Hindawi International Journal of Hypertension Volume 2018, Article ID 8681792, 14 pages https://doi.org/10.1155/2018/8681792

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

Jamshed Dalal ,1 J. C. Mohan,2 S. S. Iyengar,3 Jagdish Hiremath,4 Immaneni Sathyamurthy,5 Sandeep Bansal,6 Dhiman Kahali,7 and Arup Dasbiswas8

1 Centre for Cardiac Sciences, Kokilaben Dhirubhai Ambani Hospital, Mumbai, India 2Fortis Hospital, Shalimar Bagh, New Delhi, India 3Manipal Hospital, Bangalore, India 4Ruby Hall Clinic, Pune, India 5Apollo Hospitals, Chennai, India 6Department of Cardiology, VMMC & Safdarjung Hospital, New Delhi, India 7BMBirlaHeartResearchCentre,Kolkata,India 8NRS Medical College and Hospital, Kolkata, India

Correspondence should be addressed to Jamshed Dalal; [email protected]

Received 19 November 2017; Accepted 8 April 2018; Published 20 May 2018

Academic Editor: Tomohiro Katsuya

Copyright © 2018 Jamshed Dalal et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Calcium channel blockers are among the frst-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. Tis 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. Efcacy and safety of S-AM in HTN in comparison to racemic amlodipine, used as monotherapy and in combination with other antihypertensives, efcacy in angina, and pleiotropic benefts with S-AM, are discussed in this review.

1. Introduction R- and S-isomers of amlodipine, S-enantiomer has nearly 1000 times greater afnity for the receptor site. Further, S- Management of hypertension (HTN) involves diferent ther- amlodipine (S-AM) has less variable PK, lower intrasubject apeutic approaches. Among the medications for treating variation, and longer half-life [5]. S-AM is equally efcacious HTN, calcium channel blockers (CCBs) are one of the frst-line agents as recommended by recent Joint National at half-dose with better tolerability and lesser incidence of Committee 8 (JNC-8) guidelines [1]. Besides efcacy, occur- peripheral edema than racemic amlodipine (Amlo) [6]. rence of adverse efects (AEs) plays an important role in S-AM is marketed world-wide. Te central drugs stan- maintaining adherence with medications [2]. Occurrence of dards control organization (CDSCO), India, approved S-AM peripheral edema is the major reason for poor adherence on 16 August 2002 for its use in HTN [7]. Globally, S-AM with amlodipine. Te Anglo-Scandinavian Cardiac Out- hasbeenapprovedandisbeingusedincountrieslikeChina comes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) [8], Korea [9], Ukraine [10], Philippines [11], and Nepal [12]. [3] reported peripheral edema in 23% patients receiving Besides these, S-AM is marketed in nearly 47 countries [13]. amlodipine. Tis suggests that nearly 1 out of 4 patients Since S-AM approval in China (1999) [14] and in India (2002) treated with amlodipine may develop peripheral edema. [7], it has been studied extensively. As being researched for Conventionally used amlodipine is a mix of S- and R- nearly two decades, we performed an in-depth review of enantiomers. Development of separate enantiomers improves clinical evidence of S-amlodipine and provided key summary pharmacokinetics (PK) and avoids undesirable AEs [4]. From with identifcation of areas for further research. 2 International Journal of Hypertension

2. Search Methodology and Literature Details groups and proportion of individual AEs was nearly equal in both doses. Tis perpetuates that S-AM can be safely used of We performed search using terms “S-Amlodipine” or high-dose of 5 mg per day with incremental efcacy. “levamlodipine” across electronic databases like PUBMED, All nine observational studies were monotherapy trials Google Scholar, and clinical trials registry, http://www (Table 2). In these, racemic amlodipine was comparator in .clinicaltrials.gov. Additionally, a general search at Google four studies, lercanidipine in one, and cilnidipine in one trial. search engine was performed. Clinical studies including Four studies were single arm trials with no comparator. Four randomized trials and observational and postmarketing stud- studies without any comparator, the safety and efcacy of ies before June 2017 were included in the review. Journals S-amlodipine (SESA) studies, were the postmarketing trials articles available only as print copies were also included in that reported signifcant BP reduction with signifcantly less the review. For non-English literature articles, information or no occurrence of pedal edema in Indian hypertensive available from the abstracts was captured. patients (Table 2) [21–24]. Occurrence of edema with S-AM in Afer an extensive search, we included total 42 studies. comparison to Amlo and cilnidipine was evaluated in another In these, 26 were RCTs (20 monotherapy and 6 combination observational study from India. Incidence of peripheral studies), 14 were observational studies (13 monotherapy stud- edema with S-AM and cilnidipine was signifcantly lower ies and 1 combination study) and two were meta-analyses. than racemic amlodipine in males (6.7% and 0.0% versus �=18 From these, a maximum number of studies ( )were 36.7%, resp.) and in females (10.0% and 3.3% versus 43.3%, from China followed by 11 from India, 6 from Korea, 3 each resp.) (� < 0.001 for both drug comparisons in either gender) from Russia and Ukraine, and one from Sri Lanka. Combined (Table 2) [25]. from all the studies, over 7400 patients had received S-AM S-AM was also assessed in combination with other anti- either alone or in combination with other antihypertensives. hypertensives like atenolol [26, 27] and telmisartan [28, 29] In these studies, racemic amlodipine was the major com- and in patients receiving both angiotensin converting enzyme parator in 26 studies and in two meta-analyses as well. As inhibitor or angiotensin receptor blocker (ACEI/ARB) and monotherapy and/or combination therapy, other compara- beta blocker (BB) [16]. In studies of combination with tor molecules from 10 studies were lercanidipine (Lercan), atenolol and ACEI/ARB + BB, S-AM had similar antihyper- nifedipine sustained release (Nifed-SR), cilnidipine (CLD), tensive efcacy compared to racemic amlodipine (Table 1). ramipril (Rami), enalapril (Enala), losartan (Los), telmisartan However, in two separate studies, combination of S-AM (Telmi), and indapamide. In fve observational studies, there and telmisartan (40–80 mg) was associated with greater BP was no comparator to S-AM. In two combination studies, the reduction compared to monotherapy of telmisartan 80 mg combination treatment was compared to S-AM monotherapy. or S-AM 2.5 mg (Table 1). Tolerability of telmisartan-based combinations was reported to be similar or better than the 3. S-Amlodipine in Hypertension comparative monotherapy treatments (Table 1). In a meta-analysis (Table 3) of 15 trials, Liu et al. [30] ForitsuseinHTN,S-AMhasbeenevaluatedinvarious reported similar efect of S-AM (2.5 mg) on BP compared to RCTs (total 22) and observational studies (total 9) either as racemic amlodipine (5 mg). From three high-quality RCTs monotherapy (total 25) or in combination (total 6 RCTsonly). included in the meta-analysis, weighted mean diference Two meta-analyses were performed in 2010 and 2015 with 15 (WMD) of SBP and DBP was −2.84 (95% confdence interval and 8 studies of S-AM (levamlodipine), respectively. Major (CI), −6.42 to 0.74) and −1.71 (95% CI, −3.48 to 0.06), fndings from the RCTs, observational studies, and meta- respectively, afer 4-week treatment (one RCT) whereas it analyses are summarized in Tables 1, 2, and 3, respectively. was −1.13 (95% CI, −5.29 to 3.03) and −1.34 (95% CI, −2.67 Most of these studies were comparing S-AM (2.5 to 5 mg) to –0.01), respectively, afer 8-week treatment (two RCTs). to racemic amlodipine (5 to 10 mg) and found near equal Further, S-Amlo was associated with signifcantly less edema antihypertensive efcacy with lower incidence of side efects. than racemic amlodipine (risk diference, –0.02; 95% CI, Two RCTs especially evaluated ankle (peripheral) edema with −0.03 to 0.00). Another meta-analysis performed recently by S-AM in comparison to Amlo and reported signifcantly Zhao and Chen [31] involving 1456 patients from eight studies lower incidence of edema with better tolerability of S-AM [15, reported that levamlodipine (S-AM) was efcacious (odds 16]. Besides racemic amlodipine, S-AM was compared to ler- ratio (OR) 2.19, 95% CI 1.61–2.97; � < 0.01)andsafer(OR canidipine [17, 18] and ramipril [19] in three trials. S-AM had 0.51, 95% CI 0.34–0.77; � < 0.01) than racemic amlodipine. nearly similar efcacy and tolerability to lercanidipine. How- Tus, available evidence from RCTs, observational studies, ever, its efcacy and safety were better than that of ramipril and meta-analyses fnds equivalent BP lowering efcacy of (Table 1). A study from Chen et al. [20] needs a special men- S-AM against racemic amlodipine with better tolerability. tion as they compared higher-dose (5 mg) to the lower-dose Incidence of pedal edema is found to be signifcantly lesser (2.5 mg) of S-AM (Table 1). Afer 8-week treatment, 24-hour with S-AM than racemic amlodipine. ambulatory systolic BP (SBP) reduction was signifcantly greater in 5 mg group than in 2.5 mg of S-AM (between group 4. S-Amlodipine in Angina diference: 2.1 mmHg, � = 0.02). However, 24-hour diastolic BP (DBP) reduction was similar (between group diference: Te antianginal efects of racemic amlodipine are known. 0.9 mmHg, � = 0.17). Interestingly, the incidence of overall Systemic vasodilation with reduction aferload reducing car- AEswassimilar(20.0%versus17.0%,resp.,� = 0.05)inboth diac workload and dilatation of coronary vasculature and International Journal of Hypertension 3 A NR AEs None None None None Number: 1 vs 6 No signifcant diferences No diference, milder with S-AM − 13.4 − 15.0 12.47 9.28 ± ± − 22.32/ − 22.24/ − 13.05 − 19.24/ t N − 13.08 vs − 13.63 vs − 25.24 − 14.56 n − 14.17 vs e l − 13.68 − 13.24 a v i 8.9 vs u − 22.6/ 12.72 vs 131.74 − 19.22/ − 24.21/ − 13.18 vs Amlo) Amlo) Amlo) − 13.76 vs 11.55 vs − 27.13/ q − 14.31 vs − 13.95− 19.69/ vs ± − 26.86/ 14.17 vs Equivalent Equivalent ± − 21.6/ 13.44 − 12.76 − 19.14/ − 13.33 − 19.24/ − 21.96/ − 23.06/ − 14.28 − 22.04/ Mean change in − 22.84/ − 20.16/ − 19.87/ − 14.73 Supine: Sitting: Supine: Antihypertensive efcacy Standing: Standing: − 24.27 Standing: S-AM non-inferior to Amlo SBP: 156.26 to 131.50 vs 158.23 to DBP: Amlo: 164.30/99.30 to 134.10/85.61 S-AM: 165.30/98.22 to 132.70/81.87 DBP: 98.48 to 83.28 vs 99.18 to 83.19 Mean change of SBP/DBP (S-AM Vs Mean change of SBP/DBP (S-AM Vs Mean change of SBP/DBP (S-AM Vs SBP: Sitting: Supine: Sitting: 5 8 8 8 6 6 6 4E 40 (weeks) Duration � 44 97/91 25/25 25/25 30/30 36/36 58/60 60/60 140/140 (mg) Comparator Table 1: Randomized controlled trials of S-amlodipine in hypertension. 2.5 Amlo (5) 2.52.5 Amlo (5) Amlo (5) 2.5 Amlo (5) 2.5 Amlo (5) 2.5 Amlo (5) (mg) 2.5–5 Amlo (5–10) 2.5–5 Amlo (5–10) 2.5–5 Amlo (5–10) S-AM India India India Korea China China China China China Country Author (year) Monotherapy Studies (n =16) Liu et al. (2001) [44] Fang (2002) [45] Cheng et al. (2002) [46] Hiremath and Dighe (2002) [47] Kerkar (2003) [48] Pathak et al. (2004) [49] Zhang (2006) [50] Bae et al. (2008) [51] Zhu et al. (2008) [52] 4 International Journal of Hypertension ) ) � = 0.028 ) AEs None − 70.26 mL, 0.02 ( �<0.009 18.03% ( �<0.05 Milder with S-AM 17.0% vs 20.0 ( � = 0.05 ) edema with S-AM (AFV 5.8% vs 14.2% ( � = 0.012 ) Lower with S-AM: 6.56% vs Edema signifcantly lower with S-AM: mean change AC: 0.26 vs Signifcant improvement in ankle diference: 5.81 8.68 11.89 14.5 ± 7. 3 8 ± ± 11.96 ± ± ± − 12.0 − 26.9 − 10.88 − 12.93 − 9.6 − 19.93 − 26.82 − 14.3 − 13.4 vs � < 0.05 ) − 32.4 vs 7. 02 v s 8.07 vs 6.94 vs (� ≤ 0.003) 13.6 vs 8.76 vs 7. 9 1 v s groups ± ± ± ± ± ± Equivalent ( � = 0.047 ) ( � = 0.023 ) ( � = 0.172 ) ( � = 0.091 ) Mean change Mean change Mean change 61.4% ( � = 0.017 ) 87.3% 80.33% ( − 12.7 SBP&DBP: 75.7% vs SBP: 81.8% vs 90.8% DBP: 84.0% vs 94.2% − 18.1 − 20.5 − 14.71 − 14.03 Target BP achievement: − 21.82 SBP: 6.0 vs 8.1 ( � = 0.02 ) Antihypertensive efcacy DBP: 3.8 vs 4.7 ( � = 0.17 ) SBP change: DBP change: Overall response rate: 91.8% vs DBP: BP normalization rate: 81.3% vs SBP: sSBP: Signifcant reduction in BP in both sDBP: sDBP: sSBP: 8 8 8 8 12 12 NA (weeks) Duration ∗ Table 1: Continued. � 61/61 32/29 54/54 68/70 90/90 17/17 263/260 (mg) Lercani Comparator 2.5 Rami (2.5–5) 2.5 2.5 Amlo (5) 2.5 S-AM (5) NA Nifed-SR (mg) 2.5–52.5–5 Amlo (5–10) Amlo (5–10) S-AM India Korea Korea Korea China China China Country # Author (year) Youn et al. (2010) [17] Kim et al. (2011) [19] Shengye (2012) [53] Oh et al. (2012) [15] Zhao (2013) [54] Parvathi et al. (2014) [55] Chen et al. (2017) [20] International Journal of Hypertension 5 NA AEs Amlo )&patientrated 22.6% ARR: 15.1% � = 0.0086 ), 14.29% No diference: 21.9% vs 31.3% Number: 8 vs 16 46.51% ( � = 0.0301 ); ( � = 0.0632 )vs27.87% ( �=0.038 9.52% ( New pitting edema: 31.40 vs edema score ( � = 0.036 )with chlorthalidone 12.5 mg was added to Increase in pitting edema score No diferences: 18.6%, 20.0% vs # < 90: − 5.79 only females; ∗ − 4.55 − 2.44 − 4.93 − 1.76 < 90 mmHg: − 5.3 − 12.7 < 140 or − 4 square mean, Nifed-SR: nifedipine sustained release, NA: not for both) elmisartan; volume, Amlo: racemic amlodipine, ARR: absolute risk reduction, − 9.58 vs − 12.32 vs − 13.79 vs − 10.72 vs − 3vs − 7. 3 v s < 140 or 98.68% − 15.9 vs �− 5.61 = 0.0028 )and At 24 weeks ( � < 0.0001 ) ( � < 0.0001 ) HR: Mean change SBP: 40 vs 40 DBP: 28 vs 34 − 8.12, LSM reduction − 9.67, 5/40 vs S-AM 2.5 DBP: − 12.89, − 10.56, At 12 and 24 weeks SBP: ( � < 0.0001 2.5/40 & 5/40 Vs T80 24-h DBPV and SBPV ( � = 0.0003 ) vs 28.33% − 4.73 ( � = 0.0002 )and − 4.34 ( Antihypertensive efcacy 35.59%, 40.68% vs 11.86% DBP: Non-signifcant diference DBP: SBP: SBP: Diferences in mean change: with S-AM than Indapamide 60.32% ( � = 0.0004 ), 60.66% Signifcantly lower morning SBP, Achieving target BP SBP: Achieving BP Lower 24-h DBPV, day-time SBPV DBP: Responders Rate: Similar- 98.57% vs Mean NP change in groups: 2.5/40 & 8 8 16 24 12–24 (weeks) Duration � Table 1: Continued. 83 32/32 76/70 Total: 31 63/63/61 61/60/62 (mg) Comparator 2.5 S-AM 2.5 2.52.5 Amlo (5) Amlo (5) NA Indapamide (mg) 2.5–5 Amlo (5–10) S-AM 2.5 & 5 T (80) India Korea Korea China Russia Country Sri Lanka Author (year) Combination Studies (n =6) Rajanandh et al. (2013) [26] [+Atenolol 50 mg] Maksimova et al. (2013) [27] [+Atenolol] Hu and Xiao (2013)[S-AM + [56] Irbesartan vs Indapamide + Irbesartan] Ihm et al. (2016) [28] [Telmisartan + S-AM FDC (CKD-828): 2.5/40 and 2.5/80] Park et al. (2016)[Telmisartan [29] + S-AM FDC: 2.5/40 and 2.5/80 mg] Galappatthy et al. (2016) [16] [ACEI/ARB + BB] AT: atenolol, BB: beta blocker, BP: bloodavailable, NR: pressure, DBP: not diastolic reported, BP, RRR: DBPV: DBP relative variability, risk FDC: reduction, fxed-dose RR: combination, risk HR: reduction, heart S-AM: rate, S-amlodipine, LSM: SBP: least systolic BP, SBPV: SBP variability, and T: t AC: ankle circumference, ACEI/ARB: angiotensin converting enzyme inhibitor/angiotensin receptor blocker, AEs: adverse efects, AFV: ankle-foot treatments if BP remained uncontrolled with study medications. 6 International Journal of Hypertension AEs None None Rate: 1.61% versus 7.8% Edema: 1.77% Edema: 0.75% Lesser with S-AM Lower with lercani Incidence of Edema 93% cases, RRR: 95.4% Peripheral edema; 1.6% Reduction in pedal edema: F: 10.0% vs 43.3% and 3.3% M: 6.7% vs 36.7% and 0.0% − 14.0 − 29.2 for both for both on, Lercani: lercanidipine, M: males, MAP: mean arterial (� < 0.0001) − 3.51 − 13.30 (� < 0.0001) − 26.65 (� < 0.0001) in NR 84.2% HR: SBP: Daytime BP − 13.7 versus DBP: < 140/90: 83.3% versus − 30.7 versus Nighttime BP − 13.28 − 4.87 Daytime MAP − 24.27 Nighttime MAP Equal efcacy in Average daily BP HTN with obesity � < 0.0001 � < 0.0001 lower dose of S-AM 5mg:179/107to137/86 HR: SBP: DBP: 2.5 mg: 161/100 to 129/84 Antihypertensive efcacy SBP: DBP: 5 mg: 165.78/95.55 to 132/82.22 Target of Equal BP reduction with 2 times Similar efcacy in reducing BP in DBP: 99.1 to 77.5 versus 87.2 to 78.4 2.5 mg: 150.48/92.28 to 128.57/80.86 In both groups, signifcant reduction SBP: 154.4 to 1304 versus 157.6to 132.4 4 4 12 NA NA (weeks) Duration � 1859 31/32 5: 345 2.5: 1514 60/60/60 12 nidipine, DBP: diastolic BP, F: females, HR: heart rate, HTN: hypertensi - and CLD (mg) Amlo (10–20) Comparator Amlo (5–10) Table 2: Observational studies of S-amlodipine in hypertension. 5 Amlo (10) 10/10 NA NA Lercani NA (mg) 2.5–5 2.5–52.5–5 -2.5–5 - 2230 - 1076 4 30 4 4 2.5–5 S-AM 2.5–10 Amlo (5–10) 60/38 India India Country Author (year) SESA (2003) [21] SESA-II (2005) [22]SESA-IV (2007) [23] India SESA-IVA (2007) [24] India India Bobrof et al. (2007) [57] Ukraine Basu (2007) [58] Sierkova et al.(2009) [59]Koval et Ukraine al. (2013) [18]Mohanty et al. (2016) [25] Russia India AEs: adverse efects, Amlo: racemic amlodipine, BP: blood pressure, CLD: cil pressure, NA: not available, RRR: relative risk reduction, S-AM: S-amlodipine, SESA: safety and efcacy of S-Amlodipine, and SBP: systolic BP. International Journal of Hypertension 7 − 0.04 − 0.04; High (� < 0.01) AEs Similar; quality: OR 0.51 RD: all trials: Signifcantly lower rate of AEs: − 1.71 (� < 0.01) amlodipine, and SBP: systolic BP. − 2.84/ − 1.38/ − 1.33 8weeks: 4weeks: decrease in SBP/DBP at All trials: Similar efcacy Antihypertensive efcacy Amlo: OR 2.19 Only high-quality trials: WMD for Signifcantly better efcacy of S-AM than NA 4–40 (weeks) Duration � 15 trials 8trials:732/724 Table 3: Meta-analyses of S-amlodipine in hypertension. (mg) Comparator 2.5 Amlo (5) NA Amlo (mg) S-AM Country Author (year) Liu et al. (2010) [30]Zhao and Chen (2015) China [31] China AEs: adverse efects, Amlo: racemic amlodipine, BP: blood pressure, DBP: diastolic BP, NA: not available, OR: odds ratio, RD: risk diference, S-AM: S- 8 International Journal of Hypertension reduction in cardiac oxygen consumption underlie the relief added to enalapril is associated with further improvements in anginal cases. Being an isomer of amlodipine, S-AM in endothelial function than enalapril alone in HTN. Tis has also shown efcacy in angina. In SESA-Angina study was probably because of more pronounced reduction in (2005) [32] conducted in India, patients of ischemic heart endothelin-1 (ET-1) level afer treatment with two drugs disease (IHD) with history of angina and positive stress test (3.86 ± 0.24 to 1.95 ± 0.19 pg/mL, � < 0.05)comparedto (�=25) were included. No other concomitant treatments enalapril alone (3.32 ± 0.27 to 1.83 ± 0.21 pg/mL, � < 0.05). were allowed during the treatment period of 8 weeks. S- Terefore, though there remains uncertainty about possible AM (2.5–5 mg/d) treatment was associated with signifcant mechanisms, S-AM may exert some protection efect on reduction in average number angina attacks in every 15 endothelium by improving eNOS levels and reducing ET-1 days (� < 0.0001) and signifcant improvement in anginal levels [37]. symptoms (94.1%). Afer treatment, there was signifcant increase in exercise capacity (� < 0.0001) and nonsignifcant 5.2. Efect on Structure and Function of Lef Ventricle increase in time required for 1.5 mm ST-segment depression and Brachial Artery. Iskenderov and Saushkina (2013) [38] (� = 0.1764)andmaximumworkloadachieved(� = 0.1170). assessed S-AM (�=61) and Amlo (�=66)instages1-2HTN No AEs were reported in any patient. Tis emphasizes efcacy patients using lef ventricular (LV) and brachial artery struc- and safety of S-AM in management of angina. tural and functional parameters. Afer 24-week treatment, S- AM was associated with comparable BP reduction to Amlo, 5. S-Amlodipine and Pleiotropic Benefits but the mean dose was signifcantly lower (7.5 ± 0.8 versus 11.6 ± 1.4 mg/day; � < 0.01). Signifcant improvement in 5.1. Efect on Arterial Stifness and Endothelial Function. Ef- LV structure and function and brachial artery function were cacy of S-AM for change in arterial stifness and endothelial reported. Reductions in atherogenic lipoproteins and total functionwasassessedinfourRCTs[33–36]andinone cholesterol were also signifcant with S-AM. observational study [37]. In a 12-week randomized study, Liangjin et al. (2013) [33] compared levamlodipine (S-AM, 5.3. Efcacy in Renal Transplant Patients. Tang et al. (2003) �=40 2.5–5 mg, ) to nifedipine sustained release (Nifed- [39] observed that, in kidney transplant patients with HTN �=40 SR, 10 mg, ) for its efect on BP variety ratio (BPVR) (�=20), S-AM (2.5 to 5 mg) treatment for 2 months was and CIMT. Compared to baseline, systolic and diastolic associated with signifcant reduction in SBP (� < 0.01), DBP BPVR was signifcantly better with S-AM than Nifed-SR at (� < 0.01), and blood nitrogen (� < 0.05)withnoincrease 12 weeks. CIMT was reduced signifcantly with S-AM (�< � > 0.05 0.05 of serum creatinine ( ). Normalization of BP was ) but not with Nifed-SR (Table 4). Tere was signifcant reported in 85% of patients. correlation of BPVR with CIMT in S-AM group. Changes in lipid parameters and C-reactive protein were nonsignifcant 5.4. Efcacy in Insulin Resistance. In a randomized, in both groups. double-blind, prospective cohort study in type 2 diabetes One RCT [34] reported signifcant improvements in fow (T2D) patients, Xiao et al. [40] compared efects of S-AM mediated dilatation [FMD] afer 6-week treatment with S- (2.5–5 mg/d, � = 112) and losartan (50–100 mg/d, � = 115) AM and racemic amlodipine. Continued treatment for 12 afer treatment for 36 months (156 weeks). Tey had followed weeks was found to lower serum cholesterol equally in both patients at frst, second, and third year of the study. Diference groups. Guo et al. [35] reported signifcant improvements in the reduction in SBP and DBP at the end of 12 months was in the central BP components, brachial-ankle pulse-wave statistically signifcant between two groups. However, there velocity (PWV), ambulatory arterial stifness index (AASI), andthevariabilityofambulatoryBPinbothS-AMand were no signifcant diferences between the groups when racemic amlodipine treatment. However, both treatments assessed at the end of 24 or 36 months. Change in fasting werenotassociatedwithsignifcantchangesinCIMT.Tus, insulin levels (mIU/L) and insulin sensitivity index (ISI) was the benefts with S-AM on vascular function are similar signifcant with both S-AM and losartan by the end of 3 years � < 0.05 to those exerted by racemic amlodipine. In another 6- ( ). Tis establishes equivalent efcacy of S-AM to week, randomized, crossover trial, Si et al. [36] reported an ARB, losartan in improvement of insulin sensitivity in that FMD%, nitric oxide (NO) and endothelial nitric oxide patients with HTN and impaired fasting glucose. synthase (eNOS) levels were signifcantly improved in both groups with no between treatment diferences. Increase in 5.5. Efect on Platelet Aggregation. In patients of HTN and NO levels in cultured human umbilical vein endothelial cells T2D, Li et al. (2013) [41] studied efect of levamlodipine on was signifcant with both treatments but more marked in platelet aggregation and expression of matrix metallopro- Amlo. Authors concluded that, with S-AM, probably antihy- teinase (MMP) 9 and MMP 2. In 32 patients treated, platelet pertensive efect is the cause of improved vascular function aggregation maximal assessed by coagulation instrument and S-AM may exert its protective efect on endothelial TYXN-91A reduced signifcantly (� < 0.05)from47.77 ± function by unknown mechanism. However, a 6-month study 11.92 (pretreatment) to 40.78±13.97 (posttreatment). Platelet which assessed efects of S-AM (5–10 mg/d) and enalapril inhibition rate was 13.50 ± 25.23%. Tere was no efect on (10–20 mg/d) combination compared to enalapril alone on levels of MMP 9 and MMP 2. Tis study highlights that S- endothelial dysfunction in patients with chronic pulmonary AM has potential to prevent platelet aggregation in high-risk heart disease (CPHD) and HTN (�=65)observedthatS-AM patients like HTN with T2D. International Journal of Hypertension 9 0.33 ± � = 0.01 ) 0.28 ( � < 0.05 ) � = 0.01 ) ± 4( ± for both) for both) for both) 0.31 to 1.22 ± FMD% baPWV � < 0.0001 ) 4to3 ± ambulatory BP 0.41 to 1.08 (all CIMT (per mm) Pleiotropic efect ( � < 0.01 ( � < 0.01 ( � < 0.01 ± central BP components Signifcant improvements in � /L:20to26(Amlo)and24(S-AM) CIMT: No signifcant changes Amlo: 6.7% to 6.8% ( S-AM: 4 Nifed-SR: 1.23 � mol/L: 42 to 62 (Amlo) and 59 (S-AM) FMD%: 5.7 to 8.0 (Amlo) and 7.3 (S-AM) S-AM: 1.24 eNOS NMD%: 13.6 to 12.9 (Amlo) and 14.1 (S-AM) NO ambulatory arterial stifness index variability of ± ± 2.7 1.9 for for ± ± for both) for both) for both) 1.9to9.8 to 12.1 2.9 to 13.7 ± ± � < 0.001 A 1.8 to 8.5 ± both) both) ( � < 0.05 ) ( � < 0.05 ) 3.2 ( � > 0.05 ) 2.5 ( � > 0.05 ) 14.7 ± 3.1 SBPVR (mmHg) DBPVR (mmHg) Amlo: 152.21/93.3 to S-AM: 153.88/94.03 to Antihypertensive efcacy 132.59/81.96 ( � < 0.001 133.22/82.47 ( (S-AM) ( � < 0.01 (S-AM) ( � < 0.01 (S-AM) ( � < 0.05 S-AM: 10.2 Nifed-SR: 10.2 HR:76to72(Amlo)and73 DBP: 95 to 81 (Amlo) and 82 Nifed-SR: 14.8 S-AM: SBP: 162 to 132 (Amlo) and 131 6 6N × 12 24 6 (weeks) Duration � 24 60 40/40 126/106 Table 4: Pleiotropic efects of S-amlodipine. (10) (mg) Nifed-SR Comparator 2.5 Amlo (5) 2.5 Amlo (5) NA Amlo (mg) 2.5–5 S-AM China China China China Country Author (year) Efect on Arterial stifness and EndothelialRCTs function Liangjin et al. (2013) [33] Zhang et al. (2003) [34] Guo et al. (2012) [35] Si et al. (2014) [36] [crossover trial, 2-week washout] 10 International Journal of Hypertension ± ± 25.23 ± 0.27 to 1.83 0.24 to 1.95 ± 13.97 ( � < 0.05 ) ± � < 0.05 ± � < 0.05 cases insulin function � max) of bloodstream in BA 20.2 cm/sec) 31.6 cm/sec), Pleiotropic efect lipoproteins and TC 0.21 pg/mL, 0.19 pg/mL, 11.92 to 40.78 Improved renal function No efect on MMP levels Speed of retrograde wave: S-AM was associated with - ± Changes in endothelin-1 levels (i) initial (19.6 and 14.3 cm/sec) (i) initial (22.8 and 17.6cm/sec) Normalization of BP in 85% cases Increase in insulin sensitivity index Signifcant reduction in atherogenic (i) Combination: 3.86 (ii) afer reactive hyperaemia (41.7 and (ii) afer reactive hyperaemia (25.9 and 47.77 Platelet inhibition rate (%): 13.5 Complete regression of LVH: 51% cases (ii) Enalapril alone: 3.32 Signifcant improvement in BA vasomotor Reduced platelet aggregation maximal (%): Combination therapy had greater changes in (iii) post-occlusive dilatation (5.2% and 3.4%) Maximal speed ( Normalization of LV diastolic function: 62.4% In both groups, signifcant reduction in fasting rea nitrogen, CIMT: carotid intima media thickness, DBP: : lef ventricular hypertrophy, MMP: matrix metalloproteinase, ratio, RD: risk diference, S-AM: S-amlodipine, SBP: systolic BP, � < 0.05 ) � < 0.01 ) NR NA � < 0.01 ) SBP ( DBP ( BUN ( lower dose of S-AM Signifcant reduction in Antihypertensive efcacy andsimilarinbothgroups BP reduction was signifcant Comparable BP reduction at 8 24 24 156 NA (weeks) Duration Table 4: Continued. � 32 20 33/32 61/66 112/115 hase, FMD: fow-mediated dilation, HR: heart rate, LV: lef ventricle, LVH erine-mediated dilatation, NO: nitric oxide, NR: not reported, OR: odds o l m (mg) (50–100) Losartan Comparator -A NA - 5–10 E (10–20) (mg) 2.5–5 Amlo 2.5–5 S-AM China China China Russia Ukraine Country Author (year) Observational study Nestorovich (2013) [37] [S-AM + Enalapril versus enalapril] Efect on LV and BA function Iskenderov and Saushkina (2013) [38] Efcacy in renal transplant cases Tang et al. (2003) [39] Efect on insulin resistance [RCT] Xiao et al. (2016) [40] Efect on platelet aggregation and expression of MMP 2 and MMP 9 Li et al. (2013) [41] NA: not available, Nifed-SR: nifedipine sustained release, NMD: nitroglyc SBPVR: SBP variety ratio, and TC: total cholesterol. AEs: adverse efects, Amlo: racemic amlodipine, BA: brachial artery, baPWV: brachial artery pressure wave velocity, BP: blood pressure, BUN: blood u Diastolic BP, DBPVR: DBP variety ratio, eNOS: endothelial nitric oxide synt International Journal of Hypertension 11

6. S-Amlodipine and Pedal Edema 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% CCBs are associated with a considerable risk of peripheral and 10.3% in two groups, respectively. Tus, study suggests oedema that may reduce patient compliance or necessitate S-Amlo is more cost-efective than racemic amlodipine. switching to a diferent drug. It has been now well-established that S-AM is associated with lower incidence of pedal edema 8. Summary and improved compliance to therapy as evident from studies discussed above. Of note is a recent RCT from Galappatthy Compared to racemic amlodipine, S-AM had equivalent anti- et al. (2016) [16] where the incidence of leg edema was hypertensive efcacy at half-dose. Evidence suggests efcacy the primary outcome assessed. Patients uncontrolled with of S-AM in 24-hour ambulatory BP reduction, including � = 172 BB and ACEI/ARB ( ) were randomized to S-AM day-time and nigh-time BP reduction. It was also found to �=86 �= 2.5–5 mg ( ) and racemic amlodipine 5–10 mg ( be efective in nocturnal HTN showing its efectiveness in 86 ). With S-AM, absolute risk reduction of new edema was nondippers. Meta-analyses showed equivalent efcacy of S- 15.1%, relative risk reduction was 32.47%, and number needed AM compared to racemic amlodipine with similar or lower to treat was seven (NNT = 7). In SESA trial, edema was rates of AEs. Signifcantly lower incidence of peripheral resolved in 98.72% patients afer switching from racemate edema suggests a better tolerability of S-AM and absolute amlodipine to S-AM [21]. In SESA-II study done in 2230 risk reduction of 15.1% in peripheral edema is seen. Other- patients with HTN, incidence of pedal edema was reported wise, overall incidence of AEs was nearly similar with two in 41.90% patients who were taking racemic amlodipine treatments. Compared to cilnidipine, incidence of edema before switching over to S-AM [22]. When patients were was found to be nearly similar with S-AM, whereas it switched over to S-AM, resolution of pedal edema was was signifcantly lesser in both drugs when compared to noted in 93.07%. Overall incidence of pedal edema was racemicamlodipine.Higher-doseS-AM(5mg)wasmore 1.92%withS-AMandtherelativeriskreductionofpedal efective and equally safe as that of lower-dose (2.5 mg). In edema afer S-AM switch was 95.4%. Tus, the evidence combination with telmisartan, atenolol, and enalapril, S-AM convincingly suggests minimal incidence of edema with S- showed greater antihypertensive efect with better safety and AM compared to racemate amlodipine. Te confrmatory tolerability. Besides HTN, S-AM was found efective and evidence is observed in a meta-analysis of 15 RCT of S- safe in angina. It lowers numbers of attacks and improves � = 907 AM where Liu et al. [30] reported that S-AM ( ) symptoms.S-AMhadshownBPloweringefcacyinrenal was associated with signifcantly less edema than racemic transplant cases with no signifcant adverse efect on func- � = 897 − amlodipine ( ) (risk diference [RD], 0.02; 95% CI, tional renal parameters. − � = 2.20 � = 0.03 0.03 to 0.00; test for overall efect: ; ). Besides being potent antihypertensive, S-AM showed Higher incidence of pedal edema is likely to result in various pleiotropic benefts. Tese include improvement higher degree of discomfort. Terefore, use of chirally pure in endothelial function, slowing of CIMT progression or S-AM would be advantageous due to lower incidence of reversal of increased CIMT, improvement in arterial stifness, edema which could result in improved adherence to therapy regression of LVH and improvement in LV diastolic function, and hence optimum BP control. Amlodipine causes mainly improvement in lipid profle, improvement in insulin sensi- precapillary vasodilatation without proportional increase of tivity, and reduction in platelet aggregation. postcapillary blood fow, which leads to peripheral edema. Analysis from China identifed S-AM as the cost- Although R-amlodipine does not have calcium channel efective therapy with economic savings compared to racemic blocking properties, it reduces activity of postural vaso- amlodipine. pressor refex, which increases the pressure in capillary vessels that activates egress of fuid into surrounding tissues. 9. Limitations Studies have shown that nitric oxide (NO) released by the inducible nitric oxide synthase is responsible for development Although we did extensive search of literature, there is likely of edema. R (+) amlodipine is involved in local NO formation chance of missing on non-English literature not covered through the kinin pathway and this may lead to loss of under the databases searched. Most of the non-English the precapillary refex vasoconstriction and development articles were available as abstracts only. of edema when racemate mixture is used. S-AM at any concentration was not found to release NO and does not 10. Conclusion afect postural vasopressor refex [42]. An equivalent antihypertensive efcacy to racemic amlodip- 7. S-Amlodipine and Cost-Effectiveness ine with lesser or negligible peripheral edema proves S- amlodipine as a cost-efective treatment option in HTN. It is From China, Hu et al. (2014) [43] conducted a retrospective efective, safe, and well-tolerated in combination with other cost-efectiveness analysis from two multicentre RCTs of S- antihypertensivesaswell.BesidesHTN,itsefcacyinangina AM (2.5 mg/d, � = 110) and Amlo (5 mg/d, � = 104). With makes it suitable agent in patient with both comorbidities. 4–8 weeks of treatment, efcacy rate of both drugs was similar Pleiotropic benefts like improvement in endothelial function (84.91% and 77.45%,resp.). Cost fgures observed for 1 mmHg and insulin sensitivity show its promise in patients with reduction with S-AM and Amlo were 8.1 Yuan (∼1.2 $) and comorbidities like diabetes. Given its positive efects on BP, 12 International Journal of Hypertension endothelial function, platelet aggregation, insulin sensitivity, [10] “SAMLOPIN., Instructions for medical use. Approved. Te Order and atherogenic lipids, S-AM is likely to lower the adverse of Ministry of Health of Ukraine,” http://www.gladpharm.com/ cardiovascular outcomes. Te evidence from this review images/mod catalog prod fles/24311/Samlopin tabl insert eng clearly suggests that S-amlodipine may be considered as one 03.06.2016.pdf. of the frst-choice antihypertensive in patients with HTN [11] “Amlobes – S(-)amlodipine besylate 5 mg tablet,” VerHeiLen including those with heightened cardiovascular risk. Future GmbH - Farma Iberica, http://farmaiberica.com/products/amlobes/. research should focus on cardiovascular outcomes with S-AM [12] R. Paudel, P. Kishore, P. Mishra, S. Palaian, and B. C. Dwari, in patients with HTN and other comorbidities. “Urticarial Skin Reaction Induced by Oral Clonidine,” Journal of Pharmacy Practice and Research,vol.36,no.3,pp.218-219, 2006. 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