Beyond Amlodipine—The Case for S-amlodipine as the First Choice Calcium Channel Blocker: An Expert Opinion from India

Aim

To understand the role of S-amlodipine and its combinations for the treatment of hypertension and related cardiovascular (CV) disorders in the real-world setting in India.

The Evidence for Pedal Edema with Amlodipine

Pedal edema with amlodipine is the major cause of treatment discontinuation, with its dose-dependent occurrences. At a dose of 10 mg per day, the pedal edema is about 10.8%. ¹¹ Amlodipine induces precapillary vasodilatation without a relative elevation of postcapillary blood flow, contributing to peripheral edema development. Although R-amlodipine lacks calcium channel-blocking properties, it attenuates postural vasopressor reflex activity. This results in elevated capillary pressure and subsequent fluid egression into the surrounding tissues, as illustrated in Figure 1 . ¹² Research has demonstrated that the release of nitric oxide (NO) mediated by inducible NO synthase plays a key role in edema development. Moreover, R (+) amlodipine enhances the local NO production via the kinin pathway. This process results in the attenuation of precapillary reflex vasoconstriction, which contributes to the development of edema, particularly with the administration of a racemic mixture. ¹³

Fig. 1:

In the SESA-II study involving 2230 patients with hypertension, 41.90% of patients taking racemic amlodipine reported pedal edema. ¹⁴

The Advantage of S-amlodipine and Clinical Evidence of Benefits of Switchover from Amlodipine to S-amlodipine

S-amlodipine does not cause the release of NO. The use of chirally pure S-amlodipine reduces the incidence of edema, potentially enhancing therapy adherence and hence achieving optimum blood pressure (BP) control. S-amlodipine at any concentration does not trigger the release of NO and has no impact on the postural vasopressor reflex. ¹³

In the study by Galappatthy et al., S-amlodipine demonstrated a 15.1% absolute reduction in the risk of developing new edema, along with a 32.4% reduction in relative risk as compared to amlodipine. ⁷ In the SESA trial, 98.72% of patients reported resolution of edema after being switched from the racemic amlodipine to S-amlodipine. In the SESA II trial, 93.07% of patients noted the resolution of pedal edema after switching to S-amlodipine, with a 95.4% decrease in the relative risk of pedal edema. ¹⁴

In a meta-analysis by Liu et al. (15 RCTs of S-amlodipine), S-amlodipine ( n = 907) was found to be associated with a significantly reduced incidence of edema compared with racemic amlodipine ( n = 897) ( p = 0.03). ¹⁵

Expert Opinion

The discontinuation OR for CCBs was 1.08, and that was the least discontinued antihypertensive. ARB was 0.92, whereas for the most discontinued antihypertensive, diuretics was 1.83. ¹⁶ S-amlodipine does not cause pedal edema. In fact, switching patients of amlodipine who develop pedal edema to S-amlodipine is helpful to improve patient compliance.

However, it would be prudent to initiate treatment with S-amlodipine itself rather than amlodipine, which causes pedal edema.

The Evidence for Gingival Hypertrophy with Amlodipine

Amlodipine causes a rise in intracapillary pressure, both in the kidneys and in systemic circulation. Since arterial dilatation is not matched by venous dilatation, this results in increased intracapillary pressure, leading to the development of gingival hypertrophy. A common adverse event, such as amlodipine-induced gingival hyperplasia, was seen. Maintaining good oral hygiene practices is beneficial for prevention. ¹¹

Expert Opinion

S-amlodipine does not cause gingival hypertrophy, and this improves patient compliance. It would be prudent to replace amlodipine with S-amlodipine and initiate treatment with S-amlodipine instead of amlodipine in clinical practice.

2. How does the clinical efficacy of S-amlodipine compare with amlodipine?

S-amlodipine exhibits a dose-dependent lowering of BP. A single initial dose of S-amlodipine 2.5 mg is recommended and can be increased to 5 mg per day, based on the patient’s response. ¹⁷

S-amlodipine exhibits antihypertensive efficacy equivalent to that of amlodipine, as shown in Table 2 . In the study by Hiremath and Dighe, the standing, supine, and sitting BP reduction with S-amlodipine was greater than amlodipine, but the difference was not significant. As shown in Table 2 (also explained in Figure 2 ) the changes in BP across different positions were as follows: (standing BP: −24.21/−13.08 mm Hg vs −21.6/−13.44 mm Hg; supine BP: −27.13/−14.17 mm Hg vs −22.04/−13.68 mm Hg; sitting BP: −26.86/−14.17 mm Hg vs −23.08/−14.28 mm Hg). ¹⁸ Similar results were reported from other studies conducted in India, China, and Korea. S-amlodipine monotherapy effectively reduces BP in both treatment-naïve patients and patients treated with other antihypertensive drugs. ¹⁷ In the study by Kim et al. (Korean study) ( n = 251), pedal edema developed only in 0.8% of S-amlodipine-treated patients. ¹⁹

Fig. 2:

A study conducted by Chen et al. demonstrated that patients who had mild or moderate hypertension were randomly assigned to either of the two treatment groups, namely S-amlodipine low dose 2.5 mg/day or a high-dose S-amlodipine (5 mg/day) for 8 weeks. In the low-dose group ( n = 263), 24-hour ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP) showed a reduction from a baseline value of 131.5 ± 15.0/82.1 ± 10.7 mm Hg to 126.0 ± 13.5/78.5 ± 9.5 mm Hg at week 8. In the high-dose group ( n = 260), a reduction of BP values from 133.6 ± 13.7/83.1 ± 9.9 mm Hg at the baseline to 125.0 ± 12.0/78.2 ± 8.9 mm Hg was observed at the 8th week. Additionally, ambulatory and clinical BP measurements in daytime and nighttime demonstrated similar trends. Adverse events were comparable between both the low and high-dose groups. ²⁰

In a post-marketing, multicentric SESA-IV surveillance study ( n = 1076), S-amlodipine significantly reduced SBP and DBP along with a reduction in heart rate at the end of 30 days of treatment, as presented in Table 3 . ²³

S-amlodipine is an effective, safe, and well-tolerated treatment option for elderly patients. ²⁰

Expert Opinion

The experts opined that S-amlodipine is comparable in efficacy to amlodipine for treating patients with essential hypertension. S-amlodipine consistently lowers BP across different patient populations, such as young, elderly, and patients with CV risk factors.

3. Should S-amlodipine be prescribed as a first-line drug for hypertension?

Evidence

The recent evidence from clinical trials has demonstrated comparable efficacy of S-amlodipine and amlodipine. S-amlodipine 2.5 mg demonstrated efficacy and tolerability comparable to 5 mg of amlodipine in the management of mild to moderate hypertension. ²¹ In the SESA study ( n = 1859), S-amlodipine was reported to decrease SBP from 161 mm Hg at baseline to 129 mm Hg at day 28 and DBP from 100 mm Hg at baseline to 84 mm Hg at day 28. ²³ A subgroup analysis of the SESA study has demonstrated the efficacy of S-amlodipine in patients with isolated systolic hypertension ( n = 90) and also in the elderly population ( n = 339). The micro SESA-I study, which enrolled patients with isolated systolic hypertension, had a 21.5 ± 13.85 mm Hg reduction in SBP. ²⁴

The calculated global T/P ratio after the administration of S-amlodipine was determined by SBP as 0.75 and DBP as 0.65. This suggests that the duration of treatment of S-amlodipine was adequate and comparable with conventional amlodipine. In contrast, after a 12-week treatment period with conventional 5 mg amlodipine, the global T/P ratio was recorded at 0.56 for both SBP and DBP. S-amlodipine has a higher global T/P ratio than amlodipine. ¹⁹

Expert Opinion

The current practice of switching the patient from amlodipine to S-amlodipine when the patient develops pedal edema must be changed. The current evidence is in favor of initiating treatment with S-amlodipine instead of amlodipine in all eligible patients.

Treatment with S-amlodipine can be initiated with 2.5 mg once daily and then it can be titrated up to 5 mg daily. S-amlodipine is effective and safe both as monotherapy and in combination with other antihypertensive drugs.

Several advantages of S-amlodipine make it the drug of choice as compared to amlodipine. These include lesser pharmacokinetic variability, longer half-life, equal efficacy at a half dose of amlodipine, lesser metabolic load, improved tolerability, and reduced peripheral edema. ¹³

4. What is the effect of S- Amlodipine on BP variability?

Evidence

As shown in Table 4 and Figures 3 and 4 , S-amlodipine has been demonstrated to reduce 24-hour BP, daytime SBP, and nighttime SBP and DBP. ¹⁷

Fig. 3:

Fig. 4:

Expert Opinion

There is sparse data regarding the effect of S-amlodipine on BP variability.

5. What is the use of S-amlodipine in patients with comorbidities?

Evidence

In the SESA IV study, S-amlodipine consistently reduced SBP, DBP, and heart rate in patients with dyslipidemia, diabetes mellitus, and IHD, as shown in Tables 5 to 7 . ²³

In the study by Hiremath and Dighe, a daily dose of 2.5 mg S-amlodipine demonstrated a better effect on the lipid profile of the patients while maintaining its BP-lowering efficacy equivalent to a 5 mg daily dose of racemic amlodipine. ¹⁸

Similarly, in the study by Kerkar, 2.5 mg/day of S-amlodipine and amlodipine 5 mg/day have a comparable effect on lowering total cholesterol and triglycerides in hypertensive patients. ²¹

S-amlodipine at a dose of 2.5 mg/day and amlodipine at 5 mg/day demonstrated a similar reduction in left ventricular hypertrophy in 196 subjects with essential hypertension associated with single or multiple CV risk factors. ²⁵

S-amlodipine in Patients with Hypertension and Ischemic Heart Disease

Treatment of hypertensive patients with CAD with S-amlodipine normalizes the left ventricle diastolic function parameters and decreases end-diastolic pressure. ²⁶ As shown in Figure 5 , in the SESA angina study, 94.1% of patients had improvement in angina episodes. ²⁷

Fig. 5:

S-amlodipine in Patients with Hypertension and Cognitive Decline

S-amlodipine besylate treatment leads to improved cognition in patients with hypertension and cerebrovascular disease-associated cognitive decline. ²⁸

S-amlodipine vs Amlodipine Effects on Composite Major Cardiovascular and Cerebrovascular Events

The LEADER study ( n = 10,031) evaluated the effectiveness of levoamlodipine through an ECHO model with economic, clinical, and humanistic outcomes. Both drugs had comparable rates of composite major cardiovascular and cerebrovascular events (MACCE) (4.4 vs 5.2%). Levoamlodipine had fewer adverse events (6.0 vs 8.4%; p < 0.001). The patients without diabetes who received levoamlodipine maleate had fewer MACCE. ²⁹

Expert Opinion

The addition of S-amlodipine besylate at about 50% of the conventional dose of amlodipine improves tolerability by reducing the incidence of peripheral edema while maintaining antihypertensive efficacy comparable to standard-dose amlodipine.

S-amlodipine has been effectively used in obese hypertensive patients, patients with angina, and all stages of CKD. Although nephrologists are using benidipine and cilnidipine, they are less effective than S-amlodipine. S-amlodipine also provides the widest therapeutic window for these patients. S-amlodipine has stable and more predictable PK and pharmacodynamics compared to racemic amlodipine. It is a very safe drug to start with, and hopefully, S-amlodipine would add to that safety. The advantage for the nephrologist is that they use a high dosage of amlodipine, 10 mg, frequently. So, the peripheral edema with 5 mg of S-amlodipine will be far less, and there may be more usage of S-amlodipine with nephrologists.

6. What is your clinical experience in terms of safety and efficacy, as well as what is the ideal patient profile for the S-amlodipine + Telmisartan combination?

In the large post-marketing surveillance study conducted by Jo et al., 44,715 patients with hypertension who had received a telmisartan/S-amlodipine single-pill combination were studied. About 28,096 (62.8%) patients were treated with a combination of telmisartan 40 mg and S-amlodipine 2.5 mg, while 8,664 patients (19.4%) were treated with telmisartan 80 mg/S-amlodipine 2.5 mg, and 7,136 patients (16%) were treated with a combination of telmisartan 40 mg and S-amlodipine 5 mg. About 94.5% of patients reached the target BP. The SBP and DBP were reduced from 143.1 ± 16.1/88.1 ± 11.8 mm Hg to 129.6 ± 11.4/80.1 ± 9.0 mm Hg, with a difference of –13.5/–7.9 mm Hg ( p < 0.0001 for both). The treatments were well tolerated, and leg edema was reported by only 0.08% of patients. ³⁰

The TENUVA BP study compared the circadian efficacy of a combination of telmisartan 40 mg and S-amlodipine 2.5 mg (telmisartan 40/S-amlodipine 2.5) with telmisartan 80 mg (telmisartan 80) in patients with essential hypertension who were unresponsive to 2–4 weeks of treatment with telmisartan 40 mg. The combination of telmisartan 40 mg and S-amlodipine 2.5 mg was well tolerated and superior to telmisartan 80 in reducing 24-hour mean ambulatory BP in patients with essential hypertension who had inadequate response to telmisartan 40 mg alone. ³¹

Expert Opinion

The combination of S-amlodipine and telmisartan is a rational choice that is effective and safe in Indian patients.

7. What are the recommendations about combinations of S-amlodipine required today?

Combination therapy is often required to achieve target BP in patients with moderate hypertension. Single-pill combination therapies are associated with a lower pill burden and improved patient adherence to therapy. ³²

Expert Opinion

In order to treat stable angina more effectively, the experts opined that they perceive a need for metoprolol 50 mg as well as 100 mg in combination with S-amlodipine 5 mg.

Other combinations required in India, as discussed by the experts, were: triple combinations with S-amlodipine, S-amlodipine + telmisartan + hydrochlorothiazide, S-metoprolol 50 and 100 mg with 5 mg of S-amlodipine for stable angina, telmisartan 80 + S-amlodipine 2.5 mg, and 5 mg of S-amlodipine + ACEi.

8. What is the unmet requirement for the effective management of hypertension?

Expert Opinion

S-amlodipine works like an ARB in multiple situations, such as HF. However, there are no trials in hypertensive HF with S-amlodipine. It improves the metabolic profile of the patients. This is an added advantage for S-amlodipine. Secondly, in the real-world setting, we require S-amlodipine combination with beta-blockers such as metoprolol at different dosages.