metoprolol and doxazosin [25 (link), 26 (link)].Table 1

Overview antihypertensive drugs included in the RHYME-RCT trial

Antihypertensive drug [metabolite]	Minimal drug dose for inclusion (mg)	LLOD (μg/L) [25 (link)]
Amlodipine	5	17.1
Barnidipine	10	2.1
Bumetanide	1	4.0
Doxazosin	4	18.1
Enalapril	20	0.4
[Enalaprilat]	–	1.1
Hydrochlorothiazide	12.5	40.2
Irbesartan	150	7.7
Losartan	50	1.7
[Losartan-CA]	–	2.6
Metoprolol	50 CR or 25 mg two times daily (normal release)	0
Nifedipine	30	3.5
Perindopril	4	0.7
[Perindoprilat]	–	1.3
Spironolactone	12.5	5.2
[Canrenone]	–	26.8
Valsartan	80	21.3

CA carboxylic acid; CR controlled release, LLOD lower limit of detection

Patients are excluded from participation if they are not able to give informed consent, have end-stage kidney disease (eGFR < 15 ml/min/m²), insufficient understanding of the Dutch or Turkish language or if secondary forms of hypertension are expected but have not been excluded. Patients with secondary forms of hypertension primarily treated with AHDs such as primary aldosteronism caused by bilateral hyperplasia can be eligible for participating in the trial.
This study is approved by the Institutional Review Board (IRB) of the Erasmus MC, University Medical Centre, Rotterdam, the Netherlands (MEC-2018–027).