Results of the trycort: Cohort study of add-on antihypertensives for treatment of resistant hypertension

Abstract

Although true treatment resistant hypertension is relatively rare (about 7.3% of all patients with hypertension), optimal control of blood pressure is not achieved in every other patient due to suboptimal treatment or nonadherence. The aim of this study was to compare effectiveness, safety and tolerability of various add-on treatment options in adult patients with treatment resistant hypertension The study was designed as multi-center, prospective observational cohort study, which compared effectiveness and safety of various add-on treatment options in adult patients with treatment resistant hypertension. Both office and home blood pressure measures were recorded at baseline and then every month for 6 visits. The study cohort was composed of 515 patients (268 females and 247 males), with average age of 64.7 ± 10.8 years. The patients were switched from initial add-on therapy to more effective ones at each study visit. The blood pressure measured both at office and home below 140/90 mm Hg was achieved in 80% of patients with add-on spironolactone, while 88% of patients taking this drug also achieved decrease of systolic blood pressure for more than 10 mm Hg from baseline, and diastolic blood pressure for more than 5 mm Hg from baseline. Effectiveness of centrally acting antihypertensives as add-on therapy was inferior, achieving the study endpoints in <70% of patients. Adverse drug reactions were reported in 9 patients (1.7%), none of them serious. Incidence rate of hyperkalemia with spironolactone was 0.44%, and gynecomastia was found in 1 patient (0.22%). In conclusion, the most effective and safe add-on therapy of resistant hypertension were spironolactone alone and combination of spironolactone and a centrally acting antihypertensive drug.

1. Introduction

Essential hypertension is still the most prevalent noncommunicable disease all over the world; back in the year 2010 nothing <31.1% of adult population globally had hypertension.^[1] Although true treatment resistant hypertension (TRH) is relatively rare (about 10.3% of all patients with hypertension), almost 35.6% of patients receive suboptimal treatment, and further 50.0% is not adherent, so optimal control of blood pressure is not achieved in every other patient.^[2] Starting optimal drug treatment of treatment resistant hypertension from the moment when hypertension was diagnosed or as early as possible during its course is associated with improved cardiovascular outcomes.^[3]

Treatment resistant hypertension is defined as casual blood pressure during clinical examination of more than 140/90 mm Hg despite treatment with optimal or best-tolerated doses of 3 or more drugs, which should include a thiazide diuretic, typically an angiotensin-converting enzyme inhibitor (ACE) inhibitor or an angiotensin receptor blocker (ARB), and a calcium channel blocker (CCB).^[4,5] Resistant hypertension is treated with add-on therapy with antagonists of mineralocorticoid receptors (spironolactone[SPL]/eplerenone, esaxerenone) or with different types and dosages of diuretics (DIU), alpha 1 adrenergic blockers, alpha-2 adrenergic receptor agonists (A2A), that is, clonidine and methyldopa, or beta 1 blockers (BB).^[6,7] Central antihypertensives, which stimulate alpha-2 and/or imidazoline receptors and therefore decrease sympathetic outflow from medulla oblongata, are very effective as add-on therapy in resistant hypertension; urapidil, an antihypertensive that have both alpha 1 adrenergic blocking action and central sympatholytic effect due to activation of serotonin 5HT_1A receptors was also successfully combined with first-line antihypertensives.^[6,7]

There are several clinical trials comparing effectiveness and safety of add-on therapy of resistant hypertension. Spironolactone was tested in 5 randomized clinical trials.^[8] It reduced office systolic blood pressure (SBP) by 15.73 mm Hg and office diastolic blood pressure (DBP) by 6.21 mm Hg as compared to placebo group. The pooled changes of 24 hours ambulatory or home SBP and DBP were −8.7 mm Hg and −4.12 mm Hg, in favor of the spironolactone group. In comparison with alternative drugs for treating resistant hypertension, including beta blocker, candesartan, or alpha methyldopa, spironolactone reduced home SBP by 4.5 mm Hg. Addition of spironolactone provides beneficial effect on blood pressure in patients with resistant hypertension, as confirmed by several meta-analyses and systematic reviews of clinical trials.^[9] Although there are also invasive methods of treating resistant hypertension, that is, electrical stimulation of the carotid baroreceptors and baroreflex activation therapy, their efficacy in clinical trials needs to be confirmed with phase-3 studies.^[10–12] The catheter-based radiofrequency ablation of renal sympathetic nerves, that is, renal denervation, has emerged as an effective therapeutic option in addition to the nonpharmacological treatment and antihypertensive drugs.^[13] When various add-on drugs for resistant hypertension were compared among themselves in clinical trials and meta-analyses, spironolactone showed the best efficacy, but yet the published data are limited,^[14] and additional studies are needed to confirm already published studies. It is especially necessary to further explore adverse effects of drugs used in add-on therapy in clinical practice, on patients which are not selected like in clinical trials, but carry the burden of comorbidities and co-medication.^[15]

The aim of this study was to compare effectiveness, safety and tolerability of various add-on treatment options in adult patients with treatment resistant hypertension.

2. Patients and methods

2.1. The study design

The study was multicentric, involving 10 specialist centers for treatment of hypertension affiliated with tertiary or secondary care hospitals, and 24 primary care practices; all study sites belong to public healthcare system in Serbia. The resistant hypertension was defined as casual blood pressure during clinical examination of more than 140/90 mm Hg despite treatment with optimal or best-tolerated doses of 3 or more first-line antihypertensive drugs, including a DIU, an ACE inhibitor or an ARB, a CCB and a beta blocker. The add-on therapy was prescribed to the patients within the scope of their routine medical care, independently from the study investigators. Both office and home blood pressure measures were recorded at baseline and then every month for 6 visits. Before, during and after the study the patients were cared for by their chosen general practitioners independently from the study investigators and referred to internal medicine specialists as necessary, according to diagnostic and treatment protocols currently in power at the study sites. Role of the study investigators was limited to observation and collection of data from the patients themselves and from their medical files. The study participants were recruited from June 30^th, 2021 to June 30^th, 2022, and followed for 6 months up to December the 31^st, 2022. The study was approved by the Ethical Committee of Serbia (decision number 515-20-03493-2020-4, date 28.01.2021.) and by Ethical committees of healthcare facilities at the study sites. Protocol of the study was preregistered at ClinicalTrials.gov, with ID number: NCT05087940. The study was sponsored by Galenika a.d. Pharmaceutical Company, Belgrade, Serbia.

2.2. The patients

The study population consisted of subjects with therapy-resistant essential hypertension to whom secondary causes of hypertension were previously excluded. The inclusion criteria were: age 18 years or older, having resistant hypertension defined as casual blood pressure during clinical examination of more than 140/90 mm Hg despite treatment with optimal or best-tolerated doses of 3 or more first-line antihypertensive drugs, and inadequate control of hypertension confirmed with both office and home blood pressure measurement (morning and evening measurements after 5 minutes of relaxation in sitting position, for 6 days). The exclusion criteria were: pregnancy, anticipated pregnancy, breastfeeding, incarceration or institutionalized living which may prohibit measurement of home blood pressure, participation in another intervention study that may affect blood pressure, life expectancy < 4 months, anticipated living donor kidney transplant within 4 months, systolic blood pressure value over 220 mm Hg requiring immediate adjustments of therapy, moderate to severe renal insufficiency (acute or chronic) with glomerular filtration rate below 30 mL/minutes, active bronchospastic disorders, heart failure classes III and IV, severe bradycardia (heart rate below 50/minutes), 2nd and 3rd degree AV block, and history of hypersensitivity to any of the drugs under study. The study sample was of convenient type, and consecutive, that is, the investigators were enrolling all patients referred by general practitioners to the study sites who satisfied inclusion and did not have exclusion criteria, and who signed the informed consent for participation in the study.

2.3. The study treatments and outcomes

The study was prospective, observational, with cohort design, therefore treatment groups were formed independently from the study investigators, according to the add-on therapy prescribed by the internal medicine specialists to whom the patients were referred by general practitioners. Primary outcomes of the study were decrease of arterial blood pressure at both office blood pressure measurement (OBP) and home blood pressure self-measurement (HBPM) to levels below 140/90 mm Hg after 1, 2, 3, 4, 5, and 6 months, reduction of systolic arterial blood pressure at both OBP and HBPM for 10 mm Hg or more after 1, 2, 3, 4, 5, and 6 months, and reduction of diastolic arterial blood pressure at both OBP and HBPM for 5 mm Hg or more after 1, 2, 3, 4, 5, and 6 months. The secondary study outcomes were absolute values of systolic and diastolic blood pressure after 1, 2, 3, 4, 5, and 6 months, obtained by both office and home measurements, serum level of creatinine and presence of proteinuria, type and frequency of adverse events, and health-related quality of life.

2.4. The study procedures

The study was conducted through screening, baseline and 6 consequent monthly visits. All centers performed OBP and HBPM following the same 2017 guidelines issued by American College of Cardiology/American Heart Association Task Force.^[16] The OBP was measured by mercury sphygmomanometer, and 3 readings with 3 minutes apart were taken from each patient: a mean of the 2nd and 3rd measurements was taken as actual office blood pressure. The HBPM was measured by patients themselves, by means of automated digital oscillometric devices validated after production and supplied exclusively through state-owned community pharmacies. The patients recorded all home measurements in their diaries, which were then handed to the study investigators at the study visits.

The patients adherence to prescribed treatment was checked at each study visit by the study investigators who interviewed the patients. Demographic information, relevant medical history, including history of hypertension, and concomitant medication use (dose, route and frequency of administration) were recorded at baseline visit and updated at the 6 follow-up study visits. Comorbidities were summed-up by means of Charlson Comorbidity Index which is calculated by addition of points for each disease a patient is suffering from; the value of Charlson Comorbidity Index correlates with probability of 10-year survival.^[17] Information regarding occurrence of adverse events was captured throughout the study, and standard clinical laboratory measurements were documented at the study visits. Health-related quality of life was measured at each visit by previously validated^[18,19] visual analogue scale with a span from 0 to 100.

2.5. Statistics

The sample size was calculated on the basis of target statistical power of 80% and type I error probability of 0.05. Before processing the collected data statistically, screen/enrollment ratio and dropout ratio were reported. The unit of analysis were individual patients. The data then were first described by measures of central tendency (mean and median) and variability (standard deviation and interquartile range), depending on the normality of the data distribution. Normality of the data distribution was checked by the Kolmogorov-Smirnov test. The significance of differences in values of continuous variables among the repeated measurements was tested by the Student t test for dependent samples and 1-way analysis of variance (when the data distributions were normal) or by Wilcoxon Signed Rank test and Friedman test (when the data distributions were not normal). The significance of differences in values of continuous variables among the treatment groups was tested by the Student t test for independent samples and 1-way analysis of variance (when data distributions were normal) or by Mann–Whitney U test and Kruskall Wallis analysis of variance (when data distributions were not normal). The differences in values of categorical variables (e.g., frequencies) were tested by Chi-square or Fisher test. The results were considered significant if probability of null hypothesis was 0.05 or less. Sensitivity analysis was not included. All calculations were performed by Statistical Package for Social Sciences (SPSS, IBM) software, version 18.0 for Windows.

3. Results

In total 731 patients were enrolled, but after excluding screen failures, 522 patients actually entered the study, and 515 completed the study protocol; 7 patients were excluded at baseline visit due to protocol violation. The study flowchart is shown at Figure 1. There were 268 female and 247 male patients, with average age of 64.7 ± 10.8 years; detailes of the study cohort are given in the Table 1.

Figure 1.

The study flowchart.

Table 1.

Characteristics of the study sample (n = 515).

Parameter		Value (median and interquartile range, or frequency and percentage)
Age (yr)		66.0 [17.0]
Sex	Female	268 (52.0%)
Body weight (kg)		85.0 [17.0]
Charlson comorbidity index		2.0 [2.0]
Office systolic pressure at screening (mm Hg)		160.0 [16.7]
Office diastolic pressure at screening (mm Hg)		95.0 [8.3]
Office heart rate (beats/min)		78.3 [13.7]
Antihypertensive regimen at baseline	BB + ACE/ARB + CCB + DIU	218 (42.3%)
	BB + ACE/ARB + CCB	52 (10.1%)
	BB + ACE/ARB + DIU	68 (13.2%)
	ACE/ARB + CCB + DIU	124 (24.1%)
	BB + CCB + DIU	1 (0.2%)
	BB + ACE/ARB + CCB + DIU + A2A	50 (9.7%)
Smoking	Yes	170 (33.0%)
Drinking alcohol	Yes	96 (18.6%)
Drinking coffee	Yes	454 (88.2%)
Heart failure	Yes	26 (5.0%)
Coronary disease	Yes	84 (16.3%)
COPD	Yes	33 (6.4%)
Asthma	Yes	10 (1.9%)
Stroke	Yes	12 (2.3%)

A2A = alpha-2 adrenergic receptor agonists, ACE = angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker, BB = beta blocker, CCB = calcium channel blocker, DIU = diuretics.

Before starting with add-on antihypertensive therapy for resistant hypertension, the patients were taking one of the following combinations of antihypertensives: BB + ACE/ARB + CCB + DIU (218 patients, or 42.3%), BB + ACE/ARB + CCB (52 patients, or 10.1%), BB + ACE/ARB + DIU (68 patients, or 13.2%), ACE/ARB + CCB + DIU (124 patients, or 24.1%), BB + CCB + DIU (1 patient) and BB + ACE/ARB + CCB + DIU + A2A(50 patients, or 9.7%).

At the study visits (baseline visit and visits 1–6), the patients were given add-on antihypertensive drugs according to the preferences of the researchers. At the baseline visit, add-on antihypertensives were not prescribed to 387 patients, 61 of them received an additional drug from the group of first-line antihypertensives, 60 patients received spironolactone, and 7 patients one of the central antihypertensives. Depending on the patient’s response, at subsequent visits the add-on therapy was corrected as necessary. The number of patients by add-on therapy groups, systolic and diastolic pressures and heart rate measured in the physician’s office and at home after all visits are shown in the Table 2. Systolic and diastolic pressures measured at home after visits, depending on the add-on therapy are shown in Figure S1 and S2, Supplemental Digital Content, http://links.lww.com/MD/J84 of the Supplementary file. While at the baseline and visit 1 patients with added spironolactone had the highest SBP (P = .000 and 0.003, respectively), and patients with 1^st line antihypertensive added had the highest DBP (P = .018 and 0.017, respectively), these differences were lost at later visits, because the patients were switching add-on therapy according to a patient’s response. Number of patients with specific type of add-on therapy at visit 6 reflects its relative efficacy, that is, for 89.3% of patients spironolactone was optimal add-on therapy, followed by SPL + A2A (3.1%), a 1^st line antihypertensive (3.1%), and A2A (1.9%).

Table 2.

Blood pressure by visit according to the groups formed by antihypertensive added at certain visit (the data are presented as median and interquartile range in parenthesis.

Visit	Blood pressure	No antihypertensive added	1st line antihypertensive added	Spironolactone added	Central antihypertensive added	Spironolactone + central antihypertensive added	Probability of null hypothesis (p)
Baseline	No of patients prescribed with add-on drug at baseline	n = 387	n = 61	n = 60	n = 7	n = 0
	Systolic–office	156.6 [14.0]	158.3 [11.7]	161.0 [19.0]	153.0 [18.8]	-	0.310
	Systolic–home	156.8 [17.0]*	162.2 [12.8]	163.3 [16.2]*	155.6 [9.0]	-	0.000*
	Diastolic–office	94.7 [7.7]	95.0 [8.1]	93.3 [10.0]	90.0 [10.7]	-	0.647
	Diastolic–home	95.0 [6.8]	97.3 [8.3]*	95.7 [10.1]	93.0 [4.7]*	-	0.018*
	Heart rate at office	76.7 [12.7]	76.2 [10.1]	75.7 [13.1]	73.3 [16.7]	-	0.737
	Heart rate at home	78.0 [12.9]	78.3 [9.6]	78.8 [11.7]	80.4 [18.1]	-	0.729
Visit 1	No of patients prescribed with add-on drug at visit 1	n = 49	n = 29	n = 417	n = 15	n = 5
	Systolic–office	145.0 [18.0]	143.0 [12.8]	150.1 [22.3]	137.2 [24.2]	-	0.166
	Systolic–home	146.3 [18.2]*	152.2 [16.5]	151.7 [21.3]*	141.2 [20.9]	-	0.003*
	Diastolic–office	90.0 [9.2]	90.0 [7.3]	87.7 [10.3]	86.7 [20.0]	-	0.789
	Diastolic–home	90.0 [9.9]*	92.8 [8.2]*	87.7 [14.4]	82.8 [17.4]	-	0.017*
	Heart rate at office	74.7 [10.6]	73.8 [7.7]	74.3 [8.7]	69.7 [15.0]	-	0.665
	Heart rate at home	75.2 [10.8]	76.2 [8.2]	75.2 [9.7]	74.5 [16.2]	-	0.869
Visit 2	No of patients prescribed with add-on drug at visit 2	n = 26	n = 21	n = 447	n = 14	n = 7
	Systolic–office	143.3 [22.7]	142.5 [19.6]	137.0 [15.7]	134.2 [28.9]	131.2 [20.0]	0.083
	Systolic–home	144.3 [18.3]	144.7 [18.6]	138.0 [15.1]	136.6 [20.8]	135.1 [17.3]	0.061
	Diastolic–office	88.3 [10.0]	86.7 [9.5]	85.0 [10.0]	82.8 [10.3]	83.3 [12.5]	0.051
	Diastolic–home	87.2 [10.5]	87.1 [9.5]	85.4 [10.1]	83.8 [15.4]	78.1 [17.7]	0.135
	Heart rate at office	78.3 [10.5]*	70.7 [7.3]*	72.0 [8.3]	73.0 [8.9]	73.3 [14.0]	0.006*
	Heart rate at home	77.0 [9.9]	71.7 [9.7]	73.3 [8.5]	71.8 [7.1]	71.6 [19.2]	0.062
Visit 3	No of patients prescribed with add-on drug at visit 3	n = 19	n = 16	n = 457	n = 12	n = 11
	Systolic–office	139.2 [23.6]	139.2 [14.7]	133.3 [13.3]	133.3 [25.5]	128.3 [11.7]	0.117
	Systolic–home	137.9 [16.9]	139.8 [15.1]	135.6 [13.8]	131.9 [19.7]	131.7 [9.7]	0.272
	Diastolic–office	83.3 [10.0]	83.3 [8.3]	82.7 [8.2]	82.0 [13.7]	80.0 [15.7]	0.357
	Diastolic–home	86.8 [13.4]	84.5 [8.0]	83.2 [8.9]	82.6 [18.6]	76.5 [11.8]	0.106
	Heart rate at office	74.0 [7.8]	72.3 [11.7]	71.7 [9.0]	73.3 [11.3]	68.7 [17.0]	0.827
	Heart rate at home	74.6 [10.0]	74.3 [8.0]	72.5 [8.4]	69.4 [6.8]	68.2 [7.4]	0.206
Visit 4	No of patients prescribed with add-on drug at visit 4	n = 14	n = 16	n = 459	n = 13	n = 13
	Systolic–office	131.7 [21.7]	133.3 [10.7]	132.7 [13.3]	130.0 [22.0]	123.3 [16.7]	0.069
	Systolic–home	132.9 [18.9]	137.5 [10.8]	133.2 [11.6]	134.2 [20.0]	130.0 [7.7]	0.280
	Diastolic–office	83.3 [13.3]	87.7 [11.7]	81.7 [7.3]	83.3 [9.7]	76.7 [11.7]*	0.025*
	Diastolic–home	84.6 [14.7]	84.8 [9.1]	82.2 [8.3]	83.0 [8.3]	73.7 [7.9]*	0.001*
	Heart rate at office	71.3 [13.7]	69.3 [9.0]	71.7 [8.3]	70.7 [9.7]	67.7 [12.7]	0.317
	Heart rate at home	71.4 [8.7]	72.0 [7.3]	72.3 [7.8]	70.7 [5.1]	69.4 [9.9]	0.346
Visit 5	No of patients prescribed with add-on drug at visit 5	n = 13	n = 16	n = 460	n = 10	n = 16
	Systolic–office	126.2 [12.6]	130.8 [10.4]	130.7 [11.7]	138.3 [21.0]	128.7 [13.0]	0.056
	Systolic–home	129.0 [12.6]	132.4 [10.9]	131.8 [10.8]	134.9 [18.4]	129.0 [9.5]	0.391
	Diastolic–office	79.3 [4.1]	83.8 [4.2]	80.3 [7.3]	83.3 [9.3]	76.7 [12.0]	0.069
	Diastolic–home	79.6 [5.8]	84.1 [7.3]	81.2 [7.6]	84.7 [7.6]	74.7 [14.0]	0.030
	Heart rate at office	72.0 [12.7]	70.3 [7.4]	71.3 [8.3]	70.7 [10.3]	66.7 [12.8]	0.586
	Heart rate at home	70.0 [8.0]	72.5 [9.6]	71.3 [7.6]	69.2 [13.1]	69.6 [9.3]	0.472
Visit 6	No of patients prescribed with add-on drug at visit 6	n = 13	n = 16	n = 460	n = 10	n = 16
	Systolic – office	122.5 [7.5]	128.5 [18.3]	129.3 [10.7]	131.7 [14.9]	130.7 [15.0]	0.078
	Systolic–home	125.9 [8.3]	129.1 [10.7]	129.7 [9.4]	128.9 [12.7]	128.6 [12.6]	0.246
	Diastolic–office	79.2 [4.6]	80.7 [5.0]	80.0 [5.3]	83.3 [8.2]	80.0 [16.7]	0.370
	Diastolic–home	78.6 [8.8]	80.7 [7.3]	80.1 [6.9]	84.1 [6.8]	75.9 [19.5]	0.170
	Heart rate at office	71.0 [11.8]	69.0 [7.2]	70.7 [8.3]	71.2 [10.4]	71.7 [16.0]	0.819
	Heart rate at home	70.1 [9.0]	70.0 [10.8]	71.3 [7.5]	69.8 [8.2]	69.4 [12.3]	0.900

^* Significant difference.

Patients treated by add-on therapy with SPL, A2A or SPL + A2A achieved more rapid complete blood pressure control than patients treated with other therapeutic options. The first primary endpoint of the study (decrease of arterial blood pressure to levels < 140/90 mm Hg) was achieved in much larger fraction of patients as early as at visit 2 (≥45%, P = .049) and at visit 3 (>57%, P = .011). At the last visit (visit 6) more than 80% of patients with SPL add-on therapy, and 73.3% of patients with SPL + A2A add-on therapy achieved complete blood pressure control; the details for all therapy groups and visits are shown in the Table 3, and in the Figure 2.

Table 3.

Percent of patients achieving blood pressure < 140/90 mm Hg at each study visit (both at office and home measurements).

Visit	Row legend	No antihypertensive added	First-line AH drug added	Spironolactone added	Central antihypertensive added	Spironolactone + central antihypertensive added	Null hypothesis probability
1	No of patients with added antihypertensive at previous visit	387	61	60	7	0	0.176
	Percent of responders	20.40%	11.50%	11.70%	14.30%	0.00%
2	No of patients with added antihypertensive at previous visit	49	29	417	15	5	0.049*
	Percent of responders	30.60%	24.10%	44.80%	53.30%	60%
3	No of patients with added antihypertensive at previous visit	26	21	447	14	7	0.011*
	Percent of responders	38.50%	38.10%	58.60%	57.10%	100%
4	No of patients with added antihypertensive at previous visit	19	16	457	12	11	0.212
	Percent of responders	57.90%	50.00%	67.40%	66.70%	90.90%
5	No of patients with added antihypertensive at previous visit	14	16	459	13	13	0.052
	Percent of responders	78.60%	62.50%	73.90%	38.50%	84.60%
6	No of patients with added antihypertensive at previous visit	13	16	460	10	16	0.065
	Percent of responders	76.90%	56.30%	80.70%	60.00%	73.30%

^* Significant difference.

Figure 2.

Percent of patients achieving blood pressure < 140/90 mm Hg at each study visit (both at office and home measurements).

The second primary endpoint of the study (decrease of systolic arterial blood pressure for 10 mm Hg or more) was achieved at similar rate with all add-on therapeutic options during the first 4 visits (P > .05). Significant differences occurred at visits 5 and 6 (P = .032 and 0.005, respectively), revealing advantage of SPL (83.9% and 88.3% of patients with complete blood pressure control, respectively) and SPL + A2A (100.0% and 86.7% of patients with complete blood pressure control, respectively) add-on therapies; the details for all therapy groups and visits are shown in the Table 4, and in the Figure 3.

Table 4.

Percent of patients achieving decrease of systolic blood pressure for 10 mm Hg or more (from the baseline) at each study visit (both at office and home measurements).

Visit	Row legend	No antihypertensive added	First-line AH drug added	Spironolactone added	Central antihypertensive added	Spironolactone + central antihypertensive added	Null hypothesis probability
1	No of patients with added antihypertensive at previous visit	387	61	60	7	0	0.755
	Percent of responders	31.80%	34.40%	36.70%	42.90%	0.00%
2	No of patients with added antihypertensive at previous visit	49	29	417	15	5	0.259
	Percent of responders	61.20%	79.30%	71.90%	66.70%	100%
3	No of patients with added antihypertensive at previous visit	26	21	447	14	7	0.330
	Percent of responders	69.20%	76.20%	78.10%	64.30%	100%
4	No of patients with added antihypertensive at previous visit	19	16	457	12	11	0.387
	Percent of responders	73.70%	81.30%	82.30%	75.00%	100%
5	No of patients with added antihypertensive at previous visit	14	16	459	13	13	0.032*
	Percent of responders	100%	68.80%	83.90%	69.20%	100%
6	No of patients with added antihypertensive at previous visit	13	16	460	10	16	0.005*
	Percent of responders	92.30%	56.30%	88.30%	70.00%	86.70%

^* Significant difference.

Figure 3.

Percent of patients achieving decrease of systolic arterial blood pressure for 10 mm Hg or more at each study visit (both at office and home measurements).

Patients treated by add-on therapy with SPL or SPL + A2A achieved more rapid diastolic blood pressure control than patients treated with other therapeutic options. The third primary endpoint of the study (decrease of diastolic arterial blood pressure for 5 mm Hg or more) was achieved in much larger fraction of patients as early as at visit 2 (≥66.9%, P = .014) and at visit 4 (≥84.2%, P = .022). At the last visit (visit 6) 88.0% of patients with SPL add-on therapy, and 86.7% of patients with SPL + A2A add-on therapy achieved decrease of diastolic arterial blood pressure for 5 mm Hg or more, but this was not significantly different from effects of other add-on therapy options; the details for other therapy groups and visits are shown in the Table 5, and in the Figure 4.

Table 5.

Percent of patients achieving decrease of diastolic blood pressure for 5 mm Hg or more (from the baseline) at each study visit (both at office and home measurements).

Visit	Row legend	No antihypertensive added	First-line AH drug added	Spironolactone added	Central antihypertensive added	Spironolactone + central antihypertensive added	Null hypothesis probability
1	No of patients with added antihypertensive at previous visit	387	61	60	7	0	0.680
	Percent of responders	39.00%	32.80%	43.30%	42.90%	0.00%
2	No of patients with added antihypertensive at previous visit	49	29	417	15	5	0.014*
	Percent of responders	44.90%	58.60%	66.90%	66.70%	100%
3	No of patients with added antihypertensive at previous visit	26	21	447	14	7	0.681
	Percent of responders	65.40%	81.00%	77.40%	78.60%	85.7%
4	No of patients with added antihypertensive at previous visit	19	16	457	12	11	0.022*
	Percent of responders	63.20%	75.00%	84.20%	66.70%	100%
5	No of patients with added antihypertensive at previous visit	14	16	459	13	13	0.060
	Percent of responders	100%	81.30%	86.30%	61.50%	92.30%
6	No of patients with added antihypertensive at previous visit	13	16	460	10	16	0.161
	Percent of responders	84.60%	75.00%	88.00%	70.00%	86.70%

^* Significant difference.

Figure 4.

Percent of patients achieving decrease of diastolic arterial blood pressure for 5 mm Hg or more (from the baseline) at each study visit (both at office and home measurements).

During the study remarkably small number of adverse effects of antihypertensive therapy (9 cases) was recorded. The adverse effects observed, their association with antihypertensives and outcomes are shown in the Table 6.

Table 6.

Adverse effects of antihypertensives registered during the study.

Drug	Adverse effect	Frequency	Consequence
Amlodipine	Palpitations	1	Recovery after adjusting dose
Amlodipine	Headache	1	Recovery after adjusting dose
Amlodipine	Ankle edema	2	Spontaneous recovery
Verapamil	Bradicardia	1	Recovery after adjusting dose
Enalapril	Rash	1	Switch to another drug from the same group
Perindopril	Hypotension	1	Recovery after adjusting dose
Bisoprolol	Bradicardia	1	Recovery after adjusting dose
Spironolactone	Gynecomastia	1	Drug withdrawal

The baseline blood pressure and heart rate of the study participants are shown in the Supplementary file (see Table S1, Supplemental Digital Content, http://links.lww.com/MD/J85, which illustrates blood pressures at baseline visit according to previous unsuccessful therapy). Adherence of the patients to prescribed antihypertensive therapy was similar across the therapy groups and study visits, never dropping below 77.8%, and mostly being over 90% (see Table S2, Supplemental Digital Content, http://links.lww.com/MD/J86, which illustrates patients adherence according to the treatment regimen). Good tolerability of the prescribed add-on therapy was reflected in high values of quality of life as the patients estimated it on visual analogue scale; values over 82% were observed at last visit for patients with add-on spironolactone, central antihypertensive or combination (see Table S3, Supplemental Digital Content, http://links.lww.com/MD/J87, which illustrates quality of life according to therapeutic regimen). The effect of antihypertensive therapy on kidneys was evaluated by measuring creatinine serum levels and proteins in urine at the study visits. While serum creatinine levels were within the reference range and differences were not significant between the add-on therapy groups (see Table S4, Supplemental Digital Content, http://links.lww.com/MD/J88, which illustrates creatinine levels according to therapeutic regimen), in group of patients with added spironolactone consistent decrease in proteinuria rate from baseline to the last study visit was observed (Table 51 Supplemental Digital Content, http://links.lww.com/MD/J89 and Figure S3, Supplemental Digital Content, http://links.lww.com/MD/J90). Proteinuria rate in the group of patients with added spironolactone decreased exponentially from visit to visit (although the differences among the rates at different visits were not significant – Fisher exact test P value was 0.209), each next visit bringing further 17.5% drop.

4. Discussion

Our study showed that add-on therapy of TRH with spironolactone was the most effective, tolerable and safe option, further enhanced by combining it with a central antihypertensive. Since effectiveness of adding another first-line antihypertensive (including BBs) was lacking in great majority of patients, physicians switched their TRH patients after 1 or 2 months to spironolactone, which was the main add-on drug in 89.4% of patients at the last study visit. The main endpoint of the study, the blood pressure measured both at office and home below 140/90 mm Hg was achieved in 80% of patients with add-on spironolactone, while 88% of patients taking this drug also achieved decrease of systolic blood pressure for more than 10 mm Hg from baseline, and diastolic blood pressure for more than 5 mm Hg from baseline. Effectiveness of centrally acting antihypertensives as add-on therapy was inferior, achieving the study endpoints in <70% of patients. Add-on spironolactone was also associated with lower rate of proteinuria, with a decreasing trend from visit to visit.

The effectiveness of spironolactone in TRH observed in our study was higher than efficacy reported by key randomized clinical trials. In a multicenter clinical trial on 187 patients with TRH spironolactone as add-on therapy was more efficient than central antihypertensive clonidine, but complete control of blood pressure after 3 months of treatment was achieved in only 21% of patients.^[18,19] In another multicentric clinical trial where 285 patients with TRH were taking spironolactone as add-on therapy during 12 weeks,^[20] spironolactone was more efficient than placebo, bisoprolol or doxazosin, but blood pressure control was achieved in no more than 58% of patients. It seems that for development of spironolactone full effect in TRH patients at least 6 months of treatment is necessary, probably because this is the time needed to titrate the dose properly; in our study mean daily dose of spironolactone was 28.6 ± 10.5 mm Hg at visit 1, and then increased to 30.5 ± 11.1 mm Hg at visit 6, when higher response rate was achieved.

Two main safety concerns when using spironolactone for treatment of hypertension are elevation of serum potassium and sex-hormone related side effects, in the first-place gynecomastia. True incidence of hyperkalemia is yet unknown, but majority of studies report values below 4.2%^[21]; in our study hyperkalemia (serum potassium > 5.5 mEq/L) was observed in 3 patients at visit 5 (0.66%), and in 2 patients at visit 6 (0.44%). However, none of the patients with hyperkalemia had potassium serum levels ≥ 6 mEq/L, regardless of the fact that all patients except 1 were also taking ACE inhibitor or ARB throughout the study. The daily dose of spironolactone prescribed to patients in our study was in great majority of patients 25mg, and all of our patients had normal renal function (this was one of the inclusion criteria); since hyperkalemia is dose-dependent side effect of spironolactone, it is not becoming a problem when used in lower doses for treatment of hypertension in patients without renal impairment, even when co-administered with an ACE inhibitor or an ARB. Only 1 case of gynecomastia was observed in our study (incidence rate 0.2%), and this again was not surprising considering low doses of spironolactone recommended for hypertension, and prescribed in our study. Sex-hormone related adverse effects of spironolactone are dose-dependent; e.g., the incidence rate of gynecomastia in patients with heart failure who are treated with higher doses of spironolactone (up to 200mg daily) may reach 10%.^[22] However, such low incidence of gynecomastia was not observed in previous observational studies of spironolactone when it was used for treatment of hypertension, in spite of low doses (25–50 mg daily),^[23] probably because the observation periods were longer than in our study. Intolerability of spironolactone and other add-on drugs in our study was not an issue, too; none of the patients withdrew from our study for that or any other reason.

Spironolactone was the only add-on medication in our study that showed certain tendency of Reno protective effect: frequency of proteinuria was the lowest in comparison with other therapeutic options, and decreased with spironolactone from visit to visit. Antiproteinuric effect of spironolactone is well known, and based on its dual action in kidneys: aldosterone receptor blocking and inhibition of renin-angiotensin system. When given with ACE inhibitor or ARB, spironolactone decreases proteinuria for further 30%, and this effect becomes more pronounced with longer therapy.^[24] However, whether decreased proteinuria is associated with slowing of renal impairment progression remains to be elucidated in future.

It is characteristic for the quality of life in patients with hypertension that it improves after the introduction of antihypertensive therapy, and then increases to a maximum when the antihypertensive dose is optimally adjusted to the patient’s needs.^[25] The same phenomenon was observed in our study. Although we did not specifically measure quality of life domains, previous research has shown that optimal antihypertensive therapy improves the aspects of sleep quality, libido, quality of daily functioning and general sense of well-being the most.^[25]

Sufficiently long observation period in our study is one of its strengths, giving an opportunity to the add-on therapy to show its full potential. Also, it was focused on patients without renal impairment, creating unclouded insight in add-on drug-related safety issues. There are 2 main limitations of our study. First, due to the observational design and the free choice and dosing of the add-on therapy from visit to visit, the treatment groups became very unequal already from the second visit, because patients switched to and remained in the group with spironolactone due to a better therapeutic effect, while in the other groups formed at the baseline visit and visit 1, only patients who responded favorably to such therapy remained. In the last visits, over 90% of patients were on spironolactone therapy, which reduced the statistical power to demonstrate differences between treatment groups. Second, laboratory analyzes were performed for <50% of patients per visit, again due to the observational design, which could be the reason for the lower frequency of hypokalemia and proteinuria noted in our study compared to other studies of treatment of resistant hypertension with a different design.

5. Conclusion

The most effective and safe add-on therapy of resistant hypertension were spironolactone alone and combination of spironolactone and a centrally acting antihypertensive drug. It takes about 6 months for full benefit of add-on therapy to be achieved, which is accompanied with significant improvement in quality of life.

Acknowledgements

The authors are grateful to the TRYCORT study subinvestigators (in alphabetical order by surname): Mojsije Anđić, Nebojša Antonijević, Goranka Ašćerić, Vesna Atanasković, Danica Bačanin Jovanović, Aleksandar Bakić, Snežana Bjelić, Biljana Blagojević, Milan Bošnjak, Olivera Božić, Nenad Božinović, Samina Bronja, Zlatica Bubalo, Sreten Budisavljević, Nenad Burazor, Marina Cvetanović, Predrag Cvetković, Milenko Čanković, Suad Ćatović, Biljana Ćosić, Sonja Dakić, Goran Davidović, Vladimir Dedović, Jadranka Dejanović, Dinka Despotović, Maja Despotović, Gorica Dimčić Tasić, Emina Dimitrijević, Ivana Dizdarević, Sladjana Dostanić Đurić, Ljiljana Dugić, Radmila Dukić Simović, Dijana Đikić, Jasmina Đorđev, Ana Đorđević Dikić, Nevena Dragašević, Boris Đinđić, Dejan Đokić, Nemanja Đuričić, Sanja Đurin, Sanja Ilić, Violeta Irić Ćupić, Branislava Ivanović, Nataša Janković, Bojan Jašović, Tatjana Jozić, Stefan Juričić, Alen Karahodžić, Biljana Kastel, Slobodan Klašnja, Jasna Kmezić Grujin, Snežana Komnenović Letić, Gordana Krljanac, Nebojša Krstić, Miroslav Krstić Ranđelović, Dušanka Kurtović, Ratko Lasica, Goran Latković, Milica Lazić, Lela Lazović, Mara Ljubičić, Danijela Ljubišić, Ljiljana Mandić, Marija Mandić, Bojan Maričić, Marija Marjanović, Marija Marković, Dragan Matić, Snežana Matić, Olivera Micić, Mirjana Mihailović, Gordana Mihajlović, Suzana Mijailović, Marko Milanov, Đorđe Milićević, Branko Miljački, Tatjana Miljković, Vladimir Miloradović, Bojan Milovanović, Slađana Mirić, Biserka Mitić, Predrag Mitrović, Aleksandar Mladenović, Katica Mraković, Marina Mutavdžić, Ivana Nedeljković, Nevena Nikačević, Danijela Nikolić, Milena Pandrc, Dragan Panić, Sunčića Panić, Biljana Parapid, Miroslav Pavković, Sanja Petrović, Vojka Petrović, Dragana Pilipović, Marija Popović, Vesna Radojković, Gordana Radosavljević, Gorica Radovanović, Zorica Radovanović, Dubravka Rajić, Srđan Raspopović Dejan Sakač, Enser Regić, Žaklina Ristić, Lidija Savić, Dejan Simeunović, Dragan Simić, Bojana Siriški, Dejan Spiroski, Miodrag Srećković, Dragana Stanojević, Teodora Stanojlović, Milica Stefanović, Slavica Stevović, Goran Stoiljković, Dragan Stojanović, Vladimir Stojanović, Jadranka Stojiljković, Predrag Strugarević, Suzana Šaban Trnokopović, Milan Ševo, Anđa Šinik, Milorad Tešić, Branislava Todić, Branko Tomić, Dragana Tončev, Nemanja Vasović, Danijela Vraneš, Rada Vučić, Jelena Vučković, Jelena Vukašinović, Vesna Vukelić, Milan Zlatar, Milorad Živković, Dragoslava Živkov Šaponja, Aleksandar Živković, and Milan Živković.

Author contributions

Conceptualization: Slobodan Janković, Branko Anđelković, Renata Gocić Petrović.

Data curation: Slobodan Janković, Siniša Stojković, Milovan Petrović, Tomislav Kostić, Marija Zdravković, Slavica Radovanović, Radosava Cvjetan, Nenad Ratković, Branislav Rihor, Dejan Spiroski, Aleksandar Stanković.

Formal analysis: Slobodan Janković.

Funding acquisition: Branko Anđelković, Renata Gocić Petrović.

Investigation: Slobodan Janković, Siniša Stojković, Milovan Petrović, Tomislav Kostić, Marija Zdravković, Slavica Radovanović, Radosava Cvjetan, Nenad Ratković, Branislav Rihor, Dejan Spiroski, Aleksandar Stanković.

Methodology: Slobodan Janković.

Project administration: Slobodan Janković, Siniša Stojković, Milovan Petrović, Tomislav Kostić, Marija Zdravković, Slavica Radovanović, Radosava Cvjetan, Nenad Ratković, Branislav Rihor, Dejan Spiroski, Aleksandar Stanković, Branko Anđelković, Renata Gocić Petrović.

Resources: Branko Anđelković, Renata Gocić Petrović.

Supervision: Slobodan Janković, Siniša Stojković, Milovan Petrović, Tomislav Kostić, Marija Zdravković, Slavica Radovanović, Radosava Cvjetan, Nenad Ratković, Branislav Rihor, Dejan Spiroski, Aleksandar Stanković.

Software: Branko Anđelković.

Validation: Branko Anđelković, Renata Gocić Petrović.

Visualization: Branko Anđelković, Renata Gocić Petrović.

Writing – original draft: Slobodan Janković.

Writing – review & editing: Slobodan Janković, Siniša Stojković, Milovan Petrović, Tomislav Kostić, Marija Zdravković, Slavica Radovanović, Radosava Cvjetan, Nenad Ratković, Branislav Rihor, Dejan Spiroski, Aleksandar Stanković.