The efficacy and safety of valsartan and the combination of valsartan and hydrochlorothiazide in the treatment of patients with mild to moderate arterial hypertension — the VICTORY trial

Introduction

When Steven Hales, for the first time, measured blood pressure (BP) in an awake horse in 1733, (1) he was not aware of the fact that some individuals may have elevated BP and that this may be bad for their health. Indeed, until the beginning of the 20th century most physicians felt that elevated BP would be a response to a requirement of the organs in hypertensive patients. Today, thanks to the Framingham trial and many other large epidemiological surveys, it is obvious that high BP is indeed the underlying cause of myocardial infarction and stroke in millions of hypertensive patients. (2)

The estimated number of adults with raised BP increased from 594 million in 1975 to 1.13 billion in 2015, affecting 597 million men and 529 million women. At the global level, this increase was attributable to population growth and ageing. In 2015, age-standardised prevalence of elevated blood pressure was 24.1% in men and 20.1% in women. According to the latest data, elevated BP is a persistent health issue in Central and Eastern Europe. (3)

Dietary and lifestyle changes can improve BP control and decrease the risk of health complications, although medication therapy is still often necessary in people for whom lifestyle changes are not enough or not effective. (4)

Angiotensin receptor blockers (ARBs, e.g. valsartan) are among the first-line medications for hypertension. They can be used either alone or in combination with other antihypertensive agents (e.g. hydrochlorothiazide). (5) Many trials with the valsartan in the field of hypertension have been performed; however data about efficacy and safety of generic medications are scarce. The present article highlights the main results of the VICTORY trial (6), which was previously published in Kardiologia Polska and in which also patients from Croatia were included.

Patients and Methods

A total of 365 patients, 196 females and 169 males, were enrolled in this international, multicentre, open-label, prospective, phase IV trial named VICTORY. Hypertensive patients in 25 centres in five countries – Slovenia, Russian Federation, Ukraine, Czech Republic and Croatia – were included in the trial from May 2013 to June 2015. The patients were included according to indications in the summaries of product characteristics of the investigated medicines. At the initial visit, each patient received a detailed explanation of the objectives and procedures of the trial and was asked to sign an informed consent form before any procedure was performed. The protocol of the trial was submitted to and approved by all national medical ethics committees in the participating countries. (6)

During the 16-week period, the patients had five visits: the first visit upon inclusion in the trial, the second after one month of the treatment, the third after 2 months, the fourth after 3 months and the fifth after 16 weeks of the treatment. The treatment was initiated with one 80 mg tablet of valsartan daily in all patients (naďve and previously treated). Only in Russia, previously treated patients received valsartan at the first visit in a dose of 160 mg (request by ethical committee), which did not have any influence on trial results. After four weeks of treatment, the dose was changed to one 160 mg tablet of valsartan daily in patients whose BP was not lowered to 140/90 mm Hg or lower. After the following 4 weeks, the dose was increased to 320 mg valsartan or 160/12.5 mg FDC of valsartan and HCTZ in patients with unsatisfactory response. If target BP levels were not achieved after additional 4 weeks, the dose was increased to 320/12.5 mg FDC of valsartan and HCTZ. (6)

To assess the safety profile, an interview and physical examination were used. The patients were asked about any signs or symptoms they had experienced since the last visit and a physical examination was carried out to identify any signs of possible adverse events (AEs). All recorded AEs were stratified according to time of occurrence, frequency, relatedness to treatment, severity, therapeutic measures required and outcome. (5)

Results

Among 365 patients, 196 (54.0%) were females. The mean age was 54.6 ± 12.0 years. An intention-to-treat (ITT) analysis of primary and secondary outcome measures included 365 patients. Four patients discontinued the treatment due to AEs related to the treatment. (6)

The mean baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 156.59 ± 8.98 mmHg and 95.63 ± 6.01 mmHg, respectively. In previously treated patients, the baseline BP was measured after 1 week of a wash-out period. At the final visit after 16 weeks of active treatment, the mean SBP and the mean DBP were 130.05 ± 8.18 mmHg and 80.97 ± 5.84 mmHg, respectively. During the trial, the mean SBP and DBP were steadily decreasing. The mean absolute decreases of SBP and DBP were 26.60 ± 10.41 mmHg and 14.84 ± 7.57 mmHg, respectively. The mean relative decreases of SBP and DBP were 16.8 ± 6.1% and 15.2 ± 7.3%. The decrease of mean SBP and DBP between two consecutive visits was in every case statistically significant (p<0.0001) (Figure 1). (6)

Figure 1. Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg) during the trial for all patients. (6)

Achievement of the target BP according to the 2013 ESH/ESC Guidelines for the management of arterial hypertension was monitored at each control visit. At the last visit, 91% of the patients who appeared at the last visit had their BP lowered to the target BP. The rate of achieving target BP was higher at each subsequent visit, which can be seen in Figure 2. (6)

Figure 2. Blood pressure reduction to target blood pressure during the trial. (6)

Overall, 230 patients were included into per protocol analysis of target BP control. Fifty of them were on combination therapy with valsartan and HCTZ FDC at at least one control visit and 180 of them were on monotherapy throughout the trial. The combination therapy was initiated in patients who did not reach the target BP at visit 3 and visit 4. The difference in mean absolute and relative decreases of SBP and DBP from visit 3 to visit 5 between monotherapy and combination therapy was statistically significant (p < 0.0001). Patients on combination therapy were patients who did not have the target BP on visit 3 and/or visit 4 and patients on monotherapy were mostly patients with adequately controlled BP (Figure 3). (6)

Figure 3. Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg) at each control visit for patients treated with monotherapy (valsartan) or combination therapy (fixed-dose combination of valsartan and hydrochlorothiazide). (6)

The therapeutic effect of the treatment was assessed at the last visit of the trial. Very good therapeutic effect (BP below 140/90 mmHg or below 140/85 mmHg for high-risk and diabetic patients) was observed in 91% of the patients. In the remaining 9% of the patients the therapeutic effect was good (if the SBP was reduced by at least 10 mmHg, and the DBP by at least 5 mmHg), satisfactory (if only the SBP was reduced by at least 10 mmHg, or only the DBP by at least 5 mmHg) or unsatisfactory (if the SBP was reduced by less than 10 mm Hg, and the DBP by less than 5 mmHg). Only in 1.4% of the patients the therapeutic effect was unsatisfactory. (6)

The effect of treatment on the patients’ quality of life (QoL) was assessed with a simple questionnaire. At the end of the trial, 73.7% of the patients answered that they were feeling well or better than with previous antihypertensive therapy. In most cases, the treatment improved QoL. In 22.3% of the patients, the treatment did not aggravate the patients’ QoL. These results clearly show that QoL improved in patients treated with valsartan and patients treated with valsartan and HCTZ FDC. (6)

Concerning the tolerability profile, valsartan and the FDC of valsartan and HCTZ were very well tolerated. An analysis revealed that the adverse event incidence rate during 16 weeks of treatment was low, as during the course of the trial only 7.1% of the patients experienced AEs related to the treatment. The frequency of the observed AEs was low. Among all reported AEs, headache (1.9%), palpitations (1.6%), dizziness (1.6%) and fatigue (1.6%) were most common. Only 4 (1.1%) patients discontinued the treatment because of treatment-related AEs. (6)

Conclusion

The results of the VICTORY trial confirmed that valsartan (Valsacor®) and the FDC of valsartan and HCTZ (Valsacombi®) effectively decrease BP in patients with mild to moderate arterial hypertension. Notably, the target BP reduction, as defined by the ESC/ESH 2013 guidelines, was achieved in 91% of the patients. During the course of the trial, the incidence rate of reported AEs was low. Valsartan and the FDC of valsartan and HCTZ seem to be a beneficial option for effective BP control in mildly to moderately hypertensive patients, which is of key importance for improved cardiovascular outcomes.