Effects of Azelnidipine versus Amlodipine on LV Mass and Longitudinal Function in Hypertensive Patients with LVH
Left ventricular hypertrophy (LVH) is the structural remodelling of the heart which is a serious consequence of systemic hypertension. It is a precursor of a variety of cardiovascular diseases collectively called as Hypertensive heart diseases (1,2) and a potent predictor of myocardial infarction, stroke, as well as cardiovascular death in hypertensive patients.
Various conditions such as hypertension or aortic stenosis can cause pressure overload on heart which leads to the addition of sarcomeres and increase in myocyte width thus increasing wall thickness and leading to Hypertrophy. Clinically patients with LVH may remain in compensatory phase or near-normal reserve for years and others may transition to heart failure (3).
Generally, electrocardiogram, echocardiogram, cardiac MRI are few of the diagnostic modalities used to detect LVH (1). Advanced techniques like Tissue doppler imaging (TDI) and 2D Speckle tracking echo (STE) are the extended Echo techniques which give more insights than the conventional techniques. To overcome the limitations of TDI and 2D STE, a novel technique called the 3D STE was also developed (4) to detect LVH.
Hypertensive patients with LVH are usually treated by cautious combination therapy of β-adrenergic blockers, angiotensin-converting enzyme inhibitors (ACEI), low-dose diuretics, long-acting calcium-channel blockers (CCB), and long-acting nitrates. However, previous studies have found that no significant differences existed between ACEI or CCB when used for the management of LVH (5).
Animal models have shown that LV macrophage infiltration and LV fibrosis was significantly inhibited by two long-acting CCBs - Azelnidipine and Amlodipine. But in the animal models Azelnidipine has shown a greater cardiac remodeling effect than Amlodipine (6).
In 2014, Hirohiko Motoki et al conducted a study to investigate the serial improvement in LV mass and function after initiation of azelnidipine in hypertensive patients with LVH and compared the same with amlodipine therapy using conventional and STE.
Even though Various trials were conducted in the past comparing Azelnidipine and Amlodipine and their impact including the AORTA trial, AORTA II trial, CALVOLOC trial, and AGENT trial, this study was different as it compared the two drugs amlodipine and azelnidipine using echocardiography.
Amlodipine:
Amlodipine is a long-acting calcium channel blocker (CCB) used as an antihypertensive and anti-angina drug, acts by relaxing the smooth muscle in the arterial wall, decreasing peripheral resistance, and hence improving blood pressure (7). It was developed by of Dr. Simon Campbell.
Azelnidipine:
Azelnidipine is a dihydropyridine calcium channel blocker, first marketed by Daiichi-Sankyo pharmaceuticals, Inc. in Japan. It has a gradual onset of action and leads to a long-lasting decrease in blood pressure (BP), with only a small increase in heart rate (8).
Methodology of the study and Protocol:
Thirty-two essential hypertensive patients with LVH based on history, physical examination, and laboratory findings (systolic BP >140 mmHg and/or diastolic BP >90 mmHg) were prospectively enrolled in this study. LVH was determined by the echocardiographic criteria of LV mass index (LVMI) of >115 g/m2 in men or >95 g/m2 in women and a relative wall thickness (RWT) >0.42.
Inclusion criteria were patients not having clinical evidence of heart failure; coronary artery disease; congenital or valvular heart disease; or any systemic disease such as diabetes mellitus or connective tissue disorders that had the potential to induce changes in LV structure and function. Patients with prior treatment with CCBs or antihypertensive agents within 6 months of study initiation or having atrial fibrillation were excluded from the study.
To assess baseline cardiac function all participants were examined by standard 2D and Doppler echocardiography. After an initial assessment, an equal number of patients (16) were randomly assigned to two groups which administered 5 mg of amlodipine/day and 16 mg of azelnidipine/day. All 32 patients underwent follow-up examination with conventional echocardiography, TDI, and STE at 1, 3, 6, and 12 months after the initial assessment. LVEF and LV mass were estimated using the area length formula in accordance with the American Society of Echocardiography documentation on LV quantification. LVMI and RWT were also estimated.
LVMI = LV mass/body surface area.
RWT = (septal wall thickness + posterior wall thickness)/LV end-diastolic diameter
Peak velocities of early (E) and late-filling (A) waves, duration of A-wave, the E/A ratio, and deceleration time of the E-wave were measured from transmitral flow velocities. Peak velocities of the systolic (S), diastolic (D), and A waves (Ar), duration of Ar, and the D/S ratio were also measured from pulmonary venous flow. The time difference between Ar and mitral A-wave duration (Ar- A) was calculated to detect the age-independent variable of diastolic dysfunction.
Tissue Doppler Imaging:
An average of 3 consecutive cardiac cycles of peak systolic (s′), peak early diastolic (e′), and peak late diastolic (a′) velocities and E/e′ were measured.
Speckle Tracking Imaging:
All echocardiographic recordings were obtained, LV strain was evaluated in different views, and a region of interest was selected to approximate the myocardium between the endocardium and the epicardium to fit the wall thickness.
Statistical analysis of the difference between the groups was performed using the Student's t-test
Results:
The authors noted that the following results
• The mean age, gender, BMI, BP, heart rate, and brain-type natriuretic peptide (BNP) level were similar between 2 groups at baseline.
• Systolic and diastolic BP had decreased significantly in both groups by 1 month after initiation of treatment.
• Heart rate tended to decrease after treatment initiation in the azelnidipine group but not statistically significant in both the groups.
Conventional Echocardiographic Data:
• LV internal dimensions, left atrial diameter, LV wall thickness, RWT, and the LVEF did not significantly differ between the 2 groups.
• LV septal wall thickness decreased significantly after treatment initiation in both groups after 6 months.
• Plasma BNP levels had decreased to an equal extent in both groups by 12 months after treatment initiation.
• The LVM(I) of both groups had decreased significantly by 6 months after treatment initiation compared with baseline LVM(I).
• The effect of LVH regression did not significantly differ between the 2 groups. The 2 groups were experiencing diastolic dysfunction to a similar extent at baseline.
• The Ar-A duration was significantly decreased at 3 months after treatment initiation in both groups.
Tissue Doppler Flow Measurements:
• The e′ of the lateral mitral annulus was significantly improved in both groups at 12 months after treatment initiation.
Speckle Tracking Imaging:
• The global LV longitudinal strain had improved by 3 months after treatment initiation in both groups.
• The basal global circumferential strain improved at 3 months after treatment initiation.
Based on the above analysis the researchers observed that the subjects had been experiencing subclinical LV systolic dysfunction at baseline that was improved by long-acting CCB therapy, albeit without a parallel reduction in BP.
Thus, the researchers concluded that both azelnidipine and amlodipine therapy significantly induced regression in LV hypertrophy by 6 months after treatment initiation and maintained throughout the 12 months.
" Overall, the results of this study indicate the existence of subclinical LV dysfunction in patients with hypertensive LVH. However, CCB therapy can lead to significant and continuous longitudinal LV strain improvement, warranting early or long-term intervention for these patients. Such therapy can take the form of azelnidipine therapy, which appears to affect regression of LVH and improve longitudinal LV function in a manner comparable to that of amlodipine therapy," they said
Noting the limitations of the study, the authors stated that it did not follow a double-blinded trial design and all the subjects were asymptomatic patients with preserved LVEF, and thus the findings might not be applicable to patients with severe systolic heart failure
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Azelnidipine, click here
References:
1. Gradman AH, Alfayoumi F. From left ventricular hypertrophy to congestive heart failure: management of hypertensive heart disease. Prog Cardiovasc Dis. 2006;48(5):326-341.
2. Osler W: The principle and practice of medicine. New York: D. Appleton and Company, 1892, pp 628-635
3. Beverly H. Lorell, and Blase A. Carabello 2000. Left Ventricular Hypertrophy. Circulation, 102(4), p.470-479.
4. Baccouche H, Maunz M, Beck T, et al. Differentiating cardiac amyloidosis and hypertrophic cardiomyopathy by use of three- dimensional speckle tracking echocardiography. Echocardiography. 2012;29(6):668-677.
5. Yamamoto E, Lai ZF, Yamashita T, et al: Enhancement of cardiac oxidative stress by tachycardia and its critical role in cardiac hypertrophy and fibrosis. J Hypertens 2006;24: 2057–2069.
6. Devereux RB, Palmieri V, Sharpe M, et al: Effects of once-daily angiotension-converting enzyme inhibition and calcium channel blockade-based antihypertensive treatment on left ventricular hypertrophy and diastolic filling in hypertension: The prospective randomized enalapril study evaluating regression of ventricular enlargement
(PRESERVE) trial. Circulation 2001;104: 1248–1254
7. National Center for Biotechnology Information. PubChem Compound Summary for CID 2162, Amlodipine. https://pubchem.ncbi.nlm.nih.gov/compound/Amlodipine. Accessed Aug. 11, 2020.
8. National Center for Biotechnology Information. PubChem Compound Summary for CID 65948, Azelnidipine. https://pubchem.ncbi.nlm.nih.gov/compound/Azelnidipine. Accessed Aug. 11, 2020.
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