Impact of Combination Therapy on Arterial Stiffness and Cardiac Function in hypertensive patients: Lessons from AORTA II Trial

Many Hypertension guidelines recommend the use of combination therapy with an angiotensin II receptor blocker (ARB) and a diuretic or an ARB plus a calcium channel blocker (CCB). (6)

Several studies have emphasized on targeting the central blood pressure (CBP) rather than brachial blood pressure for cardiovascular disease outcomes. Recent literature has also recommended that ARB in combination with CCB can improve the CBP better than ARB with a diuretic.

In 2011, Takeshi Takami and Yoshihiko Saito conducted a trial called AORTA trial to study the effects of combination drug therapy (olmesartan combined with either azelnidipine or amlodipine) on central blood pressure (CBP) and left ventricular mass index (LVMI) in hypertensive patients. They found that olmesartan/azelnidipine combination had greater effects on CBP and LVMI than olmesartan/amlodipine, even though the reduction in brachial BP was similar in both groups (5).

However, noting that LV hypertrophy and LV diastolic dysfunction are often associated with hypertension, and arterial stiffness is often aggravated in hypertensive patients(9), the authors decided to further evaluate and compare the effects of antihypertensive drugs on LV hypertrophy and LV diastolic dysfunction among different classes of antihypertensive drugs

With this background, in 2013, the same authors published another study, called the AORTA II (Azelnidipine plus OlmesaRTAn versus amlodipine plus olmesartan) that compared the effects of combination drug therapy (olmesartan/azelnidipine and olmesartan /amlodipine) on clinic-measured BP, heart rate (HR), CBP, LV hypertrophy, LV diastolic function, and arterial stiffness. They also identified the factors that are associated with improvements in LV hypertrophy and LV diastolic function. Brachial-ankle pulse wave velocity (baPWV) and the augmentation index (AIx) were also measured as indices of arterial stiffness and wave reflections.

Methodology:

Hypertensive patients aged 36–75 years were recruited at the Department of Internal Medicine at Clinic Jingumae (Kashihara, Japan) between March 2007 and January 2010. The researchers defined Hypertension as clinic-measured systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg on two different occasions.

The study was a 2-year, prospective, randomized, open-label parallel-group study. It consisted of a 12-week run-in period and a 2-year randomized treatment period. During the run-in period, patients were treated with olmesartan alone (20 mg/daily). Those who were already on antihypertensive drugs were switched to olmesartan monotherapy at the start of the run-in period.

After the 12-week run-in period, patients with a clinic-measured SBP ≥140 mmHg and/or DPB ≥90 mmHg were randomized (1:1) using the permuted block method to receive either azelnidipine (16 mg/day) or amlodipine (5 mg/day) as an add-on to ongoing olmesartan. Brachial BP, HR, CBP, AIx, baPWV, LVMI, and LV diastolic function (e′, E/e′ ratio, and E/A ratio) were measured at baseline, at 6 months, and 2 years of treatment

LV hypertrophy was determined as the LVMI, while LV dysfunction was measured in terms of e′, E/e′ ratio, and E/A ratio.

Measurement of CBP, AIx, and baPWV:

An automated tonometry system was used to record the pulse pressure waveform of the radial artery with the patient in the sitting position after a ≥5 min rest. The first and second systolic pressure components (SBP1 and SBP2) were determined from the pulse pressure waveform. SBP2 was used to measure CBP as SBP2 is similar to invasively measured aortic CBP. The AI was calculated using the formula (SBP2 − DBP)/ (SBP1 − DBP) × 100 and was normalized for an HR of 75 bpm (AIx) because it is influenced by the HR.

Arterial stiffness was measured as baPWV. Pulse waveforms of both forearms and both ankles were obtained after the patient had rested in the supine position for ≥5 min and were used to determine the baPWV.

Measurement of LVMI and LF diastolic function:

Standard M-mode echocardiography was performed to determine LVMI using the formula reported by Devereux et al. From the mitral flow velocity pattern, the peak velocities of the E and A waves on mitral flow velocity were measured, and the ratio of their peak velocities (E/A ratio) was calculated.

At least 30 patients per group were enrolled.

Results of the AORTA II trial:

For the purpose of the study, out of 113 patients in the run-in period, 54 were randomised to 2 groups of each add-on Azelnidipine and add-on amlodipine. Out of these 2 pts were excluded and hence 26 in each group were carried in the study. The researchers found that

• SBP, DBP, CBP, AIx (AI normalized for a heart rate of 75 bpm), baPWV, LVMI, and E/e′ ratio decreased significantly while e′ velocity and E/A ratio increased significantly in both groups from baseline to 6 months and 2 years of treatment.
• The changes in HR, CBP, AIx, baPWV, LVMI, E/A ratio, and E/e′ ratio over 2 years were significantly greater in the olmesartan/ azelnidipine group than in the olmesartan/amlodipine group throughout the 2-year period.
• Analysis of the entire study population showed that the change in the E/e′ ratio was significantly correlated with the changes in HR, CBP, AIx, baPWV, and LVMI.
• In analyses stratified by treatment group, the change in baPWV was independently associated with the change in the E/e′ ratio in the olmesartan/azelnidipine group but not in the olmesartan/amlodipine group.
• In analyses stratified by treatment group, the change in baPWV was independently associated with the change in LVMI and E/A ratio in both groups.

From the trial, the researchers found that improvements in CBP, AIx, baPWV, LVMI, E/e′, and E/A ratio were maintained at 2 years. Despite similar reductions in brachial BP in both groups, these factors continued to be significantly greater in the olmesartan/azelnidipine group than in the olmesartan/amlodipine group. The reduction in LVMI after 2 years of treatment was directly correlated with the reduction in CBP.

The authors observed that LVMI improved and it appeared to have resulted from the reduction in CBP. The reduction in baPWV was also independently associated with the reduction in LVMI. Reduction in baPWV led to a delay in pulse wave reflection and hence reduced cardiac afterload. The reduction in baPWV also appeared to be related to the improvement in LVMI.

The researchers also detected improvements in LV diastolic function and LVMI in the study.

Based on the results of the study, the researchers made the following important observations:

• The E/e′ ratio showed greater improvements in the olmesartan/azelnidipine group than in the olmesartan/amlodipine group throughout the 2-year study period.
• The baPWV, an indicator of arterial stiffness, was independently associated with the reduction in the E/e′ ratio, suggesting baPWV is a useful indicator of LV diastolic function.
• A reduction in the E/A ratio was an indicator of LV diastolic dysfunction
• The change in baPWV was independently associated with the change in E/A ratio.
• BP and HR decreased significantly and an increase in the e′ velocity was found in patients who switched from amlodipine to azelnidipine.

The results of the present study prompted the authors to conclude that olmesartan/ azelnidipine is significantly superior to olmesartan/amlodipine in reducing HR and in improving vascular stiffness and diastolic function.

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