Statins are a class of medications that lower cholesterol by inhibiting HMG-CoA reductase, an enzyme involved in the rate limiting step of the production of cholesterol.1 They probably also work by lowering inflammation in blood vessels.2
Atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD), stroke, and peripheral artery disease, is one of the leading causes of death in the United States.3 One of the risk factors for ASCVD is high cholesterol. Other risk factors include diabetes, smoking, and hypertension. Cholesterol can be modified by diet, exercise, and medications. There is evidence that the low-density lipoprotein (LDL) component of cholesterol impacts on heart disease in a linear fashion.
Statin therapy reduces the risk of heart attack and stroke by about 20% regardless of the baseline lipid level.4 This means that the higher the risk, the greater the absolute benefit. For example, a person with a baseline risk of 8% may expect a risk reduction to 6.4% with statins. On the other hand, a person with baseline risk of 20% may expect a risk reduction to 16% with statins. It is important to discuss both relative and absolute benefits of statins, as well as the risk for side effects and costs. It is also important to understand the residual risk of ASCVD while on a statin.
Expert Recommendations for Primary Prevention of ASCVD with Statins
Experts from the American College of Cardiology (ACC), the American Heart Association (AHA), and the United Stated Preventive Services Task Force (USPSTF) have established guidelines for the use of statins in the primary prevention of ASCVD.5,6
2018 ACC/AHA Cholesterol Guidelines
The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines for the Management of Blood Cholesterol5 strongly recommends statins for individuals with pre-existing ASCVD as well as for those with:
- hypercholesterolemia (LDL-C ≥190 mg/dL)
- diabetes if they are age 40 – 75
- a 10-year risk of ASCVD ≥20% and an LDL-C ≥70 mg/dL
Statins may also benefit people who have with 10-year risk between 7.5% and 20%.5 The presence of one or more risk enhancers favors the use of statins. They include:
- elevated HbA1C
- persistently elevated LDL-C ≥160 mg/dL
- metabolic syndrome
- kidney disease
- early menopause or pre-eclampsia
- family history of premature ASCVD
- chronic inflammatory disease, South Asian descent, low ankle-brachial index, or persistently elevated triglycerides
The use of the coronary artery calcium (CAC) score can also be used to better stratify ASCVD risk when risk is uncertain.5 The CAC is a heart scan that looks for calcium deposits in the coronary arteries. When the score is zero, the 10-year risk is low. When the score is ≥100, statin therapy would likely to be of benefit. Statins are reasonable to consider when the CAC is 1 – 100.
Statins may also be considered for people younger than age 40 under certain circumstances, based on a physician-patient discussion of risk.5 The presence of familial hypercholesterolemia, family history of premature ASCVD and LDL-C ≥160 mg/dL, diabetes of long duration, or a CAC score ≥100 favors the use of a statin. Individuals over the age of 75 may also be considered for statins, if they have diabetes or are at high-risk of ASCVD, but the evidence for statin benefit in this age group is not strong.
2016 USPSTF Recommendations
- Patients who are aged 40 to 75 years, who have at least one risk factor (dyslipidemia, cigarette smoker, hypertension, diabetes) and who have a 10% or greater risk of having a stroke or heart attack over the next 10 years should be offered statin therapy with either a low- or moderate-intensity statin. [Recommendation: B]6
- Patients who are aged 40 to 75 years, who have at least one risk factor (dyslipidemia, cigarette smoker, hypertension, diabetes) and who have an ASCVD risk of 7.5% to 10% can be considered for statin therapy. [Recommendation: C]6
- There is insufficient evidence to recommend a statin for primary prevention of ASCVD in patients older than 75 years of age.6
The USPSTF recommendations emphasize the need for shared decision making between the healthcare professional and the patient, the realization that the risk calculator may overestimate risk in some and underestimate risk in others, and that significant deficits in our knowledge exist when making recommendations for primary prevention of ASCVD.6
Calculating ASCVD Risk
The AHA and ACC developed a risk calculator that estimates the risk of developing a heart attack or stroke over the next 10 years.7 There is an easy-to-use online calculator: ASCVD Risk Estimator Plus.
The risk calculator is based on several cohort studies: the Framingham Study, the Coronary Artery Risk Development in Young Adults Study, the Atherosclerosis Risk in Communities Study, and the Cardiovascular Health Study.8-11 It factors in age, gender, race, systolic blood pressure, total cholesterol, high density lipoprotein (HDL) cholesterol, LDL cholesterol, diabetes, and cigarette smoking to estimate the likelihood of developing a cardiovascular event, defined as a MI or stroke, over the next 10 years. Criticism of the calculator includes that the risk calculator may overestimate risk in some populations, specifically in socioeconomically advantaged individuals.12 Furthermore, the equations underlying the risk calculator are based on population level risks, not an individual’s risk.13 Nevertheless, the risk calculator does provide a basis to have a discussion with patients about their personal risk. It should be emphasized here that patients who have a LDL-cholesterol equal or greater than 190 mg/dL are considered to have at least a 20% risk of developing a heart attack or stroke over the next 10 years, and initiating therapy to lower their cholesterol is considered secondary prevention rather than primary prevention of ASCVD.6
To calculate the potential magnitude of risk reduction from heart disease for a patient without apparent ASCVD, it is important to consider the baseline characteristics of the patients who were in the primary prevention trials. In most of these trials, the patients were at elevated risk for ASCVD. A significant number of these patients had one or more risk factors for ASCVD including: a high baseline LDL cholesterol level, diabetes, hypertension, and smoking.
Selected Primary Prevention Trials
The West of Scotland Coronary Prevention study14 was a randomized, placebo-controlled trial that included 6595 white men between 45 to 64 years of age. The mean follow-up time was 4.9 years, and the endpoints were coronary events (nonfatal MI or death from CHD). The mean LDL cholesterol was 192 mg/dL. A significant percentage of the patients smoked cigarettes or had hypertension or diabetes. The study group was given pravastatin 40 mg. The study group realized an absolute risk reduction (ARR) of 2.3%, and the number needed to treat to avoid one event (NNT) was 50.
The Air Force/Texas Coronary Atherosclerosis Prevention Study15 was a randomized, double-blind, placebo-controlled trial, including 6,605 patients. It evaluated the impact of lovastatin (20 – 40 mg) on the development of cardiovascular events. Eighty-five percent of the patients were men, and most were white. Again, several of the patients had hypertension, were cigarette smokers, and had a family history of CHD. The mean LDL cholesterol was 150 mmol/L. Those in the test group realized a 2% ARR, with a NNT of 50.
The Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm16 evaluated the impact of atorvastatin 10 mg on men and women who had a relatively normal serum cholesterol (average LDL 131, n=10,305) who also had hypertension and three additional risk factors for ASCVD. Those who received atorvastatin realized a 2% ARR, with an NNT of 50, over a follow-up period of 3.3 years. All-cause mortality was not significantly reduced.
The Heart Outcomes Prevention Evaluation trial17 was a multi-center, international, randomized, placebo-controlled trial with over 12,000 patients., studied for a median of 5.6 years. It evaluated the impact of rosuvastatin 10 mg on the incidence of a composite outcome of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. The ARR was 1.1%, with an NNT of 100. This trial was notable as it included a large percentage of Asian patients.
The Jupiter trial18 was a randomized, double-blind, placebo-controlled trial that evaluated the impact of rosuvastatin 20 mg on lowering cardiovascular risk in patients who had a high sensitivity C-reactive protein of 2 mg/L or more, but a normal LDL cholesterol level (<130 mg/dL). Over 17,000 people participated in this trial, and approximately 38% were women. The incidence of MI, stroke, or confirmed death from cardiovascular causes was 83 cases in the rosuvastatin group compared with 157 in the placebo group. Over a median follow-up period of 1.9 years, the ARR was 1.9%, with an NNT of 50.
Most of the primary prevention trials included patients who had very elevated cholesterol and additional risk factors such as smoking, hypertension, or type 2 diabetes. It is notable that most of the primary prevention trials evaluated the impact of either a low- or moderate-intensity statin therapy on measured outcomes.
The Cholesterol Treatment Trialists’ (CTT) Collaborators performed a meta-analysis19 that evaluated the effects of lowering LDL cholesterol in patients at low risk of vascular disease. They found that statin therapy reduces the risk of ASCVD events regardless of the baseline lipid profile, and that the overall risk rather than the initial LDL cholesterol level determined the magnitude of the benefit of statin treatment. The NNT over the course of ten years was 50.
Thavendiranathan et al. performed a meta-analysis20 of seven primary prevention trials that included 42,848 patients, with a mean follow-up of 4.3 years. They found that statin therapy decreased the incidence of major coronary and cerebrovascular events and revascularizations, but not CHD or overall mortality. They also found that the higher the baseline risk, the greater the benefit of the statin, and the lower the NNT.
- Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001; 292 (5519): 1160-1164.
- Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100 (3): 230-235.
- Kochanek K, Murphy S, Xu J, Arias E. Mortality in the United States, 2016. NCHS Data Brief, no 293. Hyattsville, MD: National Center for Health Statistics; 2017.
- Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376 (9753): 1670-1681.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol. Circulation 2018: Cir0000000000000625.
- 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.
- ASCVD Risk Estimator Plus. American College of Cardiology. 2017; http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/. Accessed 1/21/2018.
- Fried LP, Borhani NO, Enright P, et al. The cardiovascular health study: design and rationale. Ann Epidemiol 1991; 1 (3): 263-276.
- Loria CM, Liu K, Lewis CE, et al. Early adult risk factor levels and subsequent coronary artery calcification: the CARDIA Study. J Am Coll Cardiol 2007; 49 (20): 2013-2020.
- Rosamond WD, Chambless LE, Heiss G, et al. Twenty-two-year trends in incidence of myocardial infarction, coronary heart disease mortality, and case fatality in 4 US communities, 1987-2008. Circulation 2012; 125 (15): 1848-1857.
- Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97 (18): 1837-1847.
- Colantonio LD, Richman JS, Carson AP, et al. Performance of the atherosclerotic cardiovascular disease Pooled Cohort risk equations by social deprivation status. J Am Heart Assoc 2017; 6 (3).
- Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA 2014; 311 (14): 1406-1415.
- 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): 1301-1307.
- 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): 1615-1622.
- 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): 1149-1158.
- Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374 (21): 2021-2031.
- Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 (21): 2195-2207.
- 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): 581-590.
- Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern Med 2006; 166 (21): 2307-2313.