Table 2.

Summary of the included studies showing a relation between lipid and MI and stroke.

Author, Year	Name of the Study	Participant	Number of Risk Factors	Findings
Heart Protection Study Collaborative Group, 2002	Heart Protection Study	20536 Age 40-80 years	Those without the diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry.	Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, stroke, and revascularization by about one-quarter.
Sever et al., 2003	Anglo Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA) Double-blind placebo-controlled trial	19342 hypertensive patients (aged 40-79 years	All coronary events, all cardiovascular events, fatal and non-fatal stroke, development of chronic stable angina, heart failure, and peripheral arterial disease.	The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time.
Scandinavian Simvastatin Survival Study Group, 1994	Scandinavian Simvastatin Survival Study (4S) Randomized double-blind trial	4444 patients	Effect of cholesterol-lowering with simvastatin on mortality and morbidity in patients with coronary heart disease (CHD).	Long-term treatment with simvastatin is safe and improves survival in CHD patients.
Tonkin, Simes, Sharpe, & Thomson, 1998	The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Randomized double-blind trial	9014 patients who were 31 to 75 years of age	The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Compared the effects of pravastatin (40 mg daily) with those of a placebo.	Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all pre-specified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.
Sacks et al., 1996	The Cholesterol and Recurrent Events (CARE) trial	4159 men and women aged 21 to 75 enrolled in 80 centers around the US and Canada	Secondary prevention of CHD 3 to 20 months post-MI Total-C < 240; LDL-C between 115 and 174; Triglycerides < 350 mg/dL 5 years Treatment with Pravastatin 40 mg vs. placebo	The benefit of cholesterol-lowering therapy extends to most patients with coronary disease who have average cholesterol levels
SPARCL Investigators, 2006.	Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study (SPARCL)	4,731 participants, 40% female Mean age 63 years	For subjects randomized to atorvastatin 80 mg/d or placebo stroke or TIA without known coronary heart disease	Atorvastatin 80 mg/d is similarly efficacious in preventing strokes and other cardiovascular events, irrespective of baseline ischemic stroke subtype.
Mitchell Elkind et al., 1990	Northern Manhattan Study (NOMAS)	Over 4,400 people from the community were enrolled	Stroke and stroke risk factors in the Northern Manhattan community in whites, blacks, and Hispanics living in the same community. A population-based incidence and case-control study.	The study has already made great advances in the understanding, prevention, and treatment of stroke. Caribbean Hispanics from the Northern Manhattan community had strokes at a younger age than blacks and whites. There was also a higher rate of stroke-related death in Caribbean Hispanic and black patients than in white patients.
Blackburn, Keys, Simonson, et al. 1984	Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT): A multicenter, randomized, double-blind study	3,806 asymptomatic middle-aged men were enrolled with primary hypercholesterolemia	Tested the efficacy of cholesterol lowering in reducing the risk of coronary heart disease (CHD)	Reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels.
Hennekens, Sacks, Tonkin, et al., 2004	Additive Benefits of Pravastatin and Aspirin to Decrease Risks of Cardiovascular Disease Randomized and Observational Comparisons of Secondary Prevention Trials and Their Meta-analyses	73 900 patient-years of observation	Secondary prevention with pravastatin sodium and aspirin (40 mg/d) decreases cardiovascular disease risks	More widespread and appropriate combined use of statins and aspirin in secondary prevention of cardiovascular disease will avoid large numbers of premature deaths.
Prospective Studies Collaboration, 1995	Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts	Review of 45 prospective observational cohorts involving 450,000 individuals with 5-30 years of follow-up	The relations of blood cholesterol and diastolic blood pressure with subsequent stroke rates were examined.	After standardization for age, there was no association between blood cholesterol and stroke except, perhaps, in those under 45 years of age when screened. However, because the types of strokes were not centrally available, lack of any overall relation might conceal a positive association with ischemic stroke together with a negative association with hemorrhagic stroke.
Zinat Nadia Hatmi, Nasrin Jalilian, and Ali Pakravan, 2019	The Relationship Between Premature Myocardial Infarction with TC/HDL-C Ratio Subgroups in a Multiple Risk Factor Model	1222 MI cases of both women and men. Cases included 523 newly diagnosed MI patients under 55 years. Whereas controls included 699 newly diagnosed cases of MI whose ages were above 55 years	CAD risk factors of cases and controls included: smoking, family history of premature CAD, fasting blood sugar, cholesterol and Triglyceride, HDL, LDL, and hypertension.	The study concluded that reduction of the level of TC/HDL-C ratio from low risk to a very low risk category, will diminish the risk of MI by about 8% in patients under 55 years of age. Therefore, the study suggests that aggressive treatment interventions aiming towards lowering TC/HDL-C ratio could be a crucial clinical implication
Amit V. Khera, Olga V. Demler, Steven J. Adelman, Heidi L. Collins, Robert J. Glynn, Paul M Ridker, Daniel J. Rader, and Samia Mora, 2018.	Cholesterol Efflux Capacity, HDL Particle Number, and Incident Cardiovascular Events	17,802 asymptomatic individuals with normal LDL cholesterol but increased C-reactive protein levels, 314 cases of CVD were compared to age and sex matched controls	Risk factors include age, race, treatment group (placebo or rosuvastatin), systolic blood pressure, smoking status, body-mass index, fasting glucose, log-transformed triglycerides, LDL cholesterol level, and family history of premature CAD.	For both baseline and on statin analyses, HDL particle number was the strongest inverse predictor among four HDL-related biomarkers, whereas cholesterol efflux capacity was associated with CVD in individuals on potent statin therapy but not at baseline.
Michael V. Holmes, Iona Y. Millwood, Christiana Kartsonaki, Michael R. Hill, Derrick A. Bennett, Ruth Boxall, Yu Guo, Xin Xu, Zheng Bian, Ruying Hu, Robin G. Walters, Junshi Chen, Mika Ala-Korpela, Sarah Parish, Robert J. Clarke, Richard Peto, Rory Collins, Liming Li, Zhengming Chen and on behalf of the China Kadoorie Biobank Collaborative Group, 2018.	Lipids, Lipoproteins, and Metabolites and Risk of Myocardial Infarction and Stroke	4,662 common control subjects aged between 30 to 79.	Age, sex, smoking, SBP, BMI, type 2 diabetes, and total cholesterol/HDL-C ratio.	Positive association between MI, IS, and Very low-, intermediate-, and low-density lipoprotein particles were concluded. High-density lipoprotein (HDL) particles were found to be inversely associated with MI.
Mee Kyoung Kim, Kyungdo Han, Hun-Sung Kim, Yong- Moon Park, Hyuk-Sang Kwon, Kun-Ho Yoon, Seung-Hwan Lee, 2017.	Cholesterol variability and the risk of mortality, myocardial infarction, and stroke: A nationwide population-based study	Study population consisted of 3,656,648 subjects with no history of MI or stroke	BMI, smoking, alcohol consumption, DM, Blood pressure, regular exercise, dyslipidemia	Cholesterol variability is an important risk factor and predictor for MI and stroke.
Emanuele Di Angelantonio, Pei Gao, Lisa Pennells,, Stephen Kaptoge, Muriel Caslake, Alexander Thompson, Adam S. Butterworth, Nadeem Sarwar, David Wormser, and Danish Saleheen, Christie M. Ballantyne, Bruce M. Psaty, Johan Sundström, Paul M Ridker, Dorothea Nagel, Richard F. Gillum,Ian Ford, Pierre Ducimetiere, Stefan Kiechl, Wolfgang Koenig, Robin P. F. Dullaart, Gerd Assmann, Ralph B. D'Agostino Sr, Gilles R. Dagenais, Jackie A. Cooper, Daan Kromhout, Altan Onat, Robert W. Tipping, Agustín Gómez-de-la-Cámara, Annika Rosengren, Susan E. Sutherland, John Gallacher, F. Gerry R. Fowkes,Edoardo Casiglia, Albert Hofman, Veikko Salomaa, Elizabeth Barrett-Connor, Robert Clarke, Eric Brunner, J. Wouter Jukema, Leon A. Simons, Manjinder Sandhu, Nicholas J. Wareham, Kay-Tee Khaw, Jussi Kauhanen, Jukka T. Salonen, William J. Howard, Børge G. Nordestgaard, Angela M. Wood, Simon G. Thompson, S. Matthijs Boekholdt, Naveed Sattar, Chris Packard, Vilmundur Gudnason, and John Danesh, 2012	Lipid-Related Markers and Cardiovascular Disease Prediction	165,544 participants without baseline CVD in 37 prospective cohorts	Age, sex, smoking status, history of diabetes, and systolic blood pressure, total cholesterol, HDL-C, assayed triglyceride, apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2	In a study of individuals without known CVD, the enrollment of lipid related markers information such as apolipoprotein B and A-I, lipoprotein(a), or lipoproteinassociated phospholipase A2 mass to risk scores containing conventional lipid markers of total cholesterol and HDL-C, led to a slight improvement in CVD prediction
Canouï-Poitrine F, Luc G, Bard J.-M, Ferrieres J, Yarnell J., Arveiler D., Morange P. Kee F., Evans A., Amouyel P., Ducimetiere P., Empana J.-P.	Relative Contribution of Lipids and Apolipoprotein to Incident Coronary Heart Disease and Ischemic Stroke: The PRIME Study	9,711 men aged 50–59 years, free of CHD and stroke at baseline	Age, systolic blood pressure, antihypertensive treatment, current smoking status, body mass index and diabetes	Total-C, HDL-C, LDL-C, non-HDL-C, Triglycerides, Apo A1 and Apo B100, their ratios and Lp(a) are significantly predictive of future CHD, weak predictors, if anything, of ischemic stroke over 10 year period.
Salim Yusuf,, D.Phil., Eva Lonn, Prem Pais, Jackie Bosch, Patricio López-Jaramillo, Jun Zhu, Denis Xavier, Alvaro Avezum, Lawrence A. Leiter, Leopoldo S. Piegas, Alexander Parkhomenko, Matyas Keltai, 2016.	Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease	12,705 participants at intermediate risk who did not have cardiovascular disease. The study included men 55 years of age or older and women 65 years of age or older	The trial included age with at least one additional risk factor besides it, female sex, smoking, BMI, waist to hip ratio, low HDL, impaired glucose tolerance, early DM, family history of coronary heart disease, early renal dysfunction, family history of premature CHD, BP, race or ethnic group and medication used.	The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) produced greater LDL reduction and was found to be associated with a significantly lower rate of cardiovascular events than dual placebo among individuals at intermediate risk who did not have cardiovascular disease.
Raffaele De Caterina, Marco Scarano, RosaMaria Marfisi, Giuseppe Lucisano, Francesco Palma, Alfonso Tatasciore and Roberto Marchioli, 2010.	Cholesterol-Lowering Interventions and Stroke Insights From a Meta-Analysis of Randomized Controlled Trials	266,973 patients, with a cumulative exposure of 946,582 person-years, with the total number of trials testing the effectiveness of cholesterol lowering interventions and stroke being 82 .	Age, patient history of MI, inclusion of patients with diabetes mellitus, heart failure, and baseline levels of TC, triglycerides, and HDL-C.	Cholesterol lowering therapy is found to be linked with a significant reduction of stroke (total and non-fatal strokes), whereas no intervention was associated with a reduction of fatal stroke. This appears to be true for both statin and non-statin cholesterol-lowering interventions, with statins being the most effective, there appears to be a proportionality between the reduction of cholesterol (mostly LDL-C) and the reduction of total stroke, with an approximation of 0.8% reduction in TC for a 1.0% reduction of the relative risk of stroke.
Heart Protection Study Collaborative Group, 2016	Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial	20 536 men and women aged about 40–80 years at high risk of vascular and non-vascular outcomes		The group assigned 20mg simvastatin achieved an average LDL reduction by 1.0 mmol/L, which was proportional to a 23% reduction in cardiovascular events with significant divergence each year, prolonged LDL-lowering statin treatment results in a significant reduction in vascular events and benefit persists for at least 5 years wich support prompt initiation and long term statin treatment.
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, 2010	Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: A double-blind randomised trial.	12,064 men and women aged 18–80 years with a history of myocardial infarction.	Men and women aged 18–80 years with a history of previous myocardial infarction were eligible provided they match the following inclusion criteria: either current statin use or clear indication for this treatment (and no clear indication for folic acid); total cholesterol of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not; and no clear contraindications to the study treatments.11 individuals with other predominant medical problems that could reduce compliance with long-term study treatment were also excluded.	Participants assigned 80mg simvastatin had a 6% (SE 3·5%) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol compared to those allocated to 20mg
Jeffrey S. Berger, Aileen P. McGinn, Barbara V. Howard, Lewis Kuller, JoAnn E. Manson, Jim Otvos, J. David Curb, Charles B. Eaton, Robert C. Kaplan, John K. Lynch, Daniel M. Rosenbaum, and Sylvia Wassertheil-Smoller, 2012	Lipid and Lipoprotein Biomarkers and the Risk of Ischemic Stroke in Postmenopausal Women.	82,591 postmenopausal women aged between 50-79 years.	Women who made the inclusion criteria provided informed consent to be a part of the study and were 50–79 years of age at baseline, postmenopausal, had no medical conditions associated with a predicted survival of <3 years	The study concluded that IDL,VLDL and triglyceride were associated with ischemic stroke. These results support the AHA guidelines that state triglycerides as stroke risk factors.
Xiaojuan Liu, Ling Yan, Fuzhong Xue, 2018.	The associations of lipids and lipid ratios with stroke: A prospective cohort study	42 005 participants (25 989 men and 16 016 women) were enrolled aged between 20-80 years.	Three lipid ratios were computed: TC/HDL-C, TG/HDL-C, and LDL-C/HDL-C, all of which have at least once been reported as a predictor of cardiovascular risk in the literature, Systolic blood pressure (SBP) and diastolic blood pressure (DBP), BMI, history or current cigarette smoking, alcohol consumption status, family history of CVD, history of hypertension, Type 2 diabetes mellitus and information on the use of lipid-lowering drugs.	In men,TC/HDL-C was the most important predictor of ischemic and total stroke, whereas TG was the most reliable in predicting ischemic and total stroke in women. These two lipid indexes may serve as potential targets for stroke prevention and are of important prognostic value.