CVDs are a spectrum of disorder affecting the heart or the blood vessels and sharing a common set of risk factors. These are the number one leading the cause of death globally with estimated 30% or 17.3 million deaths in 2008 with a projection to increase to 23.3 million by 2030 [1] . 80% of the deaths occur in low to middle-income countries. It is postulated that about 40.5% of the US population will suffer from some forms of CVD with subsequent 61% increase in total health care cost related to CVD by 2030 [2] . The gravity of the situation is reflected in developed countries as well. Heart diseases account for about half of all deaths in the European region and 1 in every 4 deaths in the US resulting in approximately $108.9 billion healthcare cost annually [3] . These facts point towards the need for global action against CVDs and more specifically promotion of preventive approaches with a goal targeted at CVD risk reduction [4] . LDL cholesterol, along with hypertension, smoking and abdominal obesity are the key CVD risk factors [3] . Worldwide about one-third of all ischemic heart diseases are attributable to high cholesterol [5] . In view of the fact that 1% decrease in cholesterol level could lead to a 2% - 4% decrease in CVD mortality, there has been various ongoing global initiatives and guidelines focusing on the reduction of cholesterol through diet and pharmacotherapy [6] . Various observational studies and randomized controlled trials (RCTs) have demonstrated that Statin medications are the most effective and number one choice for cholesterol lowering pharmacotherapy [7] . Since the inception of statin therapy, there have been paradigm shifts in the guideline and evidence for the use of Statins in CVD risk reduction.

Over the years, there were various guidelines including the European Society of Cardiology/European

Atherosclerosis Society (ESC/EAS) and American Heart Association/American College of Cardiology (AHA/ ACC) guideline, which characterized the treatment protocol with statins. For this write up we will be focusing on the recent guidelines especially the ESC/EAS guideline of 2011 and the AHA/ACC guideline of 2013 for the use of statin in the primary prevention of cardiovascular diseases. The ESC/EAS guideline promotes therapeutic intervention based on the CVD risk stratification using SCORE system estimating the 10-year risk of CV death [18] . ‘SCORE’ system classifies those without CVD risk into three categories; high risk (≥5% and <10% 10 year CVD risk); moderate risk (≥1% and <5% 10-year risk along with other risk factors) and low risk (<1%) [18] . The overall target of therapy is an absolute reduction of LDL cholesterol <1.8 mmol/L or at least 50% reduction of LDL cholesterol to provide the best benefit in CVD risk reduction [18] .

Later on in 2013, AHA/ACC put forth the most recent guideline recommending fixed-dose strategies rather than target goal to reduce LDL-cholesterol. The new guideline focuses on the reduction of total good cholesterol using various intensities of statin therapy as determined exclusively through controlled trials. The evidence was particularly effective for 4 patient groups including primary prevention of cardiac diseases in patients aged 40 - 75 years with an estimated 10 years atherosclerotic cardiovascular disease (ASCVD) ≥ 7.5% and 40 to 75 years diabetic patients with LDL level between 70 to 189 mg/dl [19] [20] .

The risk assessment for this guideline was done using a new pooled cohort risk estimator developed from 5 NHLBI-sponsored population-based cohort. The statin therapy was classified based on dose into high, moderate and low-intensity statin. There is no specific LDL cholesterol goal but specifies the need for dose adjustment once LDL cholesterol is <40 mg/dl.

Both the guidelines actually more or less complement each other. With a fundamental difference that ESC/EAS guideline recommends statin therapy based on CVD risk stratification and LDL level ≥2.5 mmol/L, whereas ACC/AHA guideline call for primary prevention in an advent of 10-year ASCVD risk of 7.5% irrespective of LDL-cholesterol. The basic treatment guideline for initiation of statin in primary prevention of ASCVD as per both guidelines is given below [19] .

v For primary prevention with LDL > 4.9 mmol/L

Ø ESC/EAS: Target LDL < 2.5 mmol/L

Ø AHA/ACC: High-intensity statin therapy until at least 50% reduction of LDL cholesterol

v Primary prevention in those with diabetes

Ø ESC/EAS: Target ≤ 1.8 mmol/> (complicated diabetes) and < 2.5 mmol/l (uncomplicated DM)

Ø AHA/ACC: High-intensity statin in high risk diabetics and moderate intensity statin in low intensity statin

v Primary prevention in high-risk

Ø ESC/EAS: Target LDL < 1.5 mmol/L

Ø AHA/ACC: 5% to 7.5% risk for CVD (Moderate intensity statin therapy) vs >7.5% risk for CVD (moderate to high-intensity statin therapy)

Various studies looking at the effectiveness of the two guidelines found that the desired reduction of the LDL cholesterol was found in 21%, 44% and 62% among very high, high and moderate risk groups under ESC/EAS guideline compared to 47% in patients on high-intensity statin therapy as per ACC/AHA guideline [19] [21] .

The ESC/EAS guideline is based on the report of meta-analyses done between 2008 and 2012 namely those done by Brugts J.J. et al. in 2009; Edward J. Mills et al. in 2008; Fiona Taylor et al. in 2012 and Trialist in 2012 [22] - [24] . The meta-analyses looked at various randomized controlled trials (RCTs) to determine the effect of different statins on single or a composite CVD effect as given in Table 1.

The current ACC/AHA guideline is based on a systemic review of RCTS with ASCVD outcomes with the exclusion of observational studies and studies less than 18 months follow-up. Only those RCTs with hard ASCVD outcomes (MI, stroke, CVD deaths published between January 1995 through December 2009 were included in the guideline with provision to consider articles published after 2009 but before the Expert panel deliberation. 6 RCTs namely MEGA, ASPEN, AFCAPS, JUPITER, CARDS and AURORA [25] - [30] . There RCTs were compared either between fixed doses of the statin with placebo or untreated controls or between high or moderate intensity statins. Table 2 provides the evidence table for this guideline.

Most of the supporting meta-analyses and clinical trials provide strong support to the notion of a relative protective effect of statin in CVD events and mortality. In line with that, CTT trial has found increased benefit of statins over harm especially for subjects in 5% to <10% major cardiovascular disease risk category on high-intensity statin therapy [31] . There is also about 10% reduction in CVD-related mortality in patients on primary prevention statin therapy [31] . The excess risk of serious myopathy, hemorrhagic stroke & DM has been found to be 0.6, 0.5 and 5 per 1000 statin-treated subjects over 5 years period [32] . Some school of thought focused on the legacy effects of statin and emphasized on the post-treatment relation of statin effect up to 8 to 11 years [33] . Also, the cost-effectiveness of the statins along with availability in generic form definitely supports the idea of prolonging statin therapy [34] . National Health and Nutrition Survey data (US NHANES) survey data revealed that even slight decrease in LDL level following statin therapy was associated with prevention of 40,020 deaths, 61,074 Acute MI-related hospitalizations, 22,272 Stroke related hospitalizations with resultant reduction of health care cost through $440 million [35] . All these characterize the need for initiation of statin early for the primary prevention.

A detailed exploration of the evidence defining the current guidelines reveal an interplay of evidence supporting the current concept with a rim of following uncertainties regarding the validity and generalizability of the evidence put forward.

Non-uniformity of clinical trials in outcome selection. Most of the clinical trials are heterogeneous in how they classify the CVDs in terms of single output versus composite CVD index, which may actually not be competent for comparison or pooling of trials [22] [24] . Some trials included prevalent CVD cases (<50% versus none), which might result in spurious association [22] .

Power. The trials, which included CVDs as secondary response variable may actually be unpowered to look at the effect of statin on CVD outcome.

Generalizability. Most of the trials include and compare the efficacy of statin for a specific group and age range of the population. But there is a need to include the various other groups including more female population,