Summary of Evidence: Impact of Statin Therapy on CVD Outcomes (MI, stroke, death) in HIV-infected individuals in SSA

Introduction

Cardiovascular Disease (CVD) encompasses the following specific diagnoses:

• Coronary heart disease (CHD)- Angina pectoris, heart failure, myocardial infarction (MI)
• Cerebrovascular disease -Transient Ischemic Attack (TIA)
• Peripheral artery disease – Intermittent Claudication
• Aortic atherosclerosis and thoracic/abdominal aortic aneurysm

Established risk factors for CVD include hypercholesterolemia, diabetes, hypertension, obesity, and smoking.

Specific to hypercholesterolemia, common lipid and lipoprotein abnormalities associated with increased CHD risk include:

• Elevated total cholesterol (TC)
• Elevated LDL cholesterol (LDL)
• Low HDL cholesterol
• Hypertriglyceridemia
• Increased non-HDL cholesterol (TC less HDL)
• Increased lipoprotein A [Lp(a)]

The prevalence of dyslipidemia is increased in patients with premature CHD.¹ For primary prevention (management of CVD risk factors in someone who has not previously experienced a CVD event), most of the evidence from clinical trials that have demonstrated a reduction in risk for CVD events have evaluated the impact of lowering LDL cholesterol on this risk^2,3 , perhaps because even within normal ranges, LDL correlates with subclinical atherosclerosis, suggesting a continuous relationship without any clear minimum set-point.⁴

Statin Therapy: – Mechanism of Action

Statins are primarily hydroxymethylglutaryl (HMG)- CoA reductase inhibitors. By interrupting cholesterol synthesis, they reduce hepatic intracellular cholesterol levels. This in turn enhances LDL receptor expression, increasing endocytosis of LDL thus lowering serum LDL.⁵

Lowering of serum lipids can lead to reduction in atherosclerotic changes. These include reduction in plaque size and subsequent increase in blood vessel luminal area^6,7.This occurs over time after initiation of statin therapy (12-26 months)⁸

However, the benefit of statin therapy on CVD risk can be attributed to other factors beyond lowering of LDL cholesterol. These have largely been observed in people who already have atherosclerosis and include: –

Plaque stabilization

Coronary plaque rupture is often a component of acute myocardial infarction. Statins have been shown to reduce the growth of atheromatous plaques and change their composition from a soft and friable lipid-rich atheroma to a calcified fibrotic core, increasing plaque stability and decreased likelihood of rapture.⁹ Mechanisms for this include reduction in prostaglandin synthesis, reduction in matrix metalloproteinases (MMPs) which promote thrombus formation by macrophages and smooth muscle cell apoptosis with reduced collagen synthesis hence formation of the protective fibrous cap on atheroma.

Reduced inflammation

Inflammation is an important component of atherosclerosis. Statin therapy reduces serum hs-CRP, an inflammatory biomarker.¹⁰ This effect is independent of lipid levels and is more marked among patients with inflammation at baseline.

Reversal of endothelial dysfunction

Atherosclerotic arteries have endothelial dysfunction, characterized by induction of vasoconstriction by acetylcholine rather than the expected, nitric oxide-mediated vasodilation¹¹. This dysfunction is attenuated by statin therapy, improving overall vasodilator capacity and myocardial blood flow reserve via increased NO synthesis.¹²

Reduced thrombogenicity

When a plaque ruptures, there’s thrombus formation at the site, further reducing the blood vessel lumen and increasing occlusion. Statins have been shown to reduce thrombogenicity through multiple mechanisms; including reduced prothrombin activation and thrombin generation¹³, decreased platelet activation¹⁴and increased fibrinolysis.¹⁵

Other mechanisms of potential benefit of statins for primary prevention include reduction in monocyte recruitment and adhesion to the endothelium, an important first step in the formation of atheromatous plaques. Antiatherogenic effects of statins could also be due to their antioxidative effect on LDL-C.¹⁶

CVD Risk Factor Assessment

While CVD risk should be assessed in all individuals with the traditional risk factors, it is recommended that all patients aged ≥ 40 years have a CVD risk assessment including a lipid profile; to determine whether they would benefit from statin therapy. There are several CVD risk calculators as summarized below in Table 1. Many have only included patients up to 79 years of age; beyond which the benefit of primary prevention with statins remains unclear.¹⁷

Table 1: Summary of select CVD risk calculators
Year	Calculator	Lipid measure	Country	Note
2013	ACC/AHA pooled cohort hard CVD risk score	TC: HDL ratio	US	Large populations of both Caucasian and African Americans, only hard outcomes (MI, stroke)
1998/2001	Framingham risk score/ATP III hard CHD risk score	TC: HDL ratio	Multi-country	Most other calculators are built on these pooled cohort equations.
2015	Multi-Ethnic Study of Atherosclerosis (MESA)	TC: HDL ratio	US	Incorporates coronary artery Ca2+
2008	Reynold’s Risk Score	TC: HDL ratio	US	Includes family history of MI and hs-CRP
2007/2018	QRISK -QRISK3	TC: HDL ratio	England & Wales
2003	SCORE	TC or TC/HDL ratio	Europe	Calculates risk scores for high and low risk regions in Europe.
2018	PREDICT CVD risk score	TC: HDL ratio	New Zealand	5-year risk; more accurate in this population compared to ACC/AHA risk calculator

Of note, although some have included people from various races and ethnicity; none have been validated in Sub-Saharan Africa. Also, none have taken HIV into account in their risk profile estimation.

Lipid Lowering Treatment Guidelines

Based on the 5 or 10-year risk scores; different world regions have proposed different treatment guidelines. Of note, none of the Western world guidelines have anything specific for HIV-infected populations.

United States

For primary prevention, the American Heart Association/American College of Cardiology (AHA/ACC) recommends statin therapy for patients aged 40-75 years with a 10-year risk of ≥7.5% and LDL-C (70-189mg/dl); with moderate to high intensity statin dose.¹⁸

The 2016 USPSTF recommended that low to moderate dose statins be used in the primary prevention of CVD events in people aged 40-75 years and a 10-year risk score of 10% or greater with one or more CVD risk factor.¹⁹ The US guidelines have no specific treatment goal for primary prevention; but rather overall reduction in the risk score; except in cases where the LDL-C remains high (≥100mg/dl) while on statins, then its recommended to intensify the statin dose.

Europe

The 2016 European Society of Cardiology/European Atherosclerosis Society guidelines recommend LDL-C treatment goals based on CVD risk (as assessed using the SCORE calculator) as shown in Table 2 below²⁰:

Table 2: ESC/EAS LDL-C treatment goals for primary CVD prevention
CV risk	Target LDL	Alternative Target LDL
Very high	<70mg/dl	50% reduction if baseline LDL-C was 70-135mg/dl
High	<100mg/dl	50% reduction if baseline LDL-C was 100-200mg/dl
Low-moderate	<115mg/dl

This guideline is very similar to the 2018 Canadian Cardiovascular Harmonized National Guidelines Endeavour (C-CHANGE) guideline for the prevention and management of cardiovascular disease in primary care, which do not recommend statin therapy for CV risk score <10% and have a similar LDL targets.

UK

The 2014-2016 National Institute for Health and Care Excellence (NICE): Clinical Guideline on Cardiovascular Disease Risk Assessment and Reduction recommends risk assessment using the QRISK2 risk calculator and low to moderate dose statins for the primary prevention of CVD to people who have a 10% or greater 10‑year risk of developing CVD, targeting a ≥40% reduction in non-HDL cholesterol.²¹

Despite having these guidelines, studies suggest they are not applied effectively in providing adequate cardiovascular care to HIV-infected patients.²² The HIV-HY study showed that 50% HIV-infected patients eligible for a statin did not get a statin prescription.²³

Africa

South Africa’s national lipid treatment guidelines recommend primary screening from 20 years of age, calculate CVD risk based on the ATP III Framingham risk calculator but recommend the European ESC/EAS treatment goals. Asides from mentioning that CVD risk is likely underestimated by the current risk calculators, the guidelines don’t offer any HIV-specific recommendations for statin therapy or treatment goals among HIV-infected populations.²⁴

In Kenya, both HIV treatment guidelines and national guidelines for CVD management outline the screening procedures for dyslipidemia among HIV-infected populations^25,26; recommending a fasting lipogram at baseline for everyone and then annually. However, the first line management is up to 6 months of lifestyle modification before adding a statin, and there are no therapy goals.

Effect of statins on MI, stroke, death

Table 3: Sentinel trials assessing the effects of statins on primary prevention of CVD
Study	Time	Setting	Population	Drugs	Duration	Outcomes
WOSCOPS27,28	1995; 2016	Pri. medical care facilities Scotland	men LDL>155mg/dl	Pravastatin 40mg	5-20 years
AFCAPS/TexCAPS2	1998	Outpatient clinics in Texas	men & women LDL130-190mg/dl	Lovastatin 20-40 mg	5.2 years
ASCOT-LLA29	2003	UK, Ireland, Nordic countries	Hypertensive 40-79 TC 6.5mmol/L	10mg Atorvastatin	3.3 years	Stroke, CVD, coronary events
MEGA30	2006	Japan	Men & women TC 5.7-7mmol/L	10-20mg Pravastatin	5.3 years
JUPITER31	2008	26 countries,71% Caucasian	men& women >50 yrs. LDL<130mg/dl & >hs-CRP,	Rosuvastatin 20mg	1.9 years
HOPE-332	2016	More culturally diverse, blacks 1.8%	LDL 128mg/dl	Rosuvastatin 10mg		< (CVD death, MI, stroke)
< Reduced risk

These treatment guidelines are informed by years of progressive clinical trials assessing the effect of various statins on CVD events (acute non-fatal MI, non-fata stroke, cardiac death). A few landmark trials assessing the effects of statins on primary prevention of CVD are summarized in Table 3 below:

In summary, from a meta-analysis of these and more trials, including those assessing statins in secondary prevention; statins were shown to have a 21% risk reduction per 1mmol/L reduction in LDL.³ There was reduction in vascular event rate across all risk groups and reduction in LDL by 1 year was greater in people with higher CVD risk.

Of note, all these trials were conducted in the developed world and none explicitly assessed HIV as a risk factor for CVD.

Smaller studies assessing lipid lowering, statin-ART drug interaction and effects of statins on viral load and CD4 have shown that statins reduce LDL levels (some with greater reductions than others), are generally well tolerated and seem to have no effect on viremia or CD4 levels.³³ These had a fairly short duration of follow-up. More recent work in HIV-infected populations has shown statins reduce the atherosclerotic plaque size and morphology.^34-36Again, none of these were conducted in SSA and none had hard outcomes (MI, stroke) as end-points.

That said, there’s no evidence to suggest that the efficacy of statin therapy would be different among HIV-infected populations. To assess this, a landmark clinical trial (REPRIEVE) enrolling 75,000 HIV-infected adults (3 sites in Africa) aged 40-75years on ART and assessing effect of Pitavastatin 4mg OD for primary prevention of CVD events is on-going.³⁷

Choice based on cost-effectiveness: Statin therapy vs dietary/lifestyle intervention

Summary of evidence on lifestyle interventions

Looking at the effects of lifestyle modification (diet, weight loss, exercise); evidence suggests that a very specific diet and regimen may work.³⁸ Some studies show that response to diet i.e. lowering of LDL could be affected by familial factors.³⁹ It also works best in combination i.e. all three components of lifestyle modification.⁴⁰ However, the greatest challenge with lifestyle modification is that compliance is difficult^41,42. In the ENCORE study⁴³ where the DASH diet was found to be highly effective in weight loss and lowering mean blood pressure; the follow-up was very intense and only for 4 months. Long-term compliance is difficult to assess or enforce.⁴⁴

Specific to SSA, there also are cultural issues at play. Obesity is considered a sign of stature and marked weight loss can be viewed with stigma. Nutritional habits don’t support very “DASH-like” diets. While this culture is changing with increased awareness of CVD and its risk factors, it will take time.

One dietary intervention that has been shown to be effective is reduction in sodium intake. This may not have a direct effect on lipids but eventually plays a role in CVD risk reduction since reduced sodium intake is associated with lowered blood pressure.^45,46 Salt reduction seems amenable to a policy intervention approach,^47,48 could be through legislation or marketing incentives^49,50 and there’s some evidence towards it being cost-effective in CVD reduction.⁵¹

Summary of literature on cost-effectiveness

Many studies have been done to assess the cost-effectiveness of statins for both primary and secondary prevention of CVD.^52-54 Some have found that while individual effects are largely dependent on existing risk, overall population effect is cost-effective.^55,56 However, this is dependent on the cost of the drugs⁵⁷ as well as adherence to treatment⁵⁸, which have not been well-studied in the real-world⁵⁹, particularly in a HIV-setting where pill overload is a possibility. Further evaluation of cost-effectiveness with lower statin prices and a better understanding of their long-term treatment effects; especially statin-ART drug interactions; and in SSA is warranted.

Summary of my choice

Based on the above evidence, I would recommend statin therapy following positive screening as a cost-effective strategy for primary prevention of CVD among older HIV-infected populations; while still promoting a healthy lifestyle for everyone.

Implementation science research around statin therapy in HIV-infected populations is still needed to further characterize this e.g. actual risk reduction conferred by statins among these individuals, LDL initiation levels and treatment targets among the HIV-infected and optimal statin-ART combinations.

REFERENCES

1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106(25): 3143-421.

2. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. Jama 1998; 279(20): 1615-22.

3. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380(9841): 581-90.

4. Fernandez-Friera L, Fuster V, Lopez-Melgar B, et al. Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors. J Am Coll Cardiol 2017; 70(24): 2979-91.

5. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001; 292(5519): 1160-4.

6. Bestehorn HP, Rensing UF, Roskamm H, et al. The effect of simvastatin on progression of coronary artery disease. The Multicenter coronary Intervention Study (CIS). Eur Heart J 1997; 18(2): 226-34.

7. Bangalore S, Fayyad R, Kastelein JJ, et al. 2013 Cholesterol Guidelines Revisited: Percent LDL Cholesterol Reduction or Attained LDL Cholesterol Level or Both for Prognosis? Am J Med 2016; 129(4): 384-91.

8. Corti R, Fuster V, Fayad ZA, et al. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years’ follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation 2002; 106(23): 2884-7.

9. Feig JE, Feig JL, Dangas GD. The role of HDL in plaque stabilization and regression: basic mechanisms and clinical implications. Coron Artery Dis 2016; 27(7): 592-603.

10. Arevalo-Lorido JC, Carretero-Gomez J, Fernandez-Recio JM, et al. Lowering C-reactive protein with statins after an ischemic stroke avoids mortality and readmissions. A prospective cohort study. Ann Med 2015; 47(3): 226-32.

11. Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995; 332(8): 481-7.

12. Landmesser U, Bahlmann F, Mueller M, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005; 111(18): 2356-63.

13. Sexton T, Wallace EL, Smyth SS. Anti-Thrombotic Effects of Statins in Acute Coronary Syndromes: At the Intersection of Thrombosis, Inflammation, and Platelet-Leukocyte Interactions. Curr Cardiol Rev 2016; 12(4): 324-9.

14. Pignatelli P, Carnevale R, Pastori D, et al. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation 2012; 126(1): 92-103.

15. Trip MD, van Wissen S, Smilde TJ, Hutten BA, Stalenhoef AF, Kastelein JJ. Effect of atorvastatin (80 mg) and simvastatin (40 mg) on plasma fibrinogen levels and on carotid intima media thickness in patients with familial hypercholesterolemia. Am J Cardiol 2003; 91(5): 604-6.

16. Lunder M, Janic M, Savic V, Janez A, Kanc K, Sabovic M. Very low-dose fluvastatin-valsartan combination decreases parameters of inflammation and oxidative stress in patients with type 1 diabetes mellitus. Diabetes Res Clin Pract 2017; 127: 181-6.

17. Odden MC, Pletcher MJ, Coxson PG, et al. Cost-effectiveness and population impact of statins for primary prevention in adults aged 75 years or older in the United States. Ann Intern Med 2015; 162(8): 533-41.

18. Goff DC, Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129(25 Suppl 2): S49-73.

19. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement. Jama 2016; 316(19): 1997-2007.

20. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37(29): 2315-81.

21. National Clinical Guideline C. National Institute for Health and Clinical Excellence: Guidance. Lipid Modification: Cardiovascular Risk Assessment and the Modification of Blood Lipids for the Primary and Secondary Prevention of Cardiovascular Disease. London: National Institute for Health and Care Excellence (UK)

Copyright (c) National Clinical Guideline Centre, 2014.; 2014.

22. Ladapo JA, Richards AK, DeWitt CM, et al. Disparities in the Quality of Cardiovascular Care Between HIV-Infected Versus HIV-Uninfected Adults in the United States: A Cross-Sectional Study. J Am Heart Assoc 2017; 6(11).

23. De Socio GV, Ricci E, Parruti G, et al. Statins and Aspirin use in HIV-infected people: gap between European AIDS Clinical Society guidelines and clinical practice: the results from HIV-HY study. Infection 2016; 44(5): 589-97.

24. Klug E. South African dyslipidaemia guideline consensus statement. S Afr Med J 2012; 102(3 Pt 2): 178-87.

25. Ministry of Health NASCP. Guidelines on Use of Antiretroviral Drugs for Treating and Preventing HIV Infection in Kenya. In: NASCOP, editor. Nairobi; 2018.

26. Ministry of Health DoN-CD. Kenya National Guidelines for Cardiovascular Diseases Management. In: NCDs Do, editor. Nairobi; 2018.

27. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333(20): 1301-7.

28. Vallejo-Vaz AJ, Robertson M, Catapano AL, et al. Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above: Analyses From the WOSCOPS (West of Scotland Coronary Prevention Study) 5-Year Randomized Trial and 20-Year Observational Follow-Up. Circulation 2017; 136(20): 1878-91.

29. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361(9364): 1149-58.

30. Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006; 368(9542): 1155-63.

31. Khera AV, Demler OV, Adelman SJ, et al. Cholesterol Efflux Capacity, High-Density Lipoprotein Particle Number, and Incident Cardiovascular Events: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Circulation 2017; 135(25): 2494-504.

32. Yusuf S, Bosch J, Dagenais G, et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med 2016; 374(21): 2021-31.

33. Feinstein MJ, Achenbach CJ, Stone NJ, Lloyd-Jones DM. A Systematic Review of the Usefulness of Statin Therapy in HIV-Infected Patients. Am J Cardiol 2015; 115(12): 1760-6.

34. Longenecker CT, Sattar A, Gilkeson R, McComsey GA. Rosuvastatin slows progression of subclinical atherosclerosis in patients with treated HIV infection. Aids 2016; 30(14): 2195-203.

35. Lo J, Lu MT, Ihenachor EJ, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV 2015; 2(2): e52-63.

36. Funderburg NT, Jiang Y, Debanne SM, et al. Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIV-infected subjects on antiretroviral therapy. J Acquir Immune Defic Syndr 2015; 68(4): 396-404.

37. Gilbert JM, Fitch KV, Grinspoon SK. HIV-Related Cardiovascular Disease, Statins, and the REPRIEVE Trial. Top Antivir Med 2015; 23(4): 146-9.

38. Butowski PF, Winder AF. Usual care dietary practice, achievement and implications for medication in the management of hypercholesterolaemia. Data from the U.K. Lipid Clinics Programme. Eur Heart J 1998; 19(9): 1328-33.

39. Denke MA, Adams-Huet B, Nguyen AT. Individual cholesterol variation in response to a margarine- or butter-based diet: A study in families. Jama 2000; 284(21): 2740-7.

40. Stefanick ML, Mackey S, Sheehan M, Ellsworth N, Haskell WL, Wood PD. Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol. N Engl J Med 1998; 339(1): 12-20.

41. Hsia J, Rodabough R, Rosal MC, et al. Compliance with National Cholesterol Education Program dietary and lifestyle guidelines among older women with self-reported hypercholesterolemia. The Women’s Health Initiative. Am J Med 2002; 113(5): 384-92.

42. Henkin Y, Shai I, Zuk R, et al. Dietary treatment of hypercholesterolemia: do dietitians do it better? A randomized, controlled trial. Am J Med 2000; 109(7): 549-55.

43. Blumenthal JA, Babyak MA, Hinderliter A, et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study. Arch Intern Med 2010; 170(2): 126-35.

44. Epstein DE, Sherwood A, Smith PJ, et al. Determinants and consequences of adherence to the dietary approaches to stop hypertension diet in African-American and white adults with high blood pressure: results from the ENCORE trial. J Acad Nutr Diet 2012; 112(11): 1763-73.

45. Taylor RS, Ashton KE, Moxham T, Hooper L, Ebrahim S. Reduced dietary salt for the prevention of cardiovascular disease. Cochrane Database Syst Rev 2011; (7): Cd009217.

46. WHO. Effect of reduced sodium intake on blood pressure, renal function, blood lipids and other potential adverse effects. 2012.

47. Antman EM, Appel LJ, Balentine D, et al. Stakeholder discussion to reduce population-wide sodium intake and decrease sodium in the food supply: a conference report from the American Heart Association Sodium Conference 2013 Planning Group. Circulation. United States: (c) 2014 American Heart Association, Inc.; 2014: e660-79.

48. Prabhakaran D, Anand S, Watkins D, et al. Cardiovascular, respiratory, and related disorders: key messages from Disease Control Priorities, 3rd edition. Lancet 2018; 391(10126): 1224-36.

49. Charlton K, Webster J, Kowal P. To legislate or not to legislate? A comparison of the UK and South African approaches to the development and implementation of salt reduction programs. Nutrients 2014; 6(9): 3672-95.

50. Gillespie DO, Allen K, Guzman-Castillo M, et al. The Health Equity and Effectiveness of Policy Options to Reduce Dietary Salt Intake in England: Policy Forecast. PLoS One 2015; 10(7): e0127927.

51. Watkins DA, Olson ZD, Verguet S, Nugent RA, Jamison DT. Cardiovascular disease and impoverishment averted due to a salt reduction policy in South Africa: an extended cost-effectiveness analysis. Health Policy Plan 2016; 31(1): 75-82.

52. Pandya A, Sy S, Cho S, Weinstein MC, Gaziano TA. Cost-effectiveness of 10-Year Risk Thresholds for Initiation of Statin Therapy for Primary Prevention of Cardiovascular Disease. Jama 2015; 314(2): 142-50.

53. Pletcher MJ, Lazar L, Bibbins-Domingo K, et al. Comparing impact and cost-effectiveness of primary prevention strategies for lipid-lowering. Ann Intern Med 2009; 150(4): 243-54.

54. Heller DJ, Coxson PG, Penko J, et al. Evaluating the Impact and Cost-Effectiveness of Statin Use Guidelines for Primary Prevention of Coronary Heart Disease and Stroke. Circulation 2017; 136(12): 1087-98.

55. Stam-Slob MC, van der Graaf Y, Greving JP, Dorresteijn JA, Visseren FL. Cost-Effectiveness of Intensifying Lipid-Lowering Therapy With Statins Based on Individual Absolute Benefit in Coronary Artery Disease Patients. J Am Heart Assoc 2017; 6(2).

56. Jeong YJ, Kim H, Baik SJ, et al. Analysis and comparison of the cost-effectiveness of statins according to the baseline low-density lipoprotein cholesterol level in Korea. J Clin Pharm Ther 2017; 42(3): 292-300.

57. Ferket BS, Hunink MG, Khanji M, Agarwal I, Fleischmann KE, Petersen SE. Cost-effectiveness of the polypill versus risk assessment for prevention of cardiovascular disease. Heart 2017; 103(7): 483-91.

58. Aarnio E, Korhonen MJ, Huupponen R, Martikainen J. Cost-effectiveness of statin treatment for primary prevention in conditions of real-world adherence–estimates from the Finnish prescription register. Atherosclerosis 2015; 239(1): 240-7.

59. Suh DC, Griggs SK, Henderson ER, Lee SM, Park T. Comparative effectiveness of lipid-lowering treatments to reduce cardiovascular disease. Expert Rev Pharmacoecon Outcomes Res 2018; 18(1): 51-69.