S-Amlodipine: An Isomer with Difference—Time to Shift from Racemic Amlodipine

Calcium channel blockers are among the first-line drugs for treatment of hypertension (HTN). S-amlodipine (S-AM), an S-enantiomer of amlodipine, is available in India and in other countries like China, Korea, Russia, Ukraine, and Nepal. Being clinically researched for nearly two decades, we performed in-depth review of S-AM. This review discusses clinical evidence from total 42 studies (26 randomized controlled trials, 14 observational studies, and 2 meta-analyses) corroborating over 7400 patients treated with S-AM. Efficacy and safety of S-AM in HTN in comparison to racemic amlodipine, used as monotherapy and in combination with other antihypertensives, efficacy in angina, and pleiotropic benefits with S-AM, are discussed in this review.


Introduction
Management of hypertension (HTN) involves different therapeutic approaches. Among the medications for treating HTN, calcium channel blockers (CCBs) are one of the first-line agents as recommended by recent Joint National Committee 8 (JNC-8) guidelines [1]. Besides efficacy, occurrence of adverse effects (AEs) plays an important role in maintaining adherence with medications [2]. Occurrence of peripheral edema is the major reason for poor adherence with amlodipine. The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) [3] reported peripheral edema in 23% patients receiving amlodipine. This suggests that nearly 1 out of 4 patients treated with amlodipine may develop peripheral edema. Conventionally used amlodipine is a mix of S-and Renantiomers. Development of separate enantiomers improves pharmacokinetics (PK) and avoids undesirable AEs [4]. From

Search Methodology and Literature Details
We performed search using terms "S-Amlodipine" or "levamlodipine" across electronic databases like PUBMED, Google Scholar, and clinical trials registry, http://www .clinicaltrials.gov. Additionally, a general search at Google search engine was performed. Clinical studies including randomized trials and observational and postmarketing studies before June 2017 were included in the review. Journals articles available only as print copies were also included in the review. For non-English literature articles, information available from the abstracts was captured.
After an extensive search, we included total 42 studies. In these, 26 were RCTs (20 monotherapy and 6 combination studies), 14 were observational studies (13 monotherapy studies and 1 combination study) and two were meta-analyses. From these, a maximum number of studies ( = 18) were from China followed by 11 from India, 6 from Korea, 3 each from Russia and Ukraine, and one from Sri Lanka. Combined from all the studies, over 7400 patients had received S-AM either alone or in combination with other antihypertensives. In these studies, racemic amlodipine was the major comparator in 26 studies and in two meta-analyses as well. As monotherapy and/or combination therapy, other comparator molecules from 10 studies were lercanidipine (Lercan), nifedipine sustained release (Nifed-SR), cilnidipine (CLD), ramipril (Rami), enalapril (Enala), losartan (Los), telmisartan (Telmi), and indapamide. In five observational studies, there was no comparator to S-AM. In two combination studies, the combination treatment was compared to S-AM monotherapy.

S-Amlodipine in Hypertension
For its use in HTN, S-AM has been evaluated in various RCTs (total 22) and observational studies (total 9) either as monotherapy (total 25) or in combination (total 6 RCTs only). Two meta-analyses were performed in 2010 and 2015 with 15 and 8 studies of S-AM (levamlodipine), respectively. Major findings from the RCTs, observational studies, and metaanalyses are summarized in Tables 1, 2, and 3, respectively. Most of these studies were comparing S-AM (2.5 to 5 mg) to racemic amlodipine (5 to 10 mg) and found near equal antihypertensive efficacy with lower incidence of side effects. Two RCTs especially evaluated ankle (peripheral) edema with S-AM in comparison to Amlo and reported significantly lower incidence of edema with better tolerability of S-AM [15,16]. Besides racemic amlodipine, S-AM was compared to lercanidipine [17,18] and ramipril [19] in three trials. S-AM had nearly similar efficacy and tolerability to lercanidipine. However, its efficacy and safety were better than that of ramipril (Table 1). A study from Chen et al. [20] needs a special mention as they compared higher-dose (5 mg) to the lower-dose (2.5 mg) of S-AM (Table 1). After 8-week treatment, 24-hour ambulatory systolic BP (SBP) reduction was significantly greater in 5 mg group than in 2.5 mg of S-AM (between group difference: 2.1 mmHg, = 0.02). However, 24-hour diastolic BP (DBP) reduction was similar (between group difference: 0.9 mmHg, = 0.17). Interestingly, the incidence of overall AEs was similar (20.0% versus 17.0%, resp., = 0.05) in both groups and proportion of individual AEs was nearly equal in both doses. This perpetuates that S-AM can be safely used of high-dose of 5 mg per day with incremental efficacy.
All nine observational studies were monotherapy trials ( Table 2). In these, racemic amlodipine was comparator in four studies, lercanidipine in one, and cilnidipine in one trial. Four studies were single arm trials with no comparator. Four studies without any comparator, the safety and efficacy of S-amlodipine (SESA) studies, were the postmarketing trials that reported significant BP reduction with significantly less or no occurrence of pedal edema in Indian hypertensive patients (Table 2) [21][22][23][24]. Occurrence of edema with S-AM in comparison to Amlo and cilnidipine was evaluated in another observational study from India. Incidence of peripheral edema with S-AM and cilnidipine was significantly lower than racemic amlodipine in males (6.7% and 0.0% versus 36.7%, resp.) and in females (10.0% and 3.3% versus 43.3%, resp.) ( < 0.001 for both drug comparisons in either gender) ( Table 2) [25].
S-AM was also assessed in combination with other antihypertensives like atenolol [26,27] and telmisartan [28,29] and in patients receiving both angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) and beta blocker (BB) [16]. In studies of combination with atenolol and ACEI/ARB + BB, S-AM had similar antihypertensive efficacy compared to racemic amlodipine (Table 1). However, in two separate studies, combination of S-AM and telmisartan (40-80 mg) was associated with greater BP reduction compared to monotherapy of telmisartan 80 mg or S-AM 2.5 mg ( Table 1). Tolerability of telmisartan-based combinations was reported to be similar or better than the comparative monotherapy treatments (Table 1).

S-Amlodipine in Angina
The antianginal effects of racemic amlodipine are known. Systemic vasodilation with reduction afterload reducing cardiac workload and dilatation of coronary vasculature and

Effect on Arterial Stiffness and Endothelial Function.
Efficacy of S-AM for change in arterial stiffness and endothelial function was assessed in four RCTs [33][34][35][36] and in one observational study [37]. In a 12-week randomized study, Liangjin et al. (2013) [33] compared levamlodipine (S-AM, 2.5-5 mg, = 40) to nifedipine sustained release (Nifed-SR, 10 mg, = 40) for its effect on BP variety ratio (BPVR) and CIMT. Compared to baseline, systolic and diastolic BPVR was significantly better with S-AM than Nifed-SR at 12 weeks. CIMT was reduced significantly with S-AM ( < 0.05) but not with Nifed-SR (Table 4). There was significant correlation of BPVR with CIMT in S-AM group. Changes in lipid parameters and C-reactive protein were nonsignificant in both groups.
One RCT [34] reported significant improvements in flow mediated dilatation [FMD] after 6-week treatment with S-AM and racemic amlodipine. Continued treatment for 12 weeks was found to lower serum cholesterol equally in both groups. Guo et al. [35] reported significant improvements in the central BP components, brachial-ankle pulse-wave velocity (PWV), ambulatory arterial stiffness index (AASI), and the variability of ambulatory BP in both S-AM and racemic amlodipine treatment. However, both treatments were not associated with significant changes in CIMT. Thus, the benefits with S-AM on vascular function are similar to those exerted by racemic amlodipine. In another 6week, randomized, crossover trial, Si et al. [36] reported that FMD%, nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) levels were significantly improved in both groups with no between treatment differences. Increase in NO levels in cultured human umbilical vein endothelial cells was significant with both treatments but more marked in Amlo. Authors concluded that, with S-AM, probably antihypertensive effect is the cause of improved vascular function and S-AM may exert its protective effect on endothelial function by unknown mechanism. However, a 6-month study which assessed effects of S-AM (5-10 mg/d) and enalapril (10-20 mg/d) combination compared to enalapril alone on endothelial dysfunction in patients with chronic pulmonary heart disease (CPHD) and HTN ( = 65) observed that S-AM added to enalapril is associated with further improvements in endothelial function than enalapril alone in HTN. This was probably because of more pronounced reduction in endothelin-1 (ET-1) level after treatment with two drugs (3.86 ± 0.24 to 1.95 ± 0.19 pg/mL, < 0.05) compared to enalapril alone (3.32 ± 0.27 to 1.83 ± 0.21 pg/mL, < 0.05). Therefore, though there remains uncertainty about possible mechanisms, S-AM may exert some protection effect on endothelium by improving eNOS levels and reducing ET-1 levels [37].

Effect on Structure and Function of Left Ventricle and Brachial
Artery. Iskenderov and Saushkina (2013) [38] assessed S-AM ( = 61) and Amlo ( = 66) in stages 1-2 HTN patients using left ventricular (LV) and brachial artery structural and functional parameters. After 24-week treatment, S-AM was associated with comparable BP reduction to Amlo, but the mean dose was significantly lower (7.5 ± 0.8 versus 11.6 ± 1.4 mg/day; < 0.01). Significant improvement in LV structure and function and brachial artery function were reported. Reductions in atherogenic lipoproteins and total cholesterol were also significant with S-AM. [39] observed that, in kidney transplant patients with HTN ( = 20), S-AM (2.5 to 5 mg) treatment for 2 months was associated with significant reduction in SBP ( < 0.01), DBP ( < 0.01), and blood nitrogen ( < 0.05) with no increase of serum creatinine ( > 0.05). Normalization of BP was reported in 85% of patients.

Efficacy in Insulin
Resistance. In a randomized, double-blind, prospective cohort study in type 2 diabetes (T2D) patients, Xiao et al. [40] compared effects of S-AM (2.5-5 mg/d, = 112) and losartan (50-100 mg/d, = 115) after treatment for 36 months (156 weeks). They had followed patients at first, second, and third year of the study. Difference in the reduction in SBP and DBP at the end of 12 months was statistically significant between two groups. However, there were no significant differences between the groups when assessed at the end of 24 or 36 months. Change in fasting insulin levels (mIU/L) and insulin sensitivity index (ISI) was significant with both S-AM and losartan by the end of 3 years ( < 0.05). This establishes equivalent efficacy of S-AM to an ARB, losartan in improvement of insulin sensitivity in patients with HTN and impaired fasting glucose.

Effect on Platelet Aggregation.
In patients of HTN and T2D, Li et al. (2013) [41] studied effect of levamlodipine on platelet aggregation and expression of matrix metalloproteinase (MMP) 9 and MMP 2. In 32 patients treated, platelet aggregation maximal assessed by coagulation instrument TYXN-91A reduced significantly ( < 0.05) from 47.77 ± 11.92 (pretreatment) to 40.78±13.97 (posttreatment). Platelet inhibition rate was 13.50 ± 25.23%. There was no effect on levels of MMP 9 and MMP 2. This study highlights that S-AM has potential to prevent platelet aggregation in high-risk patients like HTN with T2D.

S-Amlodipine and Pedal Edema
CCBs are associated with a considerable risk of peripheral oedema that may reduce patient compliance or necessitate switching to a different drug. It has been now well-established that S-AM is associated with lower incidence of pedal edema and improved compliance to therapy as evident from studies discussed above. Of note is a recent RCT from Galappatthy et al. (2016) [16] where the incidence of leg edema was the primary outcome assessed. Patients uncontrolled with BB and ACEI/ARB ( = 172) were randomized to S-AM 2.5-5 mg ( = 86) and racemic amlodipine 5-10 mg ( = 86). With S-AM, absolute risk reduction of new edema was 15.1%, relative risk reduction was 32.47%, and number needed to treat was seven (NNT = 7). In SESA trial, edema was resolved in 98.72% patients after switching from racemate amlodipine to S-AM [21]. In SESA-II study done in 2230 patients with HTN, incidence of pedal edema was reported in 41.90% patients who were taking racemic amlodipine before switching over to S-AM [22]. When patients were switched over to S-AM, resolution of pedal edema was noted in 93.07%. Overall incidence of pedal edema was 1.92% with S-AM and the relative risk reduction of pedal edema after S-AM switch was 95.4%. Thus, the evidence convincingly suggests minimal incidence of edema with S-AM compared to racemate amlodipine. The confirmatory evidence is observed in a meta-analysis of 15 RCT of S-AM where Liu et al. [30] reported that S-AM ( = 907) was associated with significantly less edema than racemic amlodipine ( = 897) (risk difference [RD], −0.02; 95% CI, −0.03 to 0.00; test for overall effect: = 2.20; = 0.03).
Higher incidence of pedal edema is likely to result in higher degree of discomfort. Therefore, use of chirally pure S-AM would be advantageous due to lower incidence of edema which could result in improved adherence to therapy and hence optimum BP control. Amlodipine causes mainly precapillary vasodilatation without proportional increase of postcapillary blood flow, which leads to peripheral edema. Although R-amlodipine does not have calcium channel blocking properties, it reduces activity of postural vasopressor reflex, which increases the pressure in capillary vessels that activates egress of fluid into surrounding tissues. Studies have shown that nitric oxide (NO) released by the inducible nitric oxide synthase is responsible for development of edema. R (+) amlodipine is involved in local NO formation through the kinin pathway and this may lead to loss of the precapillary reflex vasoconstriction and development of edema when racemate mixture is used. S-AM at any concentration was not found to release NO and does not affect postural vasopressor reflex [42]. 10 Yuan (∼1.5 $) for SBP and 16.9 Yuan (∼2.5 $) and 21.7 Yuan (∼3.2 $) for DBP, respectively. Reported AEs were 4.6% and 10.3% in two groups, respectively. Thus, study suggests S-Amlo is more cost-effective than racemic amlodipine.

Summary
Compared to racemic amlodipine, S-AM had equivalent antihypertensive efficacy at half-dose. Evidence suggests efficacy of S-AM in 24-hour ambulatory BP reduction, including day-time and nigh-time BP reduction. It was also found to be effective in nocturnal HTN showing its effectiveness in nondippers. Meta-analyses showed equivalent efficacy of S-AM compared to racemic amlodipine with similar or lower rates of AEs. Significantly lower incidence of peripheral edema suggests a better tolerability of S-AM and absolute risk reduction of 15.1% in peripheral edema is seen. Otherwise, overall incidence of AEs was nearly similar with two treatments. Compared to cilnidipine, incidence of edema was found to be nearly similar with S-AM, whereas it was significantly lesser in both drugs when compared to racemic amlodipine. Higher-dose S-AM (5 mg) was more effective and equally safe as that of lower-dose (2.5 mg). In combination with telmisartan, atenolol, and enalapril, S-AM showed greater antihypertensive effect with better safety and tolerability. Besides HTN, S-AM was found effective and safe in angina. It lowers numbers of attacks and improves symptoms. S-AM had shown BP lowering efficacy in renal transplant cases with no significant adverse effect on functional renal parameters.
Besides being potent antihypertensive, S-AM showed various pleiotropic benefits. These include improvement in endothelial function, slowing of CIMT progression or reversal of increased CIMT, improvement in arterial stiffness, regression of LVH and improvement in LV diastolic function, improvement in lipid profile, improvement in insulin sensitivity, and reduction in platelet aggregation.
Analysis from China identified S-AM as the costeffective therapy with economic savings compared to racemic amlodipine.

Limitations
Although we did extensive search of literature, there is likely chance of missing on non-English literature not covered under the databases searched. Most of the non-English articles were available as abstracts only.

Conclusion
An equivalent antihypertensive efficacy to racemic amlodipine with lesser or negligible peripheral edema proves Samlodipine as a cost-effective treatment option in HTN. It is effective, safe, and well-tolerated in combination with other antihypertensives as well. Besides HTN, its efficacy in angina makes it suitable agent in patient with both comorbidities. Pleiotropic benefits like improvement in endothelial function and insulin sensitivity show its promise in patients with comorbidities like diabetes. Given its positive effects on BP, endothelial function, platelet aggregation, insulin sensitivity, and atherogenic lipids, S-AM is likely to lower the adverse cardiovascular outcomes. The evidence from this review clearly suggests that S-amlodipine may be considered as one of the first-choice antihypertensive in patients with HTN including those with heightened cardiovascular risk. Future research should focus on cardiovascular outcomes with S-AM in patients with HTN and other comorbidities.

Conflicts of Interest
The authors declare no conflicts of interest.