Literature Review on The Benefits of Statins in Patients without CAD

This annotated bibliography researches whether statin medications should be prescribed to patients without coronary artery disease.  The search engine utilized was PubMed.  Initial search of “statin medication patient without coronary artery disease” was not successful in obtaining pertinent articles.  Utilizing the phrase “statin primary prevention coronary artery disease” and filtering article types and publication dates narrowed search to 42 articles, three of which were chosen to support topic.  In review of the initial search, two MeSH terms were noted on several of the articles: “hydroxymethylglutaryl CoA Inhibitors” and “primary prevention”.  By searching for these individually as MeSH terms and then combining search while maintaining previous filters, articles were narrowed to another set of 42 from which two additional articles were chosen.  Four of the articles were chosen based upon efficacy of benefit for patients without coronary artery disease but other predisposing factors including patients with elevated LDL, high genetic risk of coronary heart disease, diabetes and chronic kidney disease.  The fifth study validated the current American College of Cardiology/American Heart Association guidelines for primary prevention for cardiovascular disease compared to trial based and hybrid recommendations. 

Breuker, C., Clement, F., Mura, T., Macioce, V., Castet-Nicolas, A., Audurier, Y., … & Avignon, A. (2018). Non-achievement of LDL cholesterol targets in patients with diabetes at very-high cardiovascular risk receiving statin treatment: Incidence and risk factors. International Journal of Cardiology, 268, 195-199. doi: 10.1016/j.ijcard.2018.04.068

• Purpose of study: Evaluate use of statins in patients with diabetes mellitus (DM).
• Type of study: This study is an observational study over three year period from May 2014 – May 2017.
• Who was included in the study: All adult diabetic patients admitted to Diabetes and Nutrition unit of the University Hospital of Montpellier, France.  Study criteria included: patients with Type 1 or 2 DM on statin therapy for at least 3 months, had at least one fasting blood lipid profile and classified at very high cardiovascular risk according to the European Society of Cardiology (ESC) guidelines. Patients with end-stage renal disease and on Fibrate treatment were excluded.  Patient with elevated triglycerides > 4.5 mmol/L were excluded due to inability to use Friedewald formula.
• Total number of participants: 654 participants
• Statistical methods used to answer the studies purpose:  Data was collected (age, sex, tobacco smoking, body mass index, hypertension, presence and type of CVD) at admission.  LDL-C levels calculated with Friedewald formula and glomerular filtration rate according to CKD-EPI formula.  Blood samples were taken within 24 hours of admission.  Name and daily dose of lipid lowering drugs documented at admission.  Statin therapy intensity stratified into three categories according to expected reduction in LDL-C levels: high, moderate, low.  CV risk level and LDL-C target values defined according to 2011 and 2016 ESC guidelines, target of LDL-C < 1.8 mmol/L.  Patients were then divided into two subgroups, those who met target and those who were  1.8 mmol/L.  The Student t-test and Mann-Whitney U test were used for continuous variables.  The Chi square and Fisher exact test were used for categorical variables.  Variables associated with non-attainment of LDL-C cholesterol were further evaluated with resultant P scores using univariate and multivariate analysis.  
• Statistically significant results: Women had higher incidence of not reaching recommended LDL-C target, P value < 0.001.  Patients with no history of coronary artery disease (P value 0.009) nor stroke or TIA (p value 0.08) also had higher incidence of not meeting recommended LDL-C level of < 1.8 mmol/L. 
• Strengths of study: First to assess LDL-C target value and determine predictors of non-attainment in very high risk patients with diabetes mellitus treated with statins.  All blood samples were collected within 24 hours of hospital admission.
• Weaknesses of study: Monocentric, only at one hospital, in which the diabetes mellitus patients are considered part of high risk population.  The study only included patients admitted mainly for management of their diabetes and thus did not include stable patients in the outpatient setting. 

In summary this article evaluated LDL-C levels of patients admitted to Montpellier University Hospital in France to with type 1 or type 2 diabetes mellitus on statin therapy.  The patients were subdivided into high, moderate and low categories based upon their statin therapy.  Patients were further categorized into two categories, attainment of LDL-C target of < 1.8 mmol/L or non-attainment with LDL-C  1.8 mmol/L on their current therapy.  59% of patients did not meet the target LDL-C levels with median value of 2.4 mmol/L.  Risk of non-attainment was increased in women but decreased in patients with history of coronary artery disease or history of stroke/TIA.  The study concluded patients with diabetes, who are at increased risk of cardiovascular event or disease due to their diabetes disease, treatment levels were suboptimal especially in women and in those with no history of coronary disease or event.  Statin therapy should be more aggressive in treating patients with diabetes but especially with women and in primary prevention.  

Mortensen, M. B., Afzal, S., Nordestgaard, B. G., & Falk, E. (2015). Primary prevention with statins: ACC/AHA risk-based approach versus trial-based approaches to guide statin therapy. Journal of the American College of Cardiology, 66(24), 2699-2709. doi: 10.1016/j.jacc.2015.09.089

• Purpose of study: Side by side comparison of primary prevention recommendations for atherosclerotic cardiovascular disease (ASCVD) with statins based upon American College of Cardiology/American Heart Association risk assessment with trial-based and hybrid approaches.
• Type of study: Ongoing controlled study of Danish citizens randomly selected to participate through the Danish Civil Registration system.  This study chose participants between 2003-2008. 
• Who was included in the study: Those selected were narrowed to ages 40-75 to coincide with ACC/AHA guidelines and excluded individuals with diabetes, ASCVD or statin use or those missing information at baseline.
• Total number of participants: 37,892 participants
• Statistical methods used to answer the studies purpose: Calculated number and percentage of participants eligible for statin therapy with LDL-C  190 mg/dL or 10-year ASCVD risk  7.5% according to three approaches ACC/AHA risk-based guidelines, trial based approach and hybrid approach.  The observed event rate for 1,000 person years among statin eligible patients was calculated and compared.  A Venn diagram was used to show overlap in statin recommendations amongst the three approaches.  Calculated and compared sensitivity (correctly assign treatment to subjects who develop ASCVD in the future) with specificity (risk of treating subjects who do not need treatment) and binary net reclassification index (NRI).  NRI (to treat or not to treat) sum of change in sensitivity and change in specificity with theoretical range of -2 to 2.
• Statistically significant results: More patients were eligible for statin therapy under trial based approach (56% versus ACC/AHA 42% and Hybrid 21%) and fewer ASCVD events were noted (7 versus ACC/AHA 10 and Hybrid 11).  But assessment with the NRI clinical performance of the ACC/AHA approach was superior to the other approaches and prevented more ASCVD events than trial based approach by treating fewer people.  Both ACC/AHA and trial based approaches were superior to hybrid approach.  (ACC/AHA NRI reference, trial based -0.21 and hybrid -0.13). 
• Strengths of study: Number of participants in this study and large of number of participants in chosen randomized controlled trials with complete follow up. 
• Weaknesses of study: Limited ability to consider all exclusion criteria used in chosen comparison randomized controlled trials (RCT) of statins.  Only white individuals of Danish descent were evaluated thus results do not apply to other ethnicities/races.  Lastly, the CPGS follow up was less than 10 years and thus this study was based upon a 5 year model thus an assumption was made that ASCVD events would be comparable from 5 to 10 years.  

This study was created to evaluate the best recommendation in primary prevention for statin therapy to avoid under or over treatment comparing current ACC/AHA recommendations with trial based and hybrid trial/risk calculator.  The trial based reviewed results of five trials, WOSCOPS, AFCAPS/TexCAPS, ASCOT-LLA, MEGA and JUPITER.  The hybrid approach evaluated evidence from both approaches in calculating statin therapy in primary prevention.  More patients were eligible for statin therapy under trial based approach and there were fewer ASCVD event rates per 1,000 person-year.  The least number of individuals were eligible for statin therapy under the hybrid approach.  The hybrid approach also had the highest predicted ASCVD events of 11.  The ACC/AHA guidelines were superior to both approaches by discriminating for sensitivity, specificity and binary NRI.  The ACC/AHA risk based approach will prevent more ASCVD events while recommending statin therapy for fewer individuals.  

Natarajan, P., Young, R., Stitziel, N. O., Padmanabhan, S., Baber, U., Mehran, R., … & Rader, D. J. (2017). Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting. Circulation, 135(22), 2091-2101.  doi: 10.1161/CirculationAHA.116.024436

• Purpose of study: Validate and confirm statin therapy reduces risk of first coronary artery heart disease event for high genetic risk individuals as compared to currently available data from two other randomized control trials.  Secondly that individuals at high genetic risk carry a greater burden of subclinical atherosclerosis. 
• Type of study: Randomized controlled trial (RCT) and observational study of participants in three trials: West of Scotland Coronary Prevention Study (WOSCPS), Coronary Artery Risk Development in Young Adults (CARDIA) and BioImage.  Compared with participants from Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LA) and Justification for the Use of Statins in Prevention (JUPITER) trials.
• Who was included in the study: WOSCOPS trial: men 45-64 years with hypercholesterolemia, without history of myocardial infarction.  CARDIA observational cohort: 18-30 years of age (at baseline) without coronary heart disease (CHD) but with available genetic data and coronary artery calcification (CAC) assessment at the 15 year follow up.  BioImage multicentric, observational study: adults 55-80 with subclinical atherosclerosis but no clinical atherosclerotic cardiovascular disease (ASCVD).  ASCOT-LLA RCT: participants with hypertension but without cardiovascular disease.  JUPITER RCT: participants with elevated C-reactive protein but no history of cardiovascular disease. 
• Total number of participants:
  • WOSCOPS RCT: 4892
  • CARDIA study: 1154
  • BioImage study: 4929
  • ASCOT-LLA RCT: 6978
  • JUPITER RCT: 8769
• Statistical methods used to answer the studies purpose: Calculated WOSCOPS, CARDIA and BioImage study participants polygenic risk score based upon up to 57 common DNA sequence variants previously associated with coronary heart disease.  Compared those at high genetic risk (top quintile of polygenic risk score) and all others then tested different relative risk reduction with statin therapy versus placebo in each subgroup.  The two population-based cohort studies (CARDIA and BioImage) were tested to determine if prevalent subclinical atherosclerosis differed between those at high genetic risk and all others.  Total CAC was assessed at 15-year follow up for CARDIA participants.  Carotid artery plaque was assessed in BioImage participants using carotid ultrasound.  A Cox proportional hazard model was used to evaluate data of WOSCOPS trial and then participants were stratified into one of two groups: high genetic risk and all others.  Lastly tested difference relative risk reduction with statin therapy versus placebo in each subgroup.  Study level meta-analysis combined WOSCOPS data with ASCOT-LLA and JUPITER trial results. 
• Statistically significant results:Statin therapy reduced risk for a first CHD event in those at high genetic risk (P < 0.0001) as compared to all others (P value = 0.004).  With all three studies combined (WOSCOP, ASCOT-LLA and JUPITER) statin therapy reduced risk in those with high genetic risk for first CHD event by 46% (P <0.001) as compared to statin therapy risk reduction by 26% for all others (P<0.001).
• Strengths of study:  Large sample size in multiple trials across broad ages 15-80 across > 4.8 years.  Demonstrated individuals with increases in polygenic risk score correlated with increases in CAC or burden of carotid plaque. 
• Weaknesses of study:  Entry into 3 RCTs were different and with varying follow up times.  Only individuals with European descent were included.  In the WOSCOPS trial, events beyond trial cessation were included.  Lastly, utility of polygenic risk score in individuals with familial hypercholesterolemia is uncertain, risk of CHD events is already known in this population subset. 

In summary, this study served to further validate results from two other trials ASCOT-LLA and JUPITER suggesting that individuals with high genetic risk benefit from statin therapy even more than individuals without genetic risk.  This study assigned participants of the WOSCOPS, CARDIA and BioImage studies with a polygenic risk score based upon up to 57 common DNA sequence variants associated with coronary heart disease.  Results demonstrated that individuals with high polygenic risk scores received greater clinical benefit from statin therapy than those without genetic risk.  There was a 44% relative risk reduction of CHD with statin therapy among WOSCOPS trial participants as compared to 24% relative risk reduction among all others.  The study-level meta-analyses with WOSCOPS, ASCOT-LLA and JUPITER trials further supported that those at high genetic risk had a 46% relative risk reduction from statin therapy versus 26% for all others.  When assessing the data from CARDIA and BioImage trials, increases in polygenic risk scores was associated with an increase possibility of having coronary artery calcification or burden of carotid plaque.  Identification of patients with high polygenic risk scores can further determine who derives greatest benefit from statin therapy to prevent first CHD event. 

Palmer, S. C., Navaneethan, S. D., Craig, J. C., Johnson, D. W., Perkovic, V., Hegbrant, J., & Strippoli, G. F. (2014, May 31). HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database of Systematic Reviews, (5). doi: 10.1002/1461858.CD007784.pub2.

• Purpose of study: Update review of published data in 2009 to include additional evidence which evaluates: 1. Benefits of statins to reduce cardiovascular events in patients with chronic kidney disease (CKD) not on dialysis. 2. Benefit of statins to reduce incidence of cardiovascular disease and death in individuals with CKD not on dialysis who do not have heart disease. 
• Type of study: Meta-analyses of 50 studies published before June 2012
• Who was included in study: Studies included individuals with CKD not on dialysis.  Exclusion criteria: Individuals with CKD on dialysis or kidney transplant recipient.   
• Total number of participants: Reviewed 45,285 in 50 studies.  47 studies (39,820 participants) compared statins with placebo or no treatment and three studies (5547 participants) compared two different statin regimes in adults with CKD who were not on dialysis. 
• Statistical methods:  Risk bias tool was utilized in choosing studies.  Measures of treatment effect were expressed as risk ratio with 95% confidence intervals. Heterogeneity was analyzed by using CHI test.  Funnel plots were created and assessed statistically with Egger regression test.  The Grading of Recommendations Assessment Development and Evaluation guidelines were used to summarize quality of evidence together with absolute treatment effects based on estimated baseline risks.  Sensitivity analyses was performed to explore influence of unpublished studies, risk of bias, very long or very lard studies to determine how much they dominate results. 
• Statistically significant results:  Risk Ratio for decrease in major cardiovascular events was 0.72 from 20 per 1000 placebo/no treatment to 14 per 1000 statin therapy with 95% CI. 
• Strengths of study: This review updated current evidence by re-evaluating available data since 2009 by reviewing data from 50 clinical trials with > 45,000 participants.
• Weaknesses of study: There was a risk of bias in the studies.  Only 7 of the studies comparing statins with placebo or not treatment had lower risk of bias.  Another weakness of this meta-analyses was that studies did not systemically evaluate for harm of statin therapy on CKD participants including progression of known CKD. 

The number of individuals with CKD globally is increasing in individuals aged 20 years and over due to obesity, high blood pressure and diabetes.  Individuals with CKD not on dialysis have similar risk as individuals with existing heart disease for death or complications of cardiovascular disease.  This meta-analysis served to highlight that individuals with CKD not on dialysis benefit from statin therapy to reduce cardiovascular death and major cardiovascular events by 20% and 25% respectively and risk of MI by nearly half.   The review did not conclude that statin therapy can slow CKD progression nor evaluate adverse effects in individuals with CKD.   

Vallejo-Vaz, A. J., Robertson, M., Catapano, A. L., Watts, G. F., Kastelein, J. J., Packard, C. J., … & Ray, K. K. (2017). 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, 136(20), 1878-1891. doi: 10.1161/CIRCULATIONAHA.117.027966.

• Purpose of study:  Provide evidence supporting initiation of statin therapy in primary prevention for individuals with low-density lipoprotein cholesterol (LDL-C) levels  190 mg/dl.  Coronary heart disease (CHD) and major cardiovascular events (MACE) were assessed over 4.9 year randomized control trial (RCT) phase and on mortality outcomes over a total of 20 years of follow-up. 
• Type of study:  Randomized control trial and observational study
• Who was included in study:  Men aged 45-64 years without evidence of vascular disease  at baseline (evidence of angina, intermittent claudication, stroke, transient ischemic attack, and minor ECG abnormalities) and LDL-C  155 mg/dL not receiving lipid lowering therapy.  Two groups with LDL-C < 190 mg/dL and those with LDL-C  190 mg/dL.  Exclusion criteria included individuals with LDL-C > 232 mg/dL on 2 fasting lipid measurements during screening phase and evidence of prior myocardial infarction. 
• Total number of participants: 5529 participants (out of original 6595 participants in WOSCOPS study). 
• Statistical methods used to answer the studies purpose:  Effects on statin therapy and changes in LDL-C on outcomes were calculated using Cox proportional hazards model which provided estimates of hazard ratio with 9% confidence interval.  Additionally, Kaplan-Meier method based on original treatment arm was used to estimate time-to-event curves.  The Pooled Cohort Risk Equations were applied to WOSCOPS cohort who were free of atherosclerotic cardiovascular disease (ASCVD) and diabetes to assess global cardiovascular risk.  For purposes of this trial focus was placed on MACE. 
• Statistically significant results:  Primary prevention cohort long term with LDL-C  190 mg/dL CHD death, P = 0.020, cardiovascular death, P = 0.009 and all-cause mortality, P = 0.004 as compared to those with LDL-C < 190 mg/dL CHD death, P = 0.011, cardiovascular death, P = 0.382 and all-cause mortality, P = 0.247. 
• Strengths of study:  Evidence from RCT validating long term reduction in LDL-C in primary prevention of ASVCD in group higher-risk individuals (LDL-C  190 mg/dL) where evidence is lacking.   
• Weaknesses of study:  Bias may be present that individuals with LDL-C  190 may have continued on statin therapy after the trial completed at 4.9 years thus at 15 year follow the observational period might be confounded by lack of ongoing information on medication use. 

In summary, this trial evaluated statin therapy with Pravastatin versus placebo, in risk reduction of coronary heart disease in individuals in primary prevention of ASCVD with LDL-C  190 mg/dL.  The 5 year follow-up and 20 year observational follow-up of WOSCOPS study participants were the focus.  This study evaluated the control group (placebo) with those on Pravastatin in two divided groups, LDL-C < 190 mg/dL and LDL-C  190 mg/dL.  They then calculated reduction in CHD, MACE, CHD death, cardiovascular death and all-cause mortality in these groups.  In the initial trial phase Pravastatin significantly reduced risk of CHD (27%) and MACE (25%) in individuals with LDL-C  190 mg/dL.  In long-term follow up of same group, Pravastatin significantly reduced CHD (28%), cardiovascular death (25%) and all-cause mortality (18%).  These results also showed a 2-fold greater absolute reduction in the risk of death at 20 years from CHD, cardiovascular causes and any cause over the LDL-C < 190 mg/dL cohort.  This study provided direct evidence of benefit.  Current practice recommendations were obtained with indirect evidence derived from extrapolation of other data.  Study authors comment that it would unethical to perform a placebo-controlled trial in a population with LDL-C  190 mg/dL.  The ability to perform an observational study on participants of WOSCOPS trial and confirm benefit of statin therapy validates current practice further.

References

• Breuker, C., Clement, F., Mura, T., Macioce, V., Castet-Nicolas, A., Audurier, Y., … & Avignon, A. (2018). Non-achievement of LDL-cholesterol targets in patients with diabetes at very-high cardiovascular risk receiving statin treatment: Incidence and risk factors. International journal of cardiology, 268, 195-199. doi:10.1016/j.ijcard.2018.04.068.
• Mortensen, M. B., Afzal, S., Nordestgaard, B. G., & Falk, E. (2015). Primary prevention with statins: ACC/AHA risk-based approach versus trial-based approaches to guide statin therapy. Journal of the American College of Cardiology, 66(24), 2699-2709. doi: 10.1016/j.jacc.2015.09.089.
• Natarajan, P., Young, R., Stitziel, N. O., Padmanabhan, S., Baber, U., Mehran, R., … & Rader, D. J. (2017). Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting. Circulation, 135(22), 2091-2101. doi: 10.1161/ciruclationaha.116.024436.
• Palmer, S. C., Navaneethan, S. D., Craig, J. C., Johnson, D. W., Perkovic, V., Hegbrant, J., & Strippoli, G. F. (2014, May 31). HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database of Systematic Reviews, (5). doi: 10.1002/14651858.cd007784.pub2
• Vallejo-Vaz, A. J., Robertson, M., Catapano, A. L., Watts, G. F., Kastelein, J. J., Packard, C. J., … & Ray, K. K. (2017). 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, 136(20), 1878-1891. doi: 10.1161/circulationaha.117.027966.