Impact of Azelnidipine treatment on left ventricular diastolic performance in patients with BP and mild diastolic dysfunction: CALVLOC trial

One of the most common forms of heart failure is Left Ventricular Diastolic Dysfunction. Patients with hypertension are at particular risk of heart failure. Left ventricular hypertrophy, myocardial fibrosis, and chronic heart failure due to diastolic dysfunction are some of the major risk factors for patients with hypertension. Use of anti-hypertensive drugs to treat diastolic dysfunction is one of the attractive methods to prevent heart failure in such patients.

With several classes of hypertension drugs being used for treating high BP, it becomes important to determine which of these would also be effective in heart failure

In various studies, antihypertensive drugs including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated effectiveness in the management of hypertension and prevention of secondary cardiovascular complications such as heart failure (1).

One of the most common antihypertensive drugs for controlling hypertension are calcium channel blockers (CCB). However, historically they have been at a disadvantage of not having a favourable effect on heart failure due to diastolic dysfunction.

In the various types of CCBs, Azelnidipine is a relatively newly developed calcium channel blocker. It is a dihydropyridine calcium channel blocker which was first marketed by Daiichi-Sankyo pharmaceuticals, Inc. in Japan. It has a gradual onset of action and produces a long-lasting decrease in blood pressure, with only a small increase in heart rate, and does not induce reflex tachycardia unlike some other calcium channel blockers (3).

Studies have shown that it has little or no effect on the sympathetic nerve system or the renin- angiotensin system because of its unique nature of membrane approach and may be beneficial in mild essential hypertension (2).

Azelnidipine which is a unique long-acting L type CCB, cancels the reflectivity of sympathetic nerve hyperactivity (4). This suppresses the sympathetic nerve activity of the central, through the rostral ventrolateral medulla (RVLM) (5,6). It has reno-protective, cardioprotective, Cerebro-protective, insulin resistance improving features and anti-atherosclerotic effects (7).

In 2009, Hiroshi Ito et al (8) conducted a study to investigate the impact of lowering BP using azelnidipine. The study also, in particular, aimed to study its effects on diastolic function left ventricular filling pressure in patients with preserved ejection fraction and diastolic dysfunction by assessing non-invasive indices derived from the echo-Doppler study. Known as the Calvloc trial, this was the first clinical trial that showed a potential mechanism by which treating hypertension with azelnidipine might be useful to treat hypertensive patients with diastolic dysfunction.

Methodology:

The study was conducted between January 2006 and October 2007. About 253 patients participated in the study. The inclusion criteria were participants of age 20-80 years who are with stage 1 or 2 essential hypertension were screened by assessing their systolic and diastolic function using echocardiography. Those patients with left ventricular ejection fraction of <50%, septal mitral annular relaxation velocity >8 cm/s, atrial fibrillation and the administration of calcium channel blockers other than amlodipine were excluded from the study. Patients were divided into 2 groups:

1. On patients not on antihypertensive drugs or any other antihypertensive drugs other than calcium channel blocker- 16 mg of azelnidipine was administered.

2. If amlodipine was used, it was stopped and substituted with 16 mg of azelnidipine.

Patients were assessed at 4–8week intervals for at least, 24 weeks, and underwent echocardiographic assessment at the end of the study.

All participants underwent echocardiographic screening for systolic and diastolic function before the start of azelnidipine treatment. The diastolic function was assessed by tissue Doppler imaging of septal mitral annular velocity during diastole. Blood and urine tests were done at baseline and at the end of the study. BP and heart rate were measured in a sitting position.

In the echo data analysis, Doppler echocardiographic assessment included the peak velocities of E and A wave on mitral pulsed-wave Doppler. Additional analyses included changes in the chamber dimensions and left ventricular ejection fraction, the ratio of peak mitral Doppler inflow velocities (E/A ratio) and the deceleration time of the E wave. Left ventricular mass was estimated from left ventricular dimension and was calculated as an index of body surface area in m2. The relative wall thickness was calculated as 2(posterior wall thickness in diastole)/ (left ventricular end-diastolic diameter).

The primary endpoint was a change in septal mitral annular velocity during diastole, the e velocity and the ratio of mitral inflow velocity to the é velocity (E/ é ratio). Secondary endpoint included differences in changes in blood pressure, heart rate, wall thickness, left ventricular mass index and left atrial volume index. Blood samples were collected for assessment of brain natriuretic peptide (BNP) and high sensitivity C-reactive protein along with additional exploratory blood analyses, and urine was collected for assessing the albumin concentration.

Results of the study:

The authors noted that out of 253 patients 232 could complete the study. The following results were found from the study:

Azelnidipine group:

• Out of 160 patients in the azelnidipine group, the systolic and diastolic blood pressures had decreased from baseline by 26- and 11-mm Hg, respectively.
• Heart rate decreased by 3 beats per minute in AZD group.
• There were no significant changes in left ventricular wall thickness, left ventricular mass index, ejection fraction or left atrial volume, serum creatinine level, urine albumin concentration and high-sensitivity C-reactive protein level from baseline to follow-up in the AZD group.
• The e velocity significantly increased, E/ é ratio and BNP decreased significantly.

Amlodipine to azelnidipine group:

• Out of 72 patients, the systolic and diastolic blood pressures were observed to have decreased by 14- and 6-mm Hg, respectively.
• Heart rate decreased by 6 beats per minute.
• The E/ e ratio decreased, but the difference did not reach statistical difference.
• There were no changes in the other echo-Doppler parameters, BNP level, serum creatinine level, urine albumin concentration and high-sensitivity C-reactive protein level at the follow-up.

By this study, the authors observed that, that lowering blood pressure with the additional use of azelnidipine is associated with an improvement in the left ventricular diastolic performance, a reduction in left ventricular filling pressure, and reduction in BNP level in patients with hypertension and with a preserved systolic function.

The researchers also found that patients in whom amlodipine was replaced with azelnidipine, blood pressure and heart rate significantly reduced, and these reductions was associated with an increase in the e velocity. The left ventricular hypertrophy is a factor that attenuates the beneficial impact of azelnidipine on the diastolic function and left ventricular filling pressure. Another major finding was the improvement in left ventricular diastolic function with azelnidipine treatment in patients with either no or mild left ventricular hypertrophy.

"Our data implicated that greater left ventricular mass index was associated with the smaller increase in the e¢ velocity and with the smaller decrease in the E/e¢ ratio during azelnidipine treatment. In the highest left ventricular mass index quartile, the increase in the e¢ velocity was minimal and the E/e¢ ratio did not decrease. Therefore, the improvement in left ventricular diastolic function with azelnidipine treatment is expected especially in patients with either no or mild left ventricular hypertrophy. Echocardiographic assessment of left ventricular hypertrophy is useful to predict the responder of azelnidipine treatment," the researchers stated

They also mentioned the mechanisms to explain the improvement in left ventricular diastolic function associated with azelnidipine treatment including the greater reduction in systolic blood pressure, reduced left ventricular systolic load, improved vascular function by the scavenging of free radicals were some of the mechanisms with which azelnidipine improved the diastolic function.

The authors concluded that Azelnidipine does not worsen heart failure state and can be safely used in hypertensive patients with diastolic dysfunction.

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Azelnidipine, click here

References:

1. Prendergast HM, Dudley S, Brown M, et al. Antihypertensive medications and diastolic dysfunction progression in an African American population. High Blood Press Cardiovasc Prev. 2014;21(4):269-274. doi:10.1007/s40292-014-0064-1

2. Arita M, Hashizume T, Tanigawa K, Yamamoto H, Nishio I. A new Ca-antagonist, azelnidipine, reduced blood pressure during exercise without augmentation of sympathetic nervous system in essential hypertension: a randomized, double-blind, placebo-controlled trial. J Cardiovasc Pharmacol 1999; 33: 186–192.

3. National Center for Biotechnology Information. PubChem Database. Azelnidipine, CID=65948, https://pubchem.ncbi.nlm.nih.gov/compound/Azelnidipine (accessed on July 18, 2020)

4. Kiuchi, S., Hisatake, S., Kabuki, T., Oka, T., Dobashi, S., Fujii, T., Hashimoto, H., Ikeda, T. (2017). Additional aministration of azelnidipine to general heart failure therapy improves cardiac sympathetic nerve function in patients with heart failure. The Cardiologist, 1, 45- 55

5. Kimura Y., Hirooka Y., Sagara Y., Sunagawa K., (2007) Long-acting calcium channel blocker, azelnidipine, increases endothelial nitric oxide synthase in the brain and inhibits sympathetic nerve activit,. Clinical and Experimental Hypertension, 29, 13-21.

6. Konno S., Hirooka Y., Araki S. et al., (2008) Azelnidipine decreases sympathetic nerve activity via antioxdant effect in the rostral ventrolateral medulla of strokeprone spontaneously hypertensive rats, Journal of Cardiovascular Pharmacology, 52, 555- 560.

7. Shewale VU, Aher SS, Saudagar RB, Azelnidipine: A Review on Therapeutic Role in Hypertension, Journal of Drug Delivery and Therapeutics. 2019; 9(3-s):1002-1005