Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension – study protocol for a randomized controlled trial

Background Resistant hypertension is characterized when the blood pressure (BP) remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses, preferably including a diuretic. Identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether acting on the control of intravascular volume or sodium balance, or acting on the effects of the renin-angiotensin-aldosterone system (RAAS) on the kidney. Methods/design This is a randomized, open-label, clinical trial is designed to compare sequential nephron blockade and its contribution to the intravascular volume component with dual blockade of the RAAS plus bisoprolol and the importance of serum renin in maintaining BP levels. The trial has two arms: sequential nephron blockade versus dual blockade of the RAAS (with an angiotensin converting enzyme (ACE) inhibitor plus a beta-blocker) both added-on to a thiazide diuretic, a calcium-channel blocker and an angiotensin receptor-1 blocker (ARB). Sequential nephron blockade consists in a progressive increase in sodium depletion using a thiazide diuretic, an aldosterone-receptor blocker, furosemide and, finally, amiloride. On the other hand, the dual blockade of the RAAS consists of the progressive addition of an ACE inhibitor until the maximum dose and then the administration of a beta-blocker until the maximum dose. The primary outcomes will be reductions in the systolic BP, diastolic BP, mean BP and pulse pressure (PP) after 20 weeks of treatment. The secondary outcomes will evaluate treatment safety and tolerability, biochemical changes, evaluation of renal function and recognition of hypotension (ambulatory BP monitoring (ABPM)). The sample size was calculated assuming an alpha error of 5% to reject the null hypothesis with a statistical power of 80% giving a total of 40 individuals per group. Discussion In recent years, the cost of resistant hypertension (RH) treatment has increased. Thus, identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of intravascular volume or sodium balance, or by acting on the effects of the RAAS on the kidney. Trial registration Sequential Nephron Blockade vs. Dual Blockade Renin-angiotensin System + Bisoprolol in Resistant Arterial Hypertension (ResHypOT). ClinicalTrials.gov, ID: NCT02832973. Registered on 14 July 2016. First received: 12 June 2016. Last updated: 18 July 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2343-3) contains supplementary material, which is available to authorized users.

How the study:will be conducted To participate in the study Sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system a period of confirmation of their blood pressure levels is necessary. During this period all participants will be advised to follow healthy lifestyle measures, along with the use of standard therapy.

What are lifestyle measures
Lifestyle measures are behaviors that benefit the overall health and especially prevent cardiovascular diseases such as heart attack, stroke and diabetes. They are recommended for all people and mainly those who have risk factors that increase the chance of having some of them. These measures involve physical exercise, healthy eating, weight control, not smoking and not drinking.
Objectives of the lifestyle measure phases All participants in the Study Sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system before the intervention phase, should follow the lifestyle measures for three months, and at the end will have blood pressure measured again to confirm whether the blood pressure levels are normalized or not. Accord to your pressure, You will participate in one arm of the study or if it is normal, it will not be eligible to participate in the next phase.
How it will be performed You will receive guidance on physical activity practice, including activity type and length exercise; on diet to maintain or lose weight, guidelines that can help you quit smoking if your case and reducing the use of alcohol.
When you seeing a doctor 3 months, you will be carried out evaluation of blood pressure with automatic device. Questions will be asked on living habits and measuring weight, height, waist, hip again.

Drug treatment phase
Participants of resistant hypertension will be randomized to receive a sequence of diuretics or a sequence blockers of the renin-angiotensin system, which is taken once daily in the morning. Diuretics eliminate excess of water and salt from the body by decreasing the pressure. Blockers of the renin-angiotensin system cause relaxation of the arteries which reduce the pressure.
They will be held six visits at monthly intervals, the first one is to confirm the diagnosis, the other four are revisions and the last one is to check the results achieved. During the visits, it will be held physical examination and blood pressure with automatic device. Also questions will be asked about your health and lifestyle habits average, weight, waist and hips. An electrocardiography should be performed and along with blood and urine tests at the beginning and end of the study. In addition to the study drugs, the participant will receive nonpharmacological guidance to improve blood pressure control.
The blood collected will be stored and in case of further analysis we will be required a new term-compliance specifically for their achievement.

Risks and discomforts
Verification of pressure causes some discomfort when the device fills to measure the pressure and presses the arm. There may be a small bruise at the site of blood collection.
The drugs used in this study are long for the treatment of hypertension and are considered safe. The study risks are due to the possibility of occurrence of side effects of medications. The most common side effects are muscle cramps, dry mouth, increased urine volume and less frequently increased glucose and uric acid and usually do not require discontinuation of treatment.
There may also be photosensitivity and therefore should be avoided excessive sun exposure. In the event of side effects or problems related to their participation in the study, the researchers and the institution will give you free of charge medical assistance. Pregnant women cannot participate and if pregnancy occurs, should be immediately reported to researchers and the participant will be removed from the study and will remain in follow-up until delivery.

Benefits to participate
There will be no remuneration for participation in the study, but the transportation costs will be funded by research. As a benefit, the participant will receive clinical evaluation and guidance on lifestyle that contribute to a healthy lifestyle.
Participants will be collaborating so that the risk of cardiovascular disease is reduced in the population.

Privacy and confidentiality
It is ensured the anonymity of the participants. The results will be published in scientific papers without study participants are identified.
By agreeing to participate in the study, the participant will be committing to follow the study guidelines and attend the planned visits. If you change your mind during the study you can give up participating at any time, but they must attend to conduct the final visit of the study. Refusal to also participate in will not affect anything in future care in the institution. If you have any questions, you should ask before deciding.