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What vitamins and minerals should be given to breastfed and bottle-fed infants?
Breastfed and formula-fed infants should receive intramuscular vitamin K soon after birth to prevent classic hemorrhagic disease of the newborn (strength of recommendation [SOR]: A, systematic review of controlled trials).
Routine iron supplementation for all term, healthy, breastfed infants is not proven to be safe or necessary. Formula-fed infants should be consuming formula that contains 10 to 12 mg/L of iron (SOR: A, 2 small randomized controlled trials).
Healthy, term infants at the highest risk for vitamin D deficiency are those who are breastfeeding and have dark skin or little sun exposure (SOR: B, 2 case series). Infants consuming at least 500 mL of fortified formula each day do not need additional supplementation. A recommendation of vitamin D supplementation of 200 IU/day should be explained to all families, particularly those at highest risk for nutritional rickets (SOR: C, expert opinion). Infants older than 6 months should receive an oral fluoride supplement of 0.25 mg if they consume fluids with a water fluoride level less than 0.3 ppm (SOR: B, poor-quality randomized controlled trials).
Encourage breastfeeding; keep vitamin D and iron needs in mind
Julia Fashner, MD
Piqua, Ohio
Physicians can help mothers give the best nutrition to their children by encouraging breastfeeding. In most cases, no supplements are required. From this information, I will keep in mind the shorter hours of daylight in the winter and the skin tone of the child, as this may warrant discussion of vitamin D supplementation in infants who are exclusively breastfed. Knowing the recommendations for iron supplementation will help physicians when counseling parents regarding formula choices. Lastly, vitamin K has become part of the routine protocol at delivery and should not be a factor for any child.
Evidence summary
Vitamin K. The Cochrane Database of Systematic Reviews looked at randomized trials to determine the effectiveness of vitamin K prophylaxis in preventing classic hemorrhagic disease of the newborn.1 Two trials demonstrated that a single dose of intramuscular vitamin K reduced clinical bleeding at 1 to 7 days. Oral vitamin K has been studied for its effects on biochemical indices of coagulation status, but not for its clinical effects on bleeding. A single oral vitamin K dose at birth resulted in lower vitamin K levels at 2 weeks and 1 month, compared with a single dose of intramuscular vitamin K at birth.
Iron. The iron status of exclusively breastfed infants vs formula-fed infants was evaluated in a nonrandomized cohort study.2 Twenty-five healthy, breastfed infants and 15 healthy infants fed high-iron formula were followed for 9 months. No differences in mean hemoglobin values were seen at any age between the 2 groups.
A randomized controlled trial investigated the efficacy of daily and weekly iron supplementation on iron status in 67 exclusively breastfed infants.3 At age 4 months the infants were randomized into 3 groups: daily iron, weekly iron, and no iron. No significant differences were detected in the mean weight, height, and head circumference among the groups. The mean values of hemoglobin, mean corpuscular volume, serum iron, and transferrin saturation were similar among all the groups at ages 5, 6, and 7 months.
A randomized, double-blind, placebo-controlled iron supplementation trial involved 214 exclusively breastfed infants from 4 to 9 months of age in Sweden and Honduras.4 Iron supplementation did not affect weight gain in the groups, but length gain from ages 4 to 9 months was less in the iron-supplemented groups than in the placebo group (P<.05 for placebo vs Fe). This effect was greater in Sweden, and only existed in Honduras for infants aged 4 to 6 months with initial mean Hgb of at least 11 mg/dL. The researchers conclude that iron supplementation may pose risks in iron-replete infants.
Vitamin D. A case review of nutritional rickets in North Carolina between 1990 and 1999 found that all 30 patients identified were breastfed African American infants.5 Among the 166 published cases of rickets in the US from 1986 to 2003, 83% were categorized as African American or black. Ninety-six percent of cases were breastfed.6
Fluoride. No infant under 6 months of age should receive fluoride supplementation to prevent dental caries because of the risk of enamel fluorosis.7 A systematic review that evaluated fluoride for preventing dental caries in primary teeth in children aged <5 years found 6 small clinical trials. Although the studies were not of high quality, they consistently showed that the incidence of caries was reduced by 32% to 72%.8
Recommendations from others
The American Academy of Pediatrics (AAP) recommends that:
- All newborns receive vitamin K as an intramuscular dose of 0.5 to 1 mg9
- All full-term appropriate-for-gestational-age breastfed infants receive a supplemental source of iron starting at 4 to 6 months of age, preferably from iron-enriched complementary foods. Infants should only receive formula fortified with 10 to 12 mg/L for weaning or supplementing breastmilk10
- All infants, including those exclusively breastfed, should have a minimum intake of 200 IU of vitamin D per day starting in the first 2 months of life.
The National Academy of Sciences recommends 200 IU of vitamin D daily for all normal infants, children, and adolescents.11
The US Preventative Services Task Force (USPSTF) states evidence is insufficient to recommend for or against the routine use of iron supplements for healthy infants.12
The USPSTF, AAP, and the American Academy of Pediatric Dentistry recommends 0.25 mg/d of fluoride supplement for children ages 6 months to 3 years if the fluoride concentration in the community drinking water is less than 0.3 ppm. Older children may benefit from supplements if the fluoride concentration is between 0.3 and 0.6 ppm.13
1. Puckett RM, Offringa M. Prophylactic vitamin K for vitamin K deficiency bleeding in neonates. Cochrane Database Syst Rev 2000;(4):CD002776.-
2. Calvo EB, Galindo AC, Aspres NB. Iron status in exclusively breastfed infants. Pediatrics 1992;90:375-379.
3. Yurdakok K, Temiz F, Yalcin SS, Gumruk F. Efficacy of daily and weekly iron supplementation on iron status in exclusively breastfed infants. J Pediatr Hematol Oncol 2004;26:284-288.
4. Dewey KG, Domellof M, Cohen RJ, Landa Rivera L, Hernell O, Lonnerdal B. Iron supplementation affects growth and morbidity of breastfed infants: results of a randomized trial in Sweden and Honduras. J Nutr 2002;132:3249-3255.
5. Kreiter SR, Schwartz RP, Kirkman HN, Jr, Charlton PA, Calikoglu AS, Davenport ML. Nutritional rickets in African American breastfed infants. J Pediatr 2000;137:153-157.
6. Weisberg P, Scanlon KS, Li R, Cogswell ME. Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003. J Clin Nutr 2004;80:1697S-1705S.
7. Centers for Disease Control and Prevention. Recommendations for using fluoride to prevent and control dental caries in the United States. MMWR Recomm Rep 2001;50:1-59.
8. Bader JD, Rozier G, Harris R, Lohr KN. Dental Caries Prevention: The Physician’s Role in Child Oral Health. Systematic Evidence Review no. 29. Rockville, Md: Agency for Healthcare Research and Quality, 2004. Available at: www.ahrq.gov/downloads/pub/prevent/pdfser/dentser.pdf. Accessed on November 15, 2005.
9. American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. Pediatrics 2003;112:191-192.
10. Gartner LM, Greer FR. Section on Breastfeeding and Committee on Nutrition, American Academy of Pediatrics. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics 2003;111:908-910.
11. Institute of Medicine, Food and Nutrition Board, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Vitamin D. In: Dietary Reference Intakes: For Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997;250-287.
12. DiGuiseppi C. Screening for iron deficiency anemia-including iron prophylaxis. In: US Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. Washington, DC: US Department of Health and Human Services, Agency for Healthcare Research and Quality; 1996:231–246. Available at: www.ahrq.gov/clinic/2ndcps/anemia.pdf. Accessed on November 15, 2005.
13. American Academy of Pediatric Dentistry. Special issue: reference manual 1994-95. Pediatric Dent 1995;16:1-96.
Breastfed and formula-fed infants should receive intramuscular vitamin K soon after birth to prevent classic hemorrhagic disease of the newborn (strength of recommendation [SOR]: A, systematic review of controlled trials).
Routine iron supplementation for all term, healthy, breastfed infants is not proven to be safe or necessary. Formula-fed infants should be consuming formula that contains 10 to 12 mg/L of iron (SOR: A, 2 small randomized controlled trials).
Healthy, term infants at the highest risk for vitamin D deficiency are those who are breastfeeding and have dark skin or little sun exposure (SOR: B, 2 case series). Infants consuming at least 500 mL of fortified formula each day do not need additional supplementation. A recommendation of vitamin D supplementation of 200 IU/day should be explained to all families, particularly those at highest risk for nutritional rickets (SOR: C, expert opinion). Infants older than 6 months should receive an oral fluoride supplement of 0.25 mg if they consume fluids with a water fluoride level less than 0.3 ppm (SOR: B, poor-quality randomized controlled trials).
Encourage breastfeeding; keep vitamin D and iron needs in mind
Julia Fashner, MD
Piqua, Ohio
Physicians can help mothers give the best nutrition to their children by encouraging breastfeeding. In most cases, no supplements are required. From this information, I will keep in mind the shorter hours of daylight in the winter and the skin tone of the child, as this may warrant discussion of vitamin D supplementation in infants who are exclusively breastfed. Knowing the recommendations for iron supplementation will help physicians when counseling parents regarding formula choices. Lastly, vitamin K has become part of the routine protocol at delivery and should not be a factor for any child.
Evidence summary
Vitamin K. The Cochrane Database of Systematic Reviews looked at randomized trials to determine the effectiveness of vitamin K prophylaxis in preventing classic hemorrhagic disease of the newborn.1 Two trials demonstrated that a single dose of intramuscular vitamin K reduced clinical bleeding at 1 to 7 days. Oral vitamin K has been studied for its effects on biochemical indices of coagulation status, but not for its clinical effects on bleeding. A single oral vitamin K dose at birth resulted in lower vitamin K levels at 2 weeks and 1 month, compared with a single dose of intramuscular vitamin K at birth.
Iron. The iron status of exclusively breastfed infants vs formula-fed infants was evaluated in a nonrandomized cohort study.2 Twenty-five healthy, breastfed infants and 15 healthy infants fed high-iron formula were followed for 9 months. No differences in mean hemoglobin values were seen at any age between the 2 groups.
A randomized controlled trial investigated the efficacy of daily and weekly iron supplementation on iron status in 67 exclusively breastfed infants.3 At age 4 months the infants were randomized into 3 groups: daily iron, weekly iron, and no iron. No significant differences were detected in the mean weight, height, and head circumference among the groups. The mean values of hemoglobin, mean corpuscular volume, serum iron, and transferrin saturation were similar among all the groups at ages 5, 6, and 7 months.
A randomized, double-blind, placebo-controlled iron supplementation trial involved 214 exclusively breastfed infants from 4 to 9 months of age in Sweden and Honduras.4 Iron supplementation did not affect weight gain in the groups, but length gain from ages 4 to 9 months was less in the iron-supplemented groups than in the placebo group (P<.05 for placebo vs Fe). This effect was greater in Sweden, and only existed in Honduras for infants aged 4 to 6 months with initial mean Hgb of at least 11 mg/dL. The researchers conclude that iron supplementation may pose risks in iron-replete infants.
Vitamin D. A case review of nutritional rickets in North Carolina between 1990 and 1999 found that all 30 patients identified were breastfed African American infants.5 Among the 166 published cases of rickets in the US from 1986 to 2003, 83% were categorized as African American or black. Ninety-six percent of cases were breastfed.6
Fluoride. No infant under 6 months of age should receive fluoride supplementation to prevent dental caries because of the risk of enamel fluorosis.7 A systematic review that evaluated fluoride for preventing dental caries in primary teeth in children aged <5 years found 6 small clinical trials. Although the studies were not of high quality, they consistently showed that the incidence of caries was reduced by 32% to 72%.8
Recommendations from others
The American Academy of Pediatrics (AAP) recommends that:
- All newborns receive vitamin K as an intramuscular dose of 0.5 to 1 mg9
- All full-term appropriate-for-gestational-age breastfed infants receive a supplemental source of iron starting at 4 to 6 months of age, preferably from iron-enriched complementary foods. Infants should only receive formula fortified with 10 to 12 mg/L for weaning or supplementing breastmilk10
- All infants, including those exclusively breastfed, should have a minimum intake of 200 IU of vitamin D per day starting in the first 2 months of life.
The National Academy of Sciences recommends 200 IU of vitamin D daily for all normal infants, children, and adolescents.11
The US Preventative Services Task Force (USPSTF) states evidence is insufficient to recommend for or against the routine use of iron supplements for healthy infants.12
The USPSTF, AAP, and the American Academy of Pediatric Dentistry recommends 0.25 mg/d of fluoride supplement for children ages 6 months to 3 years if the fluoride concentration in the community drinking water is less than 0.3 ppm. Older children may benefit from supplements if the fluoride concentration is between 0.3 and 0.6 ppm.13
Breastfed and formula-fed infants should receive intramuscular vitamin K soon after birth to prevent classic hemorrhagic disease of the newborn (strength of recommendation [SOR]: A, systematic review of controlled trials).
Routine iron supplementation for all term, healthy, breastfed infants is not proven to be safe or necessary. Formula-fed infants should be consuming formula that contains 10 to 12 mg/L of iron (SOR: A, 2 small randomized controlled trials).
Healthy, term infants at the highest risk for vitamin D deficiency are those who are breastfeeding and have dark skin or little sun exposure (SOR: B, 2 case series). Infants consuming at least 500 mL of fortified formula each day do not need additional supplementation. A recommendation of vitamin D supplementation of 200 IU/day should be explained to all families, particularly those at highest risk for nutritional rickets (SOR: C, expert opinion). Infants older than 6 months should receive an oral fluoride supplement of 0.25 mg if they consume fluids with a water fluoride level less than 0.3 ppm (SOR: B, poor-quality randomized controlled trials).
Encourage breastfeeding; keep vitamin D and iron needs in mind
Julia Fashner, MD
Piqua, Ohio
Physicians can help mothers give the best nutrition to their children by encouraging breastfeeding. In most cases, no supplements are required. From this information, I will keep in mind the shorter hours of daylight in the winter and the skin tone of the child, as this may warrant discussion of vitamin D supplementation in infants who are exclusively breastfed. Knowing the recommendations for iron supplementation will help physicians when counseling parents regarding formula choices. Lastly, vitamin K has become part of the routine protocol at delivery and should not be a factor for any child.
Evidence summary
Vitamin K. The Cochrane Database of Systematic Reviews looked at randomized trials to determine the effectiveness of vitamin K prophylaxis in preventing classic hemorrhagic disease of the newborn.1 Two trials demonstrated that a single dose of intramuscular vitamin K reduced clinical bleeding at 1 to 7 days. Oral vitamin K has been studied for its effects on biochemical indices of coagulation status, but not for its clinical effects on bleeding. A single oral vitamin K dose at birth resulted in lower vitamin K levels at 2 weeks and 1 month, compared with a single dose of intramuscular vitamin K at birth.
Iron. The iron status of exclusively breastfed infants vs formula-fed infants was evaluated in a nonrandomized cohort study.2 Twenty-five healthy, breastfed infants and 15 healthy infants fed high-iron formula were followed for 9 months. No differences in mean hemoglobin values were seen at any age between the 2 groups.
A randomized controlled trial investigated the efficacy of daily and weekly iron supplementation on iron status in 67 exclusively breastfed infants.3 At age 4 months the infants were randomized into 3 groups: daily iron, weekly iron, and no iron. No significant differences were detected in the mean weight, height, and head circumference among the groups. The mean values of hemoglobin, mean corpuscular volume, serum iron, and transferrin saturation were similar among all the groups at ages 5, 6, and 7 months.
A randomized, double-blind, placebo-controlled iron supplementation trial involved 214 exclusively breastfed infants from 4 to 9 months of age in Sweden and Honduras.4 Iron supplementation did not affect weight gain in the groups, but length gain from ages 4 to 9 months was less in the iron-supplemented groups than in the placebo group (P<.05 for placebo vs Fe). This effect was greater in Sweden, and only existed in Honduras for infants aged 4 to 6 months with initial mean Hgb of at least 11 mg/dL. The researchers conclude that iron supplementation may pose risks in iron-replete infants.
Vitamin D. A case review of nutritional rickets in North Carolina between 1990 and 1999 found that all 30 patients identified were breastfed African American infants.5 Among the 166 published cases of rickets in the US from 1986 to 2003, 83% were categorized as African American or black. Ninety-six percent of cases were breastfed.6
Fluoride. No infant under 6 months of age should receive fluoride supplementation to prevent dental caries because of the risk of enamel fluorosis.7 A systematic review that evaluated fluoride for preventing dental caries in primary teeth in children aged <5 years found 6 small clinical trials. Although the studies were not of high quality, they consistently showed that the incidence of caries was reduced by 32% to 72%.8
Recommendations from others
The American Academy of Pediatrics (AAP) recommends that:
- All newborns receive vitamin K as an intramuscular dose of 0.5 to 1 mg9
- All full-term appropriate-for-gestational-age breastfed infants receive a supplemental source of iron starting at 4 to 6 months of age, preferably from iron-enriched complementary foods. Infants should only receive formula fortified with 10 to 12 mg/L for weaning or supplementing breastmilk10
- All infants, including those exclusively breastfed, should have a minimum intake of 200 IU of vitamin D per day starting in the first 2 months of life.
The National Academy of Sciences recommends 200 IU of vitamin D daily for all normal infants, children, and adolescents.11
The US Preventative Services Task Force (USPSTF) states evidence is insufficient to recommend for or against the routine use of iron supplements for healthy infants.12
The USPSTF, AAP, and the American Academy of Pediatric Dentistry recommends 0.25 mg/d of fluoride supplement for children ages 6 months to 3 years if the fluoride concentration in the community drinking water is less than 0.3 ppm. Older children may benefit from supplements if the fluoride concentration is between 0.3 and 0.6 ppm.13
1. Puckett RM, Offringa M. Prophylactic vitamin K for vitamin K deficiency bleeding in neonates. Cochrane Database Syst Rev 2000;(4):CD002776.-
2. Calvo EB, Galindo AC, Aspres NB. Iron status in exclusively breastfed infants. Pediatrics 1992;90:375-379.
3. Yurdakok K, Temiz F, Yalcin SS, Gumruk F. Efficacy of daily and weekly iron supplementation on iron status in exclusively breastfed infants. J Pediatr Hematol Oncol 2004;26:284-288.
4. Dewey KG, Domellof M, Cohen RJ, Landa Rivera L, Hernell O, Lonnerdal B. Iron supplementation affects growth and morbidity of breastfed infants: results of a randomized trial in Sweden and Honduras. J Nutr 2002;132:3249-3255.
5. Kreiter SR, Schwartz RP, Kirkman HN, Jr, Charlton PA, Calikoglu AS, Davenport ML. Nutritional rickets in African American breastfed infants. J Pediatr 2000;137:153-157.
6. Weisberg P, Scanlon KS, Li R, Cogswell ME. Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003. J Clin Nutr 2004;80:1697S-1705S.
7. Centers for Disease Control and Prevention. Recommendations for using fluoride to prevent and control dental caries in the United States. MMWR Recomm Rep 2001;50:1-59.
8. Bader JD, Rozier G, Harris R, Lohr KN. Dental Caries Prevention: The Physician’s Role in Child Oral Health. Systematic Evidence Review no. 29. Rockville, Md: Agency for Healthcare Research and Quality, 2004. Available at: www.ahrq.gov/downloads/pub/prevent/pdfser/dentser.pdf. Accessed on November 15, 2005.
9. American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. Pediatrics 2003;112:191-192.
10. Gartner LM, Greer FR. Section on Breastfeeding and Committee on Nutrition, American Academy of Pediatrics. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics 2003;111:908-910.
11. Institute of Medicine, Food and Nutrition Board, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Vitamin D. In: Dietary Reference Intakes: For Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997;250-287.
12. DiGuiseppi C. Screening for iron deficiency anemia-including iron prophylaxis. In: US Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. Washington, DC: US Department of Health and Human Services, Agency for Healthcare Research and Quality; 1996:231–246. Available at: www.ahrq.gov/clinic/2ndcps/anemia.pdf. Accessed on November 15, 2005.
13. American Academy of Pediatric Dentistry. Special issue: reference manual 1994-95. Pediatric Dent 1995;16:1-96.
1. Puckett RM, Offringa M. Prophylactic vitamin K for vitamin K deficiency bleeding in neonates. Cochrane Database Syst Rev 2000;(4):CD002776.-
2. Calvo EB, Galindo AC, Aspres NB. Iron status in exclusively breastfed infants. Pediatrics 1992;90:375-379.
3. Yurdakok K, Temiz F, Yalcin SS, Gumruk F. Efficacy of daily and weekly iron supplementation on iron status in exclusively breastfed infants. J Pediatr Hematol Oncol 2004;26:284-288.
4. Dewey KG, Domellof M, Cohen RJ, Landa Rivera L, Hernell O, Lonnerdal B. Iron supplementation affects growth and morbidity of breastfed infants: results of a randomized trial in Sweden and Honduras. J Nutr 2002;132:3249-3255.
5. Kreiter SR, Schwartz RP, Kirkman HN, Jr, Charlton PA, Calikoglu AS, Davenport ML. Nutritional rickets in African American breastfed infants. J Pediatr 2000;137:153-157.
6. Weisberg P, Scanlon KS, Li R, Cogswell ME. Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003. J Clin Nutr 2004;80:1697S-1705S.
7. Centers for Disease Control and Prevention. Recommendations for using fluoride to prevent and control dental caries in the United States. MMWR Recomm Rep 2001;50:1-59.
8. Bader JD, Rozier G, Harris R, Lohr KN. Dental Caries Prevention: The Physician’s Role in Child Oral Health. Systematic Evidence Review no. 29. Rockville, Md: Agency for Healthcare Research and Quality, 2004. Available at: www.ahrq.gov/downloads/pub/prevent/pdfser/dentser.pdf. Accessed on November 15, 2005.
9. American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. Pediatrics 2003;112:191-192.
10. Gartner LM, Greer FR. Section on Breastfeeding and Committee on Nutrition, American Academy of Pediatrics. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics 2003;111:908-910.
11. Institute of Medicine, Food and Nutrition Board, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Vitamin D. In: Dietary Reference Intakes: For Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997;250-287.
12. DiGuiseppi C. Screening for iron deficiency anemia-including iron prophylaxis. In: US Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. Washington, DC: US Department of Health and Human Services, Agency for Healthcare Research and Quality; 1996:231–246. Available at: www.ahrq.gov/clinic/2ndcps/anemia.pdf. Accessed on November 15, 2005.
13. American Academy of Pediatric Dentistry. Special issue: reference manual 1994-95. Pediatric Dent 1995;16:1-96.
Evidence-based answers from the Family Physicians Inquiries Network
Do statins reduce the risk of stroke?
HMG Co-A reductase inhibitors (statins) are effective for primary prevention of ischemic stroke in people who have a history of occlusive artery disease, coronary artery disease, or diabetes without history of cerebrovascular disease (strength of recommendation [SOR]: A, based on 1 randomized controlled trial [RCT]).
Statins reduce the risk of ischemic stroke in hypertensive patients with multiple cardiovascular risk factors and nonfasting total cholesterol <250 mg/dL (SOR: A, based on RCT). Statins also reduce the risk of ischemic stroke for patients with coronary disease or equivalents (such as diabetes or peripheral artery disease), including patients who have a normal fasting lipid profile (SOR: A, based on RCT). For patients with ischemic stroke who have coronary disease, statins prevent recurrent ischemic stroke; evidence is conflicting about whether this benefit is proportional to initial cholesterol levels (SOR: A, systematic review). Statins do not prevent hemorrhagic stroke (SOR: A, based on RCTs).
Evidence summary
We found no studies evaluating statins for the primary prevention of stroke. An observational study of 433 patients with ischemic stroke found that patients who were taking statins before hospital admission more often had better outcomes (51%) than those who were not taking statins (38%). However, the groups differed in many respects.1 Many coronary event prevention and treatment trials using statins include the risk of primary and recurrent ischemic stroke as secondary endpoints for patients with high cardiac risk.
Primary prevention of stroke in vascular disease. The Heart Protection Study followed 20,536 patients in the United Kingdom (aged 40–80 years), 3280 with a history of cerebrovascular disease (defined as nondisabling stroke, transient cerebral ischemic attack, or carotid endarterectomy or angioplasty) and 17,256 with other occlusive arterial disease, coronary artery disease, or diabetes. Patients were randomized to receive either simvastatin 40 mg or placebo for an average of 5 years. The endpoint was major vascular events: myocardial infarction, stroke of any type, and revascularization procedure.
Simvastatin reduced the combined risk of non-fatal or fatal ischemic stroke for patients with no history of cerebrovascular disease (3.2% for simvastatin vs 4.8% with placebo; relative risk reduction=33%, number needed to treat [NNT]=63; P=.0001).2 As noted in other well-done studies, the Heart Protection Study showed no difference in the number of hemorrhagic strokes between treatment and placebo groups. There were 3500 subjects with pretreatment low-density lipoprotein (LDL) cholesterol <100 mg/dL; lowering LDL to 65 mg/dL reduced major vascular event risk by about 25%.3
Hypertension with multiple cardiovascular risk factors and cholesterol <250 mg/dL. The ASCOT-LLA study compared atorvastatin with placebo in 10,305 hypertensive Caucasian patients with multiple cardiovascular risk factors and a total nonfasting cholesterol of 250 mg/dL (6.5 mmol/L) or less. Patients were aged 40 to 79 years and had at least 3 other cardiovascular risk factors (left ventricular hypertrophy, abnormal electrocardiogram, type 2 diabetes, peripheral artery disease, stroke or transient ischemic attack, male sex, age >55 years, proteinuria or microalbuminuria, smoking, family history of premature coronary heart disease). The study was stopped early at a median of 3.3 years because atorvastatin significantly reduced cardiac events. Atorvastatin also significantly reduced ischemic strokes when compared with placebo (relative risk [RR]=0.73, 95% confidence interval [CI], 0.56–0.96; P=.024). This study did not differentiate between first or second stroke. The NNT was 155.4
Ischemic stroke and coronary disease. The LIPID trial randomized 9014 patients with a history of acute coronary syndromes and total cholesterol of 150 to 270 mg/dL (4 to 7 mmol/L) to either pravastatin or placebo and followed them for 6 years. Among the 350 patients with prior ischemic stroke, there were 388 new ischemic stokes over the course of the study. When adjusted for risk factors (atrial fibrillation, history of cerebrovascular accident, diabetes, hypertension, cigarette smoking, body mass index, and male sex), pravastatin reduced recurrent ischemic stroke by 21% relative to placebo (P=.024). The reduction was not modified by baseline lipid level.5
A meta-analysis of 15 randomized placebo-controlled trials using various statins (32,684 participants) assessed the risk of strokes for patients with a history of coronary disease. Among patients who had cerebrovascular disease, statins significantly reduced recurrent ischemic stroke (RR=0.74; 95% CI, 0.64–0.86). One recurrence of ischemic stroke would be prevented for every 110 coronary disease patients treated with a statin. Achieving final total cholesterol <232 mg/dL correlated with reduced risk of recurrent stroke.6 Three of the studies evaluated primary prevention of stroke and did not show a significant risk reduction (RR=0.85; P=.4). Statins did not reduce the rate of hemorrhagic stroke or fatal strokes.
Risks of statins. In 1 study involving 35,000 participants and 158,000 person-years of observation, there were 8 cases of rhabdomyolysis in the treatment groups vs 5 in the placebo groups.7 Forty-three deaths attributed to statin therapy have been reported to the Food and Drug Administration from 1987 to 2001, or 1 per million person-years of use. The Heart Protection Study found simvastatin and placebo users reported myopathy or muscle pain at the same annual rate of 0.01%.
Recommendations from others
We found no recommendations specifically regarding the use of statins to prevent stroke. However, the Third Report of the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III) describes symptomatic carotid artery disease as a coronary heart disease risk equivalent and recommends therapy to reduce the LDL below 100 mg/dL.8
Statins prevent cerebrovascular accidents and have low adverse event rates
Alex Krist, MD
Fairfax Family Practice Residency, Virginia Commonwealth University, Fairfax
Statins are effective for primary and tertiary cardiovascular disease prevention. For those with vascular disease or significant risks, statins prevent cerebrovascular accidents and have low adverse event rates.
While no evidence is available about primary prevention of cerebrovascular accidents for those at lower risk, in practice statins are often appropriately initiated. NCEP-ATP III,8 the key guideline on when to start statins, is based more on cardiac benefits. Most studies evaluating statins use a triple outcome of mortality, myocardial infarction, or cerebrovascular accident. Since myocardial infarction is more common than the other adverse endpoints, there is a greater demonstrated cardioprotective effect (prevention of myocardial infarction: NNT=95; prevention of cerebrovascular accidents: NNT=735).9 However, regardless of whether the benefits are cardiac or cerebrovascular, statins will prevent disease for many patients.
1. Yoon SS, Dambrosia J, Chalela J, Ezzeddine M, Warach S, Haymore J, Davis L, Baird AE. Rising statin use and effect on ischemic stroke outcome. BMC Med 2004;2:4.-Available at: www.biomedcentral.com/1741-7015/2/4. Accessed on April 8, 2004.
2. Collins R, Armitage J, Parish S, Sleight P, Peto R. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-767.
3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
4. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, 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;361:1149-1158.
5. West MJ, White HD, Simes RJ, Kirby A, Watson JD, Anderson NE, et al. Risk factors for non-haemorrhagic stroke in patients with coronary heart disease and the effect of lipid-modifying therapy with pravastatin. J Hypertens 2002;20:2513-2517.
6. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, Lechat P. Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med 2003;163:669-676.
7. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low-density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-1427.
8. National Cholesterol Education Program. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. NIH Pub. No. 02-5215. Bethesda, Md: National Heart, Lung, and Blood Institute; 2002.
9. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, Lechat P. Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med 2003;163:669-676.
HMG Co-A reductase inhibitors (statins) are effective for primary prevention of ischemic stroke in people who have a history of occlusive artery disease, coronary artery disease, or diabetes without history of cerebrovascular disease (strength of recommendation [SOR]: A, based on 1 randomized controlled trial [RCT]).
Statins reduce the risk of ischemic stroke in hypertensive patients with multiple cardiovascular risk factors and nonfasting total cholesterol <250 mg/dL (SOR: A, based on RCT). Statins also reduce the risk of ischemic stroke for patients with coronary disease or equivalents (such as diabetes or peripheral artery disease), including patients who have a normal fasting lipid profile (SOR: A, based on RCT). For patients with ischemic stroke who have coronary disease, statins prevent recurrent ischemic stroke; evidence is conflicting about whether this benefit is proportional to initial cholesterol levels (SOR: A, systematic review). Statins do not prevent hemorrhagic stroke (SOR: A, based on RCTs).
Evidence summary
We found no studies evaluating statins for the primary prevention of stroke. An observational study of 433 patients with ischemic stroke found that patients who were taking statins before hospital admission more often had better outcomes (51%) than those who were not taking statins (38%). However, the groups differed in many respects.1 Many coronary event prevention and treatment trials using statins include the risk of primary and recurrent ischemic stroke as secondary endpoints for patients with high cardiac risk.
Primary prevention of stroke in vascular disease. The Heart Protection Study followed 20,536 patients in the United Kingdom (aged 40–80 years), 3280 with a history of cerebrovascular disease (defined as nondisabling stroke, transient cerebral ischemic attack, or carotid endarterectomy or angioplasty) and 17,256 with other occlusive arterial disease, coronary artery disease, or diabetes. Patients were randomized to receive either simvastatin 40 mg or placebo for an average of 5 years. The endpoint was major vascular events: myocardial infarction, stroke of any type, and revascularization procedure.
Simvastatin reduced the combined risk of non-fatal or fatal ischemic stroke for patients with no history of cerebrovascular disease (3.2% for simvastatin vs 4.8% with placebo; relative risk reduction=33%, number needed to treat [NNT]=63; P=.0001).2 As noted in other well-done studies, the Heart Protection Study showed no difference in the number of hemorrhagic strokes between treatment and placebo groups. There were 3500 subjects with pretreatment low-density lipoprotein (LDL) cholesterol <100 mg/dL; lowering LDL to 65 mg/dL reduced major vascular event risk by about 25%.3
Hypertension with multiple cardiovascular risk factors and cholesterol <250 mg/dL. The ASCOT-LLA study compared atorvastatin with placebo in 10,305 hypertensive Caucasian patients with multiple cardiovascular risk factors and a total nonfasting cholesterol of 250 mg/dL (6.5 mmol/L) or less. Patients were aged 40 to 79 years and had at least 3 other cardiovascular risk factors (left ventricular hypertrophy, abnormal electrocardiogram, type 2 diabetes, peripheral artery disease, stroke or transient ischemic attack, male sex, age >55 years, proteinuria or microalbuminuria, smoking, family history of premature coronary heart disease). The study was stopped early at a median of 3.3 years because atorvastatin significantly reduced cardiac events. Atorvastatin also significantly reduced ischemic strokes when compared with placebo (relative risk [RR]=0.73, 95% confidence interval [CI], 0.56–0.96; P=.024). This study did not differentiate between first or second stroke. The NNT was 155.4
Ischemic stroke and coronary disease. The LIPID trial randomized 9014 patients with a history of acute coronary syndromes and total cholesterol of 150 to 270 mg/dL (4 to 7 mmol/L) to either pravastatin or placebo and followed them for 6 years. Among the 350 patients with prior ischemic stroke, there were 388 new ischemic stokes over the course of the study. When adjusted for risk factors (atrial fibrillation, history of cerebrovascular accident, diabetes, hypertension, cigarette smoking, body mass index, and male sex), pravastatin reduced recurrent ischemic stroke by 21% relative to placebo (P=.024). The reduction was not modified by baseline lipid level.5
A meta-analysis of 15 randomized placebo-controlled trials using various statins (32,684 participants) assessed the risk of strokes for patients with a history of coronary disease. Among patients who had cerebrovascular disease, statins significantly reduced recurrent ischemic stroke (RR=0.74; 95% CI, 0.64–0.86). One recurrence of ischemic stroke would be prevented for every 110 coronary disease patients treated with a statin. Achieving final total cholesterol <232 mg/dL correlated with reduced risk of recurrent stroke.6 Three of the studies evaluated primary prevention of stroke and did not show a significant risk reduction (RR=0.85; P=.4). Statins did not reduce the rate of hemorrhagic stroke or fatal strokes.
Risks of statins. In 1 study involving 35,000 participants and 158,000 person-years of observation, there were 8 cases of rhabdomyolysis in the treatment groups vs 5 in the placebo groups.7 Forty-three deaths attributed to statin therapy have been reported to the Food and Drug Administration from 1987 to 2001, or 1 per million person-years of use. The Heart Protection Study found simvastatin and placebo users reported myopathy or muscle pain at the same annual rate of 0.01%.
Recommendations from others
We found no recommendations specifically regarding the use of statins to prevent stroke. However, the Third Report of the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III) describes symptomatic carotid artery disease as a coronary heart disease risk equivalent and recommends therapy to reduce the LDL below 100 mg/dL.8
Statins prevent cerebrovascular accidents and have low adverse event rates
Alex Krist, MD
Fairfax Family Practice Residency, Virginia Commonwealth University, Fairfax
Statins are effective for primary and tertiary cardiovascular disease prevention. For those with vascular disease or significant risks, statins prevent cerebrovascular accidents and have low adverse event rates.
While no evidence is available about primary prevention of cerebrovascular accidents for those at lower risk, in practice statins are often appropriately initiated. NCEP-ATP III,8 the key guideline on when to start statins, is based more on cardiac benefits. Most studies evaluating statins use a triple outcome of mortality, myocardial infarction, or cerebrovascular accident. Since myocardial infarction is more common than the other adverse endpoints, there is a greater demonstrated cardioprotective effect (prevention of myocardial infarction: NNT=95; prevention of cerebrovascular accidents: NNT=735).9 However, regardless of whether the benefits are cardiac or cerebrovascular, statins will prevent disease for many patients.
HMG Co-A reductase inhibitors (statins) are effective for primary prevention of ischemic stroke in people who have a history of occlusive artery disease, coronary artery disease, or diabetes without history of cerebrovascular disease (strength of recommendation [SOR]: A, based on 1 randomized controlled trial [RCT]).
Statins reduce the risk of ischemic stroke in hypertensive patients with multiple cardiovascular risk factors and nonfasting total cholesterol <250 mg/dL (SOR: A, based on RCT). Statins also reduce the risk of ischemic stroke for patients with coronary disease or equivalents (such as diabetes or peripheral artery disease), including patients who have a normal fasting lipid profile (SOR: A, based on RCT). For patients with ischemic stroke who have coronary disease, statins prevent recurrent ischemic stroke; evidence is conflicting about whether this benefit is proportional to initial cholesterol levels (SOR: A, systematic review). Statins do not prevent hemorrhagic stroke (SOR: A, based on RCTs).
Evidence summary
We found no studies evaluating statins for the primary prevention of stroke. An observational study of 433 patients with ischemic stroke found that patients who were taking statins before hospital admission more often had better outcomes (51%) than those who were not taking statins (38%). However, the groups differed in many respects.1 Many coronary event prevention and treatment trials using statins include the risk of primary and recurrent ischemic stroke as secondary endpoints for patients with high cardiac risk.
Primary prevention of stroke in vascular disease. The Heart Protection Study followed 20,536 patients in the United Kingdom (aged 40–80 years), 3280 with a history of cerebrovascular disease (defined as nondisabling stroke, transient cerebral ischemic attack, or carotid endarterectomy or angioplasty) and 17,256 with other occlusive arterial disease, coronary artery disease, or diabetes. Patients were randomized to receive either simvastatin 40 mg or placebo for an average of 5 years. The endpoint was major vascular events: myocardial infarction, stroke of any type, and revascularization procedure.
Simvastatin reduced the combined risk of non-fatal or fatal ischemic stroke for patients with no history of cerebrovascular disease (3.2% for simvastatin vs 4.8% with placebo; relative risk reduction=33%, number needed to treat [NNT]=63; P=.0001).2 As noted in other well-done studies, the Heart Protection Study showed no difference in the number of hemorrhagic strokes between treatment and placebo groups. There were 3500 subjects with pretreatment low-density lipoprotein (LDL) cholesterol <100 mg/dL; lowering LDL to 65 mg/dL reduced major vascular event risk by about 25%.3
Hypertension with multiple cardiovascular risk factors and cholesterol <250 mg/dL. The ASCOT-LLA study compared atorvastatin with placebo in 10,305 hypertensive Caucasian patients with multiple cardiovascular risk factors and a total nonfasting cholesterol of 250 mg/dL (6.5 mmol/L) or less. Patients were aged 40 to 79 years and had at least 3 other cardiovascular risk factors (left ventricular hypertrophy, abnormal electrocardiogram, type 2 diabetes, peripheral artery disease, stroke or transient ischemic attack, male sex, age >55 years, proteinuria or microalbuminuria, smoking, family history of premature coronary heart disease). The study was stopped early at a median of 3.3 years because atorvastatin significantly reduced cardiac events. Atorvastatin also significantly reduced ischemic strokes when compared with placebo (relative risk [RR]=0.73, 95% confidence interval [CI], 0.56–0.96; P=.024). This study did not differentiate between first or second stroke. The NNT was 155.4
Ischemic stroke and coronary disease. The LIPID trial randomized 9014 patients with a history of acute coronary syndromes and total cholesterol of 150 to 270 mg/dL (4 to 7 mmol/L) to either pravastatin or placebo and followed them for 6 years. Among the 350 patients with prior ischemic stroke, there were 388 new ischemic stokes over the course of the study. When adjusted for risk factors (atrial fibrillation, history of cerebrovascular accident, diabetes, hypertension, cigarette smoking, body mass index, and male sex), pravastatin reduced recurrent ischemic stroke by 21% relative to placebo (P=.024). The reduction was not modified by baseline lipid level.5
A meta-analysis of 15 randomized placebo-controlled trials using various statins (32,684 participants) assessed the risk of strokes for patients with a history of coronary disease. Among patients who had cerebrovascular disease, statins significantly reduced recurrent ischemic stroke (RR=0.74; 95% CI, 0.64–0.86). One recurrence of ischemic stroke would be prevented for every 110 coronary disease patients treated with a statin. Achieving final total cholesterol <232 mg/dL correlated with reduced risk of recurrent stroke.6 Three of the studies evaluated primary prevention of stroke and did not show a significant risk reduction (RR=0.85; P=.4). Statins did not reduce the rate of hemorrhagic stroke or fatal strokes.
Risks of statins. In 1 study involving 35,000 participants and 158,000 person-years of observation, there were 8 cases of rhabdomyolysis in the treatment groups vs 5 in the placebo groups.7 Forty-three deaths attributed to statin therapy have been reported to the Food and Drug Administration from 1987 to 2001, or 1 per million person-years of use. The Heart Protection Study found simvastatin and placebo users reported myopathy or muscle pain at the same annual rate of 0.01%.
Recommendations from others
We found no recommendations specifically regarding the use of statins to prevent stroke. However, the Third Report of the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III) describes symptomatic carotid artery disease as a coronary heart disease risk equivalent and recommends therapy to reduce the LDL below 100 mg/dL.8
Statins prevent cerebrovascular accidents and have low adverse event rates
Alex Krist, MD
Fairfax Family Practice Residency, Virginia Commonwealth University, Fairfax
Statins are effective for primary and tertiary cardiovascular disease prevention. For those with vascular disease or significant risks, statins prevent cerebrovascular accidents and have low adverse event rates.
While no evidence is available about primary prevention of cerebrovascular accidents for those at lower risk, in practice statins are often appropriately initiated. NCEP-ATP III,8 the key guideline on when to start statins, is based more on cardiac benefits. Most studies evaluating statins use a triple outcome of mortality, myocardial infarction, or cerebrovascular accident. Since myocardial infarction is more common than the other adverse endpoints, there is a greater demonstrated cardioprotective effect (prevention of myocardial infarction: NNT=95; prevention of cerebrovascular accidents: NNT=735).9 However, regardless of whether the benefits are cardiac or cerebrovascular, statins will prevent disease for many patients.
1. Yoon SS, Dambrosia J, Chalela J, Ezzeddine M, Warach S, Haymore J, Davis L, Baird AE. Rising statin use and effect on ischemic stroke outcome. BMC Med 2004;2:4.-Available at: www.biomedcentral.com/1741-7015/2/4. Accessed on April 8, 2004.
2. Collins R, Armitage J, Parish S, Sleight P, Peto R. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-767.
3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
4. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, 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;361:1149-1158.
5. West MJ, White HD, Simes RJ, Kirby A, Watson JD, Anderson NE, et al. Risk factors for non-haemorrhagic stroke in patients with coronary heart disease and the effect of lipid-modifying therapy with pravastatin. J Hypertens 2002;20:2513-2517.
6. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, Lechat P. Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med 2003;163:669-676.
7. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low-density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-1427.
8. National Cholesterol Education Program. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. NIH Pub. No. 02-5215. Bethesda, Md: National Heart, Lung, and Blood Institute; 2002.
9. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, Lechat P. Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med 2003;163:669-676.
1. Yoon SS, Dambrosia J, Chalela J, Ezzeddine M, Warach S, Haymore J, Davis L, Baird AE. Rising statin use and effect on ischemic stroke outcome. BMC Med 2004;2:4.-Available at: www.biomedcentral.com/1741-7015/2/4. Accessed on April 8, 2004.
2. Collins R, Armitage J, Parish S, Sleight P, Peto R. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-767.
3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
4. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, 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;361:1149-1158.
5. West MJ, White HD, Simes RJ, Kirby A, Watson JD, Anderson NE, et al. Risk factors for non-haemorrhagic stroke in patients with coronary heart disease and the effect of lipid-modifying therapy with pravastatin. J Hypertens 2002;20:2513-2517.
6. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, Lechat P. Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med 2003;163:669-676.
7. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low-density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-1427.
8. National Cholesterol Education Program. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. NIH Pub. No. 02-5215. Bethesda, Md: National Heart, Lung, and Blood Institute; 2002.
9. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, Lechat P. Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med 2003;163:669-676.
Evidence-based answers from the Family Physicians Inquiries Network