Combined therapy in the treatment of early hypertension

In hypertension, target blood pressure can not be achieved with monotherapy in most patients. The guidelines of associations of drugs that can be used to start treatment, mentions only a combination of a beta-blocker with a diuretic. Use of polytherapy in these patients may be beneficial because it allows for quick reduction of the pressure to a normal level, and also improves the long-term pressure control. Previous studies comparing monotherapy treatment of complex included a short follow-up period (average 6 weeks) and were carried out numerically too small a group of patients characterized by severe hypertension, to be able to exclude symptomatic hypertension as a complication. Moreover, in most of these studies, patients underwent more complex group of monotherapy treatment than treatment started from the beginning of several drugs. To check whether the long-term blood pressure may depend on the initial treatment regimen, designed a study in which all patients at the end of the study applied the same treatment – a combination of amlodipine (US trade name: Norvasc) and aliskiren (brand name: Tekturna) – with half of them began therapy of 2 drugs six months earlier, and the others were treated with only one of those measures.

For the presented randomized, double-blind study enrolled patients ≥ 18 years of age, if their systolic blood pressure was 150-180 mm Hg and diastolic blood pressure below 110 mm Hg in the sitting position. After the first visit, patients underwent an initial period of study in which placebo and drug administration earlier was left on hold. This period lasted for two weeks or longer, as during the first two weeks failed to obtain the pressure values ​​for the inclusion into the study, or if they differed from the initial 20 mm of Hg. This phase is followed by three treatment periods of double-blind nature.

In the first period (weeks 0-16.), Half of the patients started monotherapy with aliskiren or amlodipine, and the other began – two drugs. In the second phase (16.-24.) All used the combination of amlodipine and aliskiren. In the third phase, all patients depending on their third pressure receiving drug – hydrochlorothiazide – or placebo. Primary end points were assessed at the end of the second phase. The third phase allowed to start long-term effect of treatment with combination therapy without maintaining the initial treatment regimen.

Enrolled in the study, patients were randomized 1:1:2 in relation to treatment: 150 mg aliskiren + placebo, 5 mg amlodipine + placebo or 150 mg aliskiren + amlodipine 5 mg. After 8 weeks the dose was doubled. After 16 weeks, all received a combination of 300 mg aliskiren and 10 mg amlodipine. After 24 weeks, patients used 12.5 mg hydrochlorothiazide or placebo if their systolic blood pressure was ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm ​​Hg. The study was terminated after 32 weeks. Blood pressure was measured in a sitting position at each visit, pulling the average of 3 measurements lasting ≥ 5 min. The aim of the study was to examine whether the initial treatment consisting of amlodipine and aliskiren monotherapy is better than any of these drugs with respect to systolic blood pressure after 8, 16 and 24 weeks. Secondary endpoints included the reduction in diastolic blood pressure after 16 and 24 weeks and a reduction in systolic blood pressure after 32 weeks.

Between 8 and 24 weeks following estimates systolic blood pressure: 25.3 mm Hg in the combination therapy group, 18.9 mm Hg in both groups alone. The difference between the groups, calculated using the least squares method (LSM), was 6.5 mm Hg (95% CI -7.7 to -5.3, p <0.0001). After 24 weeks, systolic blood pressure reduction was 27.4 mm Hg in the combination therapy group and 25.9 mm Hg in the monotherapy groups. LSM difference was -1.4 mm Hg (-2.9 to -0.05, p = 0.059). The average reduction in diastolic blood pressure at weeks 8-24. was as follows: 12.4 mm Hg in the combination therapy group, 8.7 mm Hg in the monotherapy groups. LSM value was -3.7 mm (95% CI -4.4 to -3.0, p <0.0001). Received a similar number of patients in both groups hydrochlorothiazide after 24 weeks (27% in the combination therapy group and 26% in the monotherapy). Despite the inclusion of this drug found a difference in pressure control in patients who responded to treatment between the treatment group and the group consisting of amlodipine [372 (62%) of 604 in the treatment group complex and 167 (53%) of 313 in the amlodipine group after 32 weeks ; p = 0.019]. Demonstrated similar pressure drops obtained with the combination therapy after 24 weeks in groups of both previously treated (28.2 / 13.4 mm Hg from baseline 162.4 / 92.1 mm Hg) and untreated patients (28.6 / 14 , six of 161.2 mm Hg / 93.6 mm Hg).

ACCELERATE test results indicate that patients randomly assigned to treatment groups consisting of initial use of aliskiren and amlodipine are characterized by significantly greater decreases in blood pressure after 24 weeks compared with those start-treatment with one of the medicines, wherein there is no increase in the number of adverse events or withdrawal from the study. When the inclusion of a second group, the drug alone, the pressure fell, but never not enjoying the initial value of combination therapy group. Although the difference in systolic blood pressure between the groups after 8 weeks polytherapy group was smaller than assumed before the test, 2.5 mm Hg, 95 percent confidence interval suggested that the persistent gap could not be neglected. Indeed, the benefits of starting combination therapy persisted in comparisons of monotherapy groups in the later weeks of observation. The ACCELERATE study clearly confirmed the benefits of initial combination therapy with the inclusion of patients with hypertension, which has also been shown in previous studies with shorter follow-up.

Interesting project study using consecutive endpoints allowed for the discovery of previously unexplored hypothesis concerning the compensation of response without splitting the alpha value between primary hypotheses. In contrast to other studies, the primary endpoint was evaluated at the time when all the patients received the maximum dose of the same drugs in order to determine the consequences of the original, not the current therapy. Although the primary advantage over monotherapy polytherapy was lower than expected, proved to be sufficient (in particular 2/1 mm Hg, compared to the group that initially amlodipine) to suggest that the initial choice of combination therapy has long therapeutic effect.

Prospective studies have shown that an increase in pressure up to 2/1 mm Hg, significantly increases the risk of, and reduction of the pressure value it decreases proportionally.

ACCELERATE study is an important step towards the routine use of combination therapy at baseline in patients with hypertension.