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

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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 risk2,3 , 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 area6,7.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 populations25,26; 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 <MI
<CHD Mortality
AFCAPS/TexCAPS2 1998 Outpatient clinics in Texas men & women LDL130-190mg/dl Lovastatin 20-40 mg 5.2 years <Angina & MI
<sudden cardiac death
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 <major CVD
<all-cause mortality
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 difficult41,42. 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 incentives49,50 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.

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