Central blood pressure lowering effect of telmisartan‐rosuvastatin single‐pill combination in hypertensive patients combined with dyslipidemia: A pilot study

Abstract This multicenter, phase 4, Prospective Randomized Open, Blinded End‐point (PROBE) study aimed to evaluate safety and efficacy of telmisartan/rosuvastatin single‐pill combination (SPC) therapy on lowering central blood pressure (BP) compared with telmisartan monotherapy in hypertensive patients with dyslipidemia in Korea. Study was terminated earlier than planned due to COVID‐19 pandemic, thus should be considered as a pilot study. Among 125 patients who met the inclusion criteria of hypertension and dyslipidemia (defined as 10‐year Atherosclerotic Cardiovascular Disease risk score over 5%), 80 patients went through 4‐week single‐group run‐in period with telmisartan 40–80 mg, then randomized to telmisartan 80 mg + rosuvastatin (10 or 20 mg) SPC group or telmisartan 80 mg monotherapy group. The central/brachial BP, brachial‐ankle pulse wave velocity (baPWV), and augmentation index (AIx) were assessed at baseline and 16 weeks later. Mean brachial SBP changed from 135.80 ± 14.22 mmHg to 130.69 ± 13.23 mmHg in telmisartan/rosuvastatin group and from 134.37 ± 12.50 mmHg to 133.75 ± 12.30 mmHg in telmisartan monotherapy group without significant difference (between‐group difference p = .149). Mean central SBP were reduced significantly in the telmisartan/rosuvastatin group with change from 126.72 ± 14.44 mmHg to 121.56 ± 14.56 mmHg while telmisartan monotherapy group showed no significant change (between‐group difference p = .028). BaPWV changed from 1672.57 ± 371.72 m/s to 1591.75 ± 272.16 m/s in telmisartan/rosuvastatin group and from 1542.85 ± 263.70 m/s to 1586.12 ± 297.45 m/s in telmisartan group with no significance (between‐group difference p = .078). Change of AIx had no significant difference (between‐group difference p = .314). Both groups showed excellent compliance rate of 96.9 ± 4.5% with no significant difference in adverse rate. Telmisartan/rosuvastatin SPC therapy was more effective in lowering central BP compared with the telmisartan monotherapy. The results of this study showed benefit of additive statin therapy in hypertensive patients combined with dyslipidemia.


INTRODUCTION
Hypertension (HTN) is a known leading cause of death and disability over the world. 1 Although lowering the blood pressure (BP) has been proven to reduce cardiovascular events, 2 recent studies have suggested that the central BP might be more closely related to future cardiovascular events than brachial BP. 3 Studies have shown stronger association of central BP with surrogate markers of cardiovascular diseases (eg, carotid intima media thickness, 4 diastolic function, 5 left ventricular mass 6 ) and target organ damage (eg, renal failure, 7 cognitive deficiency 8 ) than brachial BP.
The central BP is a sum of incident wave from left ventricle and reflected wave from peripheral vessels at the ascending aorta. The measured contribution of reflected wave on the incident wave at the ascending aorta is defined as augmentation index (AIx). 9 The AIx is affected by pulse wave velocity (PWV), which is defined by distance between two arterial sites divided by pulse transmit time. 10 The AIx and PWV both have a predictive power on cardiovascular events. 11,12 Thus, current studies are also focusing on the predictive role of the AIx and PWV measurement as well as central BP.
Despite the rising importance of central BP, current antihypertensive medications are mainly focused on controlling brachial BP. However, it is well known that antihypertensive classes have different impact on central BP reduction. For example, beta-blocker atenolol, was inferior in reducing central BP to brachial BP to other antihypertensive classes. 13 And angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have revealed more promising effect of lowering central BP than other classes of antihypertensives. 14 Along with HTN, dyslipidemia is also known to increase the risk of cardiovascular events. 15 The co-existence of HTN and dyslipidemia is relatively abundant, with its prevalence of at least over 15%. 16 The co-existence leads to a higher risk of cardiovascular event than a sim-ple sum of the two factors. 17 Among the treatments of dyslipidemia, hydroxyl-methyl-glutaryl-coenzyme A reductase inhibitors, statins, are the fundamental drug. 18 Statins were reported to have modest BP lowering effect and is expected to have a beneficial role in arterial stiffening. 19 Telmisartan is a highly selective blocker to angiotensin type-1 receptor with a long elimination half-life that effectively reduces BP for 24-h dosage interval. 20 Rosuvastatin is highly effective in lowering low-density lipoprotein-cholesterol (LDL-C) and increasing high-density lipoprotein-cholesterol (HDL-C). 21 Previously, the telmisartan/rosuvastatin single-pill combination (SPC) has shown noninferiority compared to the telmisartan or rosuvastatin monotherapy in lowering brachial BP and LDL-C levels, respectively. 22 However, the role of telmisartan/rosuvastatin combination therapy in central BP has not been evaluated yet.
Thus, this study investigated the efficacy and safety of telmisartan/rosuvastatin SPC therapy in patients with HTN and mild dyslipidemia of 10-year Atherosclerotic Cardiovascular Disease (ASCVD) risk score over 5% compared with telmisartan monotherapy.

Study population
The study population consisted of hypertensive patients aged 50-75 years old, with a calculated ASCVD risk of more than 5%.
The participants should also be untreated with dyslipidemia (not under medication or stopped medication for at least 4 weeks prior to randomization). The exclusion criteria were the following: (1) ARB hypersensitivity, (2)

Study design and procedures
This study was a randomized, multicenter, phase 4, Prospective, Randomized, Open-label, Blinded End-point (PROBE) study, which took place from January 11, 2018 to September 2, 2020. All patients were informed thoroughly about the trial and agreed upon written consent.
The study protocols were approved by the Institutional Review Board (SNUH 2017-0412) and were done according to the principles of the Declaration of Helsinki. This study was registered in Clinicaltrials.gov: NCT03267329.
The patients were randomized after 4 weeks of run-in period with telmisartan 40 or 80 mg if they met the inclusion criteria. During the run-in period, the patients who were already taking anti-hypertensive therapy had their medicine changed to telmisartan 80 mg monotherapy. Others with no experience of anti-hypertensive therapy were prescribed with telmisartan 40 or 80 mg. After the run-in period, the patients were randomized via 1:1 stratified randomization by the institute. Depending on the ASCVD risk score during the screening, those with a risk score between 5% and 7.4% received rosuvastatin 10 mg, and those with a risk score above 7.5% received rosuvastatin 20 mg. All medications were taken orally once a day, and the patients were evaluated about the efficacy and safety three times during the 16 weeks of the treatment period ( Figure 1).

BP measurement
Electronic BP monitors (Omron HEM-7080IC, Omron Corporation, Kyoto, Japan) were used to measure brachial BP, and all laborato-ries used the same product. The BP of both arms was measured by a trained study coordinator at the screening visit after an initial 5 min of seated rest, and the arm with the higher average SBP obtained by three measurements was selected as the reference arm. The average value of the three measurements at screening visit was used as a baseline.
The central hemodynamic parameters were evaluated in the sitting position after 10 min of resting with overnight fasting using a Sphyg-moCor software version 7.0 (AtCor Medical, Sydney, Australia). 23 The overnight fasting state was defined as fasting over 8 h. Mean arterial pressure was determined by mathematical integration of the radial pressure waveform and calibrated using the oscillometric value of brachial SBP and DBP. Pulse pressure (PP) amplification was calculated as the ratio of brachial PP: central PP. Brachial-ankle pulse wave velocity (baPWV) was measured according to the manufacturer's protocol using VP-1000 (Omron Healthcare CO., Ltd., Kyoto, Japan) after participants were supine for 5-10 min. 24

Efficacy outcomes
The change in central SBP at 16 weeks from the baseline was evaluated as the primary efficacy outcome ( Figure 1). The secondary out-

Sample size and statistical analysis
To estimate the appropriate sample size, the non-inferiority margin of change of central SBP at 16 weeks was assumed as 4 mmHg with the Abbreviations: BPM, beats per minute; DBP, diastolic blood pressure; RAS inhibitors, renin-angiotensin system inhibitors including angiotensin receptor blockers and angiotensin converting enzyme inhibitors; SBP, systolic blood pressure; SD, standard deviation. a Wilcoxon rank sum test. b Chi-square test. c Two sample t-test.
standard deviation (SD) as 6.8 mmHg. With a significance level of 5% and a power of 80%, the estimated sample size was 46 participants.
Assuming the dropout rate of 10%, minimum of 52 participants for each group (a total of 104) was needed for the enrollment.
The intention to treat (ITT) population was defined as participants who had at least one measurement of primary efficacy endpoint among those enrolled after evaluating inclusion/exclusion criteria. Per protocol (PP) set was defined as participants who completed the study without major protocol deviation among the ITT population. The safety set was defined as any of the participants who were treated at least once after randomization. The analysis of baseline characteristics was done at the ITT population. All statistical analyses were done via SAS version 9.4 (SAS Institute, Inc, NC, USA) with a two-tailed test with a significance level of 5%.
The primary efficacy endpoint of change from baseline in central SBP at 16 weeks was analyzed at the ITT population with paired t-test (or Wilcoxon signed-rank test) in each treatment group. For betweengroup comparison, analysis of covariance was used with baseline central SBP as a covariate. In addition, the between-group difference of all the adverse events and the adverse drug reaction was analyzed using the Chi-square test (or Fisher's exact test).

Changes in brachial and central BP
The

Compliance and tolerability
The overall compliance rate of two groups were 96.14 (SD 4.86)% for the telmisartan group and 97.53 (SD 4.03)% for the telmisartan/rosuvastatin SPC group with no significant difference (p = .274).
Of the 77 patients treated with the medication at least once after enrollment, 10 patients experienced 16 adverse events in total.
The telmisartan group had five participants with nine events, and the telmisartan/rosuvastatin group had four participants with seven events. The incidence rate between the two groups did not differ sig-nificantly (p = 1.000). A major adverse event was found once at one participant in the telmisartan group: a renal cyst (not an adverse drug reaction). The adverse event that resulted in discontinuation of the treatment was found once each for both telmisartan and telmisartan/rosuvastatin group (p = 1.000). The most common adverse event was asthenia, which was found in a total of two participants, one from each group. The adverse event that resulted in the treatment's discontinuation was a headache in the telmisartan group, and hepatic enzyme increase in the telmisartan/rosuvastatin group. The headache was considered as an adverse drug reaction related to the clinical trial medication.

DISCUSSION
In this study, we found that the telmisartan/rosuvastatin SPC group had more significantly reduced mean central SBP than the telmisartan monotherapy group in patients with HTN and mild dyslipidemia.
The brachial SBP were also reduced in telmisartan/rosuvastain SPC group but without significance compared to telmisartan monotherapy group. The between-group difference of AIx and baPWV were statistically insignificant despite the baPWV being reduced only in telmisartan/rosuvastatin SPC group.
Although statin's effect on lowering BP has been identified previously, its effect on lowering central BP is still controversial. In a smallscale randomized controlled trial, the statin usage reduced central BP and aortic stiffness. 25 However, in the CAFE-LLA study, statin did not lower central BP. 26 Most recently, in the study from the CARTaGENE cohort, the statin use was significantly associated only in patients who were targets of primary prevention. 27 This result is in line with our study as all the participants in this study were at least over 5% of the ASVCD risk factor, which makes them the target of primary prevention.

Difference between baseline and post-baseline in each group ( b paired t-test, c Wilcoxon signed rank test). Difference between control and treatment group ( d paired t-test, e two sample t-test).
Although insignificant in between-group analysis, the baPWV of the telmisartan/rosuvastatin SPC group showed greater reduction at PWV is the most known measure of arterial stiffness, along with AIx. 33 Arterial stiffness is caused by hemodynamic forces, extrinsic factors including hormones, and inflammations. 34 The meta-analysis of 52 studies done by McGaughey and colleagues have shown that ACEIs and ARBs can significantly reduce AIx. 35 Furthermore, meta-analysis by Yen and colleagues suggested that ARBs can also reduce PWV. 36 Not only ACEIs and ARBs but also meta-analyses on statin have significantly reduced the aortic stiffness, defined by PWV and AIx. [37][38][39] Such effect of the drugs is explained by renin-angiotensin-axis system mechanism of ARBs and antioxidant and anti-inflammatory activity of statin. 36,40 As the telmisartan monotherapy group showed no reduction in PWV at all, the reducing tendency shown at telmisartan/rosuvastatin SPC group might have been due to the addition of statin. The effect of statin on PWV is expected to be dose dependent. 41  AIx may be due to baPWV being independent from treatment duration but AIx being more dependent on the duration. Also, although study by Van Doornum and colleagues showed reduction of AIx in rheumatoid arthritis patients after 12 weeks of atorvastatin, the potency of statin is thought to differ between the type of statin. 39 44 On the other hand, PWV increases along with age even after 50 years. 45 And the aging influences on baPWV more prominently in female. 46 As the mean age of our study population was 61.5 years, the AIx might not have been a suitable marker leaving baPWV as a more feasible one. This is one of the limitations of our study, and fur- Because of the small study population, the result was interpreted with careful consideration of the possible weak points derived by the small study design. As a small study, the probability of false positive (type 1 error) is increased and over-estimation of the magnitude of association can be found more easily. 48 Not only type 1 error, but also previous evaluation on randomized controlled trials also showed a need for caution to the occurrence of type 2 error in underpowered randomized controlled trials. 49 Consequently, the result of our study cannot be confirmative and necessitates the need for larger confirmatory study.
The marginal significance of PWV mostly came from the smaller sample size than originally planned. Besides underpowered study, the marginal significance of PWV may be due to the other factors that influence PWV. The PWV is known to be influenced by PP, age, sex, BP, body mass index, triglyceride, blood glucose, salt intake, electrocardiogram voltage, urine albumin, and genetic factors. [50][51][52] In this study, the two groups did not differ between the PP, age, and sex. However, other factors including salt intake, urine albumin, genetic factors were not considered. Thus, such factors might have attenuated the PWV difference in this study. This is one of the limitations of our study, and further study comprising younger age group would be necessary to clear this point.
On the contrary, there is also a chance that the effect has been exaggerated due to higher baseline baPWV in telmisartan/rosuvastatin SPC group. Although the participants were randomly assigned to each group, there was numerical difference in baseline PWV yet without statistical significance (p = .130). We did not exclude the possibility that the difference might be significant if the original enrolment was completed (type 2 error). However, telmisartan the monotherapy group showed numerically increased PWV by 2.9%, whereas the telmisartan/rosuvastatin SPC group showed decreased PWV by 4.8%. Therefore, even though the extent of change might be influenced by the baseline values, we think that the difference between two groups remains significant.

CONCLUSIONS
In this study, telmisartan/rosuvastatin combination therapy showed a reduction in both central and brachial SBP when the telmisartan monotherapy group failed to show significant reduction in patients with HTN and mild dyslipidemia. The results of this study showed another benefit of statin therapy in hypertensive patients combined with dyslipidemia.

ACKNOWLEDGMENTS
This study was sponsored by Yuhan Corporation. The sponsor supported all the expenses needed for the medication supply, laboratory testing, and clinical research coordinator. The sponsor also participated in the study design, data collection, and analysis. The sponsor did not involve the interpretation of data, writing of the report, or the decision to submit the article for publication. All authors contributed to the data collection, data interpretation, and literature research, and were involved in all stages of manuscript development.

CONFLICT OF INTEREST
The authors have indicated that they have no conflicts of interest regarding the content of this article.

AUTHOR CONTRIBUTIONS
This study was coordinated by Hae-Young Lee as the principal inves-