1. Introduction

An alarming increase in the prevalence of CVD over the past two decades has been observed in India. CVDs such as ischaemic heart disease and cerebrovascular such as stroke account for 17.7 million deaths and are the leading cause [1,2]. The course of ASCVD also appears to be more fulminant with higher mortality. Around 10- 25% of myocardial infarctions (MI) occur before the age of 40 in India, and more than half of all CAD-related deaths occur before the age of 50 [3,4,5]. The increased incidence of CAD in Asian Indians cannot be attributed directly to the common risk factors of dyslipidemia or hypertension. It is estimated that 60% of CAD cases in Indians have residual risk that may be explained by the high inflammatory indices including hs-CRP [3]. Guideline-directed medical therapy (GDMT) with statins has been widely considered the initial and preferred approach for the majority of patients with ASCVD. Though the guidelines have evolved for the varied lipid goals suggested across the American College of Cardiology/American Heart Association (ACC/AHA) [6,7] European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) [8] and the Lipid Association of India (LAI) [9] guidelines for ASCVD, the pertinent need for effective and safe therapies as oral options remains for ASCVD management despite the availability and guidance on the use of high–intensity statin. This was further highlighted by real-world evidence involving the South East population wherein <60% of participants achieved LDL-C targets of 70 mg/dL despite the induction of high-intensity statin therapy in most cases [10].

1.1 ASCVD and Lipid goals

ESC recommendations for ASCVD with T2D or End-Organ damage (EOD) including LVD, and CKD as <55 mg/dl remain relevant, especially for cases with additional risk traits including hypertension, obesity, smoking, and dyslipidemia. Other risk-enhancing determinants are belonging to race or ethnicities at high risk, increased ASCVD risk related to persistently elevated primary hypertriglyceridemia or other biomarkers like elevated high-sensitivity C-reactive protein (hs-CRP), elevated Lp(a), elevated apoB, or ankle-brachial index <0.9 [6,8]. On the other hand, ASCVD cases with ACS requiring revascularization, recurrent ischemic events within the last two years, and/or familial hypercholesterolemia require an aggressive approach with LDL-C goals as <40 mg/dl [8]. The DA-VINCI study [11] highlighted the great disparity in the lipid goal achievement for ASCVD and ACS despite the induction with moderate or high–intensity statins in 75% of cases. In established ASCVD (eASCVD) cases, only 21% of patients receiving high-intensity statins or Ezetimibe combination regimens achieved LDL-C targets of <55 mg/dL further accentuating the need for novel complementary agents with multimodal actions to cut the primary and residual cardiovascular risk associated with high inflammatory (hs-CRP), apo B and non-HDL-C. In this line, though statins reduce the hs-CRP level, neither PCSK9 inhibitors nor ezetimibe monotherapy have been shown to significantly reduce the biomarkers associated with inflammation.

1.2 Non-Statin Strategies & Bempedoic Acid

Bempedoic acid is a novel first-in-class oral inhibitor of adenosine triphosphate (ATP)-citrate lyase (ACL) approved worldwide as an adjunctive to maximally tolerated statin therapy to lower LDL-C for patients with ASCVD, Mixed hyperlipidemia and for patients with heterozygous familial hypercholesterolemia (HeFH). In the EU, it is also approved for the treatment of patients who are unable to take any dose of a statin (statin intolerant) or for whom a statin is contraindicated. Recently Gunn et al [12] published a simulation study estimating the 10-year risk of three-point major adverse cardiovascular events in ASCVD patients with participants from the four-phase III CLEAR trials of bempedoic acid. The 10-year CV event risk reduction was further reduced by 3.3% in statin-treated (cohort 1) and 6% in statin-intolerant (cohort 2) patients. The CLEAR-OUTCOMES [13] again demonstrated equivocal 13% risk reduction in 4P-MACE that is construed to be similar with PCK9i trials suggesting incremental benefits for the first time with a non-statin including Bempedoic acid. In this line to further assess the scope, potential, and current contemporary practices towards management of high-risk ASCVD patients in real-world settings of India with non-statins and bempedoic acid, a Knowledge, Attitude, Perception (KAP) survey was planned to be conducted.

2. Materials and Methods

A KAP survey questionnaire was developed to discuss some of the pertinent issues in the management of ASCVD with special emphasis on high-risk patients in the Indian context. This questionnaire was validated by an expert panel of eight members that included eminent interventional and practicing cardiologists with national academic and/or clinical standing with relevant experience in the development of consensus statements. The KAP survey questionnaire was shared electronically with seventy-five HCPs across India with relevant experience in the management of ASCVD before its analyses and consolidation during the phygital meet conducted between Aug-Oct ‘2022. A second round of meetings in the Dec ’22 discussed the responses while reviewing the literature and evolving treatment recommendations on the choice and role of Bempedoic acid in ASCVD management. The steering panel of eight specialists and experts responded, and reviewed the literature before developing clinical recommendations on the clinical role and positioning of non–statins in the management of ASCVD patients. The Level of Evidence (LoE) and Level of Agreement (LoA) was developed after a review of literature and publications featuring in indexed databases of Medline, PubMed, SCOPUS, INDEX MEDICUS, and COCHRANE Systemic reviews using the keywords as Cardiovascular disease, Atherosclerotic cardiovascular disease, low-density lipoprotein cholesterol, Bempedoic Acid, Statins, Chronic coronary syndrome, Type 2 diabetes. A systemic review of 12 RCTs involving >23000 cases for BA with eASCVD was conducted using PubMed, Google Scholar, and Cochrane Database of Systematic Reviews search while including the topline results from CLEAR OUTCOMES. Treatment recommendations based on a successful problem-based clinical assessment method were evolved while assessing the Strength and Quality of evidence as per Agency of Health Care and Quality Systems (AHRQ) criteria and general expert opinion shared by the panel. Levels of evidence were assigned for meta-analyses, randomized, case-cohort longitudinal, cross-sectional case-control, and Case reports as Level I, II, III, IV, and V respectively. The expert opinion was accepted as a recommendation in case of acceptance by 80 % of the panelist based on a LIKERT scale score (1: strongly disagree; 2: disagree; 3: neither agree nor disagree; 4: agree; 5: strongly agree) conducted during the meet. Descriptive statistics for mean, median, and proportion analyses were carried out for each of the responses generated for the 10-point questionnaire.

3. Results:

Seventy-five interventional and practicing Cardiologists provided clinical insights on the contemporary positioning of recently introduced non-statin therapy i.e. bempedoic acid as oral formulations in the management of Chronic stable angina, Chronic Coronary Syndrome (CCS), & Acute Coronary Syndrome (ACS) undergoing or not undergoing revascularization procedures including Percutaneous Intervention (PCI) using structured KAP based questionnaire. Responses received from HCPs based in different geographic locations across India were collated and analyzed.

Table 1: KAP questionnaire with responses on the clinical role and positioning of Non-statins and Bempedoic acid

4. Discussion

The residual risk with statin therapy in ASCVD remains a clinical challenge with recurrent Angina and impaired QoL. Nearly half of the cardiac coronary tomography (CCTA) and Angiography cases for Angina or stable CAD (SCAD) demonstrate little or non-significant central artery stenosis that requires aggressive lipid-lowering therapy in line with the stiff lipid targets of <70 mg/dl in most of these cases [14]. However, despite the advances in GDMT, up to 40% of statin-treated patients continue to suffer from life-threatening CV events even if high-dose statin treatment achieves the LDL-C target.  This is likely to be caused by unresolved 'residual risk' that may be related to non-HDL-C and/or underlying inflammation (hs-CRP) as corroborated by landmark trials for icosapent ethyl and canakinumab [15]. In addition, the safety signal on the induction or progression of Type 2 diabetes with high dose statins [16] seems significant concern as highlighted by WOSCOPS, SPARCL, and JUPITER trials warranting the need for novel approaches like bempedoic acid. Third, the high rate of recurrence after the first episode of ACS often depending on non-culprit lesions, some of them initially appearing as angiographically mild and inconspicuous at the index procedure [17] makes the case curious yet pertinent for the complementary induction of the nonstatin approach as a pre-emptive strategy.

4.1 BA: Beyond LDL-C reduction for complementary Synergy with Statins

Bempedoic acid is a novel non-statin compound with selective action in hepatic tissues acting on the upstream cholesterol pathway of Acetyl-CoA synthesis inhibition leading to a significant drop in cholesterol, triglycerides, apo-B, and hs-CRP due to LDL-C receptor upregulation, fatty acid (FA) synthesis, and oxidation inhibition, unlike statins and ezetimibe. The actions are further complemented by AMPK activation-led control of intracellular glucose- and lipotoxicity with inhibition of Glucose-6-Phosphate dehydrogenase (G-6-PD) and FA entry or oxidation leading to anti-ischemic effects in heart and myocardium musculature [18].

Figure 1: Complementary dual mechanisms of Acetyl-CoA and AMPK regulation with Bempedoic acid leading to differential outcomes in ASCVD cases

The ancillary actions of BA in mitigating residual risk associated with statin therapy highlighted by the KAP responses were corroborated by CLEAR-WISDOM [19] and CLEAR-HARMONY [20] trials that suggested incremental anti-inflammatory actions of hs-CRP (-22.4 vs. 2.6 with placebo, p<.001) modulation despite background therapy of High-intensity statin (≤50%) in most cases of ASCVD. Systematic review and meta–analyses of 10 RCTs (n = 3,788) further demonstrated change in atherogenic lipids as non-HDL (-18.2%, p<.001) and hs-CRP (-27.0%, p<.001). Patients with background CV risk receiving maximally tolerated statin further demonstrated the differential impact of BA on atherogenic markers of non-HDL-C (-17.8 % vs. -12.1%), hs-CRP (-31.9% vs. -8.2%) and Total–C (-14.2% vs. -10.4%) when compared with EZE respectively [21].

4.2 BA: Ideal Nonstatin for ASCVD

KAP responses for the initial choice of oral nonstatin including BA were in line with the recent publication of CLEAR Trials pooled analyses and CLEAR OUTCOMES trial for ASCVD cases that is novel and first-of-kind for any oral nonstatin strategy. The dual mechanisms for BA offer incremental action in control of LDL-C, non-HDL-C, and hs-CRP through novel pathways of ACL and AMPK regulation that are independent unlike EZE [22]. The CLEAR OUTCOMES mediated ARR of 1.6 with BA over 4-y follow-up for ASCVD cases with baseline LDL-C >/=139 mg/dl was complemented by McQueen RB et al [23] for cases with differing LDL-C levels and risk assessment. The study estimated the risk reduction (RR) in 16,926 patients who were divided into two groups based on the baseline LDL-C of 101–110 mg/dL (n = 15,237) and LDL-C of > 200 mg/dL (n = 1689). The study predicted an incremental or additional CV risk reduction with BA/EZE (-10.9%) versus EZE. Taking into consideration the cardiovascular outcomes observed with Ezetimibe in the IMPROVE-IT trial of (-6%), the findings of McQueen RB et al draw inspiration for BA/EZE as a pragmatic oral strategy for implementation in ACS cases requiring LDL-C target of <55 or <40 mg/dl despite background therapy with maximally tolerated statin dose while ensuring compliance and adherence to therapy. The ARR and NNT with BA were equivocal with the landmark/pivotal Cardiovascular Outcome Trial (CVOT) of Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) and ezetimibe suggesting the clinical consideration as a rational choice for initial combination therapy in cases with high CV risk or ASCVD with baseline LDL-C 110 to 185 mg/dl [24] (Table 2)

Table 2: CVOTs with Nonstatin drugs including Bempedoic acid, Evolocumab, and Ezetimibe [13,25,26]

RRR: Relative risk reduction; ARR: Absolute risk reduction; NNT: Number needed to treat; FU: follow-up

5. Recommendations on Bempedoic Acid in ASCVD

1. LDL-C goals for ASCVD cases with at least one additional risk factor including T2D would qualify for achievement of </=55 mg/dL (LoA, 100%)
2. LDL-C, non-HDL-C, apo B, Lp (a), and hs-CRP assessment and target goal achievement remain relevant for ASCVD cases with MI history within the past < 12 mo (LoA, 100%)
3. Non-statin oral therapy remains a pragmatic or pertinent strategy in real-life outpatient settings for the management of ASCVD with recent MI history within or >12 mo; ischemic stroke, or symptomatic PAD (history of claudication with ABI <0.85) (LoA, 100%)
4. In ASCVD cases requiring aggressive LLT, Statin intensity-associated muscle symptoms (SAMS) may switch to a non-statin approach involving Bempedoic and/or Ezetimibe (LoA, 100%)
5. In ASCVD with T2D or coronary artery calcium (CAC) >300 HU or Non-stenotic coronary lesion cases requiring >50% LDL-C reduction while targeting LDL-C levels of </=55 mg/dl, initial add-on strategy with BA may be considered as a pragmatic strategy (LoA, 100%)
6. In ASCVD with revascularization history (Recent MI <12 mo) with HeFH, BA, or EZE as an initial add-on strategy with High-intensity statins can be considered (LoA, 100%)

6. Conclusion

The growing burden of ASCVD in India is accentuated by high disease progression leading to premature CVD and events. There is a significant residual risk requiring the addition of non-statin drugs to ESC-recommended targets. This makes bempedoic acid a welcome addition to the existing non-statin therapies such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. A low frequency of muscle-related side effects, minimal drug interactions, a significant reduction in high-sensitivity C-reactive protein (hs-CRP), and a lower incidence of new-onset or worsening diabetes make it a useful adjunct for LDL-C lowering. The CLEAR OUTCOMES corroborate ancillary actions of bempedoic acid that are likely to offer incremental CV event risk reduction, particularly in ASCVD cases.

Acknowledgment

The author would like to thank the following CLEAN panel for their responses to KAP survey: Dr. KP Pramod Kumar Chennai, Dr. Vidyut Jain Indore, Dr. B Yugandhar Tirupati, Dr. Sanjay Sharma New Delhi, Dr. Bhaskar P Shah Mumbai, Dr. P Manokar                Chennai, Dr. Dharmesh Solanki Rajkot, Dr. Tarun Dave Ahmedabad, Dr. Girish Navasundi Bangalore, Dr. Nagamalesh U M Bangalore, Dr. J Kannan Bangalore, Dr. Anupam Jena Bhubaneswar, Dr. Ashok Kumar Patna, Dr. Aniruddha Chandorkar Pune, Dr. Rajesh Badani Pune, Dr. Jayagopal PB Palakkad, Dr. G R Kane Mumbai, Dr. SS Binu Thiruvananthapuram, Dr. Ramesh Natarajan Anamugam, Dr. Mukesh Sharma Udaipur, Dr. S K Kaushik Udaipur, Dr. D K Garg Jaipur, Dr. Ajay Kumar Pandey Varanasi, Dr. Guru Prakash A Hyderabad, Dr. K Sarat Chandra Hyderabad, Dr. K Ravinder Reddy Karimnagar, Dr. Rajiv Agarwal New Delhi, Dr. Tushar Roy New Delhi, Dr. DK Baruah Visakhapatnam, Dr. Jayal Shah Ahmedabad, Dr. Thomas Alexander Coimbatore, Dr. KA Sambasivam Coimbatore, Dr. Debasis Ghosh Kolkata, Dr. Dhiman Kahali Kolkata, Dr. Niraj Prasad Ranchi, Dr. Dilip Ratnani Durg, Dr. C S Srinivasa Raju Nellore, Dr. N Murali Krishna Vijayawada, Dr. P C Sarma Silchar, Dr. Arindam Pande Kolkata, Dr. Spandan Bhadury Kolkata, Dr. Mahesh Fulwani Nagpur, Dr. BB Chanana New Delhi, Dr. Ashwani Mehta New Delhi, Dr. Subhash Chandra New Delhi, Dr. Dilip Kumar Kolkata, Dr. Viveka Kumar New Delhi, Dr. M Srinivasa Rao Hyderabad, Dr. Abhinav  Bhagat Patna, Dr. BB Bharti Patna, Dr. Rishi Gupta Faridabad, Dr. Naveen Bhamri New Delhi, Dr. Rohit Parti Panchkula, Dr. Jitendra Singh Makkar Jaipur, Dr. Sandipta Ray Kalyani, Dr. Sujay J. Chitradurga, Dr. Sunip Banerjee Kolkata, Dr. Peeyush Jain New Delhi, Dr. Soumitra Kumar Kolkata, Dr. Prasant Kumar Sahoo Bhubaneswar, Dr. S. N. Routray Cuttack, Dr. Devanu Ghosh Roy Kolkata, Dr. Santanu Guha Kolkata, Dr. Pramod Mundra Nagpur, Dr. Rajiv Karnik Mumbai, Dr. T. Sashikant Secunderabad.

Disclosure

The authors and panelists did not receive any honorarium for the scientific meeting or development of the manuscript. The authors and panelists would like to thank Torrent Pharmaceuticals Ltd, for the unrestricted educational grant provided for the meeting.

Conflict of Interest

Krishnaprasad K, and Ashutosh Kakkad declare(s) being employees of Torrent Pharmaceuticals Ltd. These listed authors are paid employees of Torrent Pharmaceuticals Ltd.

The authors report no other potential conflicts of interest in this work.

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