Introduction
Cardiovascular diseases (CVDs) are the predominant cause of death globally, and are today at an even higher level in women in comparison with men (1). Croatia follows a similar pattern, with CVDs being the leading cause of mortality for decades. According to published data for 2021, 23 184 people in Croatia died from CVDs, which accounts for 37% of all deaths. Analysis by sex shows that CVDs were the cause of death in 41.8% of women and in 32.0% of men. (2)
Despite hypertension being a significant modifiable risk factor contributing to this high CVD burden (3) in Croatia, nearly half (48%) of adults aged 30 to 79 years have hypertension, with the prevalence being higher among men (51%) than women (45%). Among those affected, 75% have been diagnosed with arterial hypertension (AH), yet only 54% were receiving treatment. Effective blood pressure (BP) control was achieved only in 20% of patients with hypertension. (4)
Sex-related differences have recently been more thoroughly discussed and investigated, with the goal of improving the current situation of BP control. (5) Both European guidelines for the management of AH (the 2023 ESH Guidelines for the management of arterial hypertension and the 2024 ESC Guidelines for the management of elevated blood pressure and hypertension) discuss sex differences across a range of aspects, from epidemiology and pathophysiology to hypertension-mediated organ damage (HMOD), antihypertensive treatment, target BP values, and cardiovascular (CV) outcomes. (6,7)
However, due to lack of sex-specific data, the guidelines recommend the use of combination therapy in most patients with hypertension, both men and women. Single-pill combinations (SPCs) are the preferred form of therapy at all treatment steps, as this enables patients to remain on a simple treatment regimen with a single pill throughout the treatment, thus increasing the likelihood of adherence to therapy and progressing to better BP control. (6) Such an approach is expected to markedly increase BP control from the current low levels in Croatia (15% in men and 25% in women) (4) to approximately 60% with the use of dual combination therapy and even 90% with triple combination therapy. (6)
Currently, it is known that important sex differences exist, ranging from the interaction of BP with CV risks and comorbidities, the pathophysiological mechanism regulating BP, development of BP over the course of a patient’s life, development of AH, HMOD in the heart and the arteries, impact on incident CVDs, and differences in the effect of antihypertensive treatment. (5) In addition to the above, there are known sex differences in prescription of different classes of antihypertensives, with women more often being prescribed diuretics and men more often receiving angiotensin converting-enzyme inhibitors (ACEi) and calcium channel blockers (CCBs). (5,8,9) In general, both sexes are prescribed a comparable number of antihypertensives (2 in women and 2.1 in men). (9)
Clinical Trial Results With Single-Pill Combinations (Precious Clinical Trial)
The PRECIOUS clinical trial was designed to assess the treatment response in men and women to perindopril/amlodipine and perindopril/amlodipine/indapamide dual and triple SPCs by evaluating a conventional measure of treatment efficacy such as BP control. (10)
This 16-week interventional, open-label, prospective, international, multicenter clinical trial assessed 440 adults with essential hypertension. It was conducted in seven countries, including Croatia, from which 53 patients were recruited. The clinical results were not evaluated separately for each country. (11,12) Analysis of sex- and age-related differences was conducted for 399 patients: 254 men and 145 women aged 35-74 years. Patients under 35 and over 74 were excluded due to insufficient numbers for comparison. (10)
At inclusion, naïve or patients uncontrolled on previous mono or dual therapy other than perindopril and amlodipine were assigned to the dual SPC arm with an initial dose of 4/5 mg perindopril/amlodipine (P/A). Patients uncontrolled on previous dual or triple therapy were assigned to the triple SPC arm with an initial dose of 4/5/1.25 mg perindopril/amlodipine/indapamide (P/A/I) (Figure 1). If office BP control was not achieved, the initial dose was up-titrated in 4-week intervals to 8/5 mg, 8/10 mg P/A, or 8/10/2.5 mg P/A/I in the dual SPC arm and to 8/5/2.5 mg or 8/10/2.5 mg P/A/I in the triple SPC arm. Office BP was measured with a validated automated BP-measuring device by qualified health professionals following the ESH guidelines protocol. Ambulatory blood pressure measurement (ABPM) was performed at baseline and at the end of the trial (Mobilograph PWA).
After only 4 weeks, a significant decrease in office BP was observed (-16.1/-10.1 mmHg) from the mean baseline. (11) By the end of the study (after 16 weeks), mean office BP in the dual SPC arm decreased from 156.3±10.9/98.6±8 mmHg to 128.4±9.4/81.7±7.2 mmHg, and decreased in the triple SPC arm from 157.9±12.6/97.5±9.5 mmHg to 127.7±11.4/80.3±7.5 mmHg (in 16 weeks) (Figure 2). (12) Absolute office systolic blood pressure (SBP) and diastolic blood pressure (DBP) reductions were higher in women in all age groups. However, sex differences were not statistically significant. (10) The proportion of patients reaching BP control increased with each visit. (11) At the end of the trial (after 16 weeks) 75% of men and 87% of women achieved office BP control with the SPC treatment strategy (Figure 3). (10)
After 16 weeks, an average 24 h SBP decrease was observed in the dual SPC arm, from 142.9±9.6 mmHg to 125.0±9.8 mmHg, whereas a decreased was observed in the triple SPC arm from 147.3.9±11.8 mmHg to 124.3±10.2 (Figure 2). (12) Similarly to office BP, the absolute reductions in 24 h BP were higher in women, but the sex differences were not statistically significant. In total, 68% of men and 76% of women achieved target 24 h SBP. BP control rates were higher for office BP than for 24 h SBP in both sexes, due to the lower rate of success for 24 h DBP (Figure 3). (10)
The PRECIOUS clinical trial also reported results on central systolic blood pressure (cSBP), a relevant prognostic risk factor, for which data about control with SPC were lacking. After 16 weeks, the average cSBP decreased from 132.1±9.4 mmHg to 115.4±8.9 mmHg in the dual SPC arm and from 135.8±11.1 mmHg to 114.7±9.8 mmHg in the triple SPC arm. All BP reductions were statistically significant (p < 0.001) (Figure 2). (12) A reduction of cSBP below 120 mmHg was achieved by 68% of men and 73% of women (Figure 3). (10)
Discussion
BP control remains the main clinical goal in the management of patients with hypertension. (6) Currently, despite various available treatment strategies, fewer than ¼ of patients treated for hypertension in Croatia achieve adequate BP control. (2) Effective BP management is essential for reducing the risk of cardiovascular events and improving overall CV health in both men and women. (6)
The results of the PRECIOUS trial demonstrate that the perindopril-based treatment strategies – dual SPC (perindopril/amlodipine) and triple SPC (perindopril/amlodipine/indapamide) – result in effective reduction of office BP, leading to high rates of office BP target achievement in men and women after four months of treatment.
Another important focus of the PRECIOUS trial was the assessment of the efficacy of the studied medications in lowering 24 h BP. ABPM constitutes a valuable supplement to office BP results in the assessment of the efficacy of antihypertensive treatments strategies. (6) In the PRECIOUS trial, statistically significant as well as clinically meaningful reductions in 24 h BP were observed after four months of active treatment, leading to high rates of 24 h SBP control in both sexes.
Favorable outcomes in office BP and 24 h BP target achievement and reductions were further supported by the clinically significant decrease in 24 h cSBP observed in this trial. Previous studies have demonstrated that central BP in patients with hypertension is pathophysiologically more relevant than brachial BP, as cSBP is more strongly associated with HMOD and is a better predictor of CV events. However, relevant data on life outcomes are still missing. Antihypertensive drugs exhibit differential effects on central and brachial BP. (13) The PRECIOUS trial demonstrated that cSBP statistically significantly decreased to <120 mmHg. A high percentage of patients achieved cSBP control, confirming the BP-lowering benefits of perindopril-based SPC treatment.
Overall BP reduction was greater and faster in women, especially in younger women compared with same-aged men. This could be due to a better response in women to the selected antihypertensives or to the regulation of BP by different physiological mechanisms. (14) Irrespective of the BP parameter examined (office BP, 24 h BP, cSBP), women achieved better overall BP control. Similarly, the IDEAL trial, which included 122 naïve patients with hypertension, demonstrated that indapamide and perindopril led to a greater reduction of office SBP in women. (15) Additionally, treatment with amlodipine was associated with a stronger antihypertensive effect in women. (16)