Mark Gwynne, DO

PRACTICE CHANGER

Counsel patients at high risk for cardiovascular disease and stroke to follow a Mediterranean diet, which is associated with a 30% risk reduction.¹

STRENGTH OF RECOMMENDATION

B: Based on one well-designed randomized controlled trial.¹

ILLUSTRATIVE CASE

A 62-year-old patient with diabetes, obesity, and a family history of early-onset coronary artery disease is motivated to make significant lifestyle changes. You recommend moderate aerobic exercise (30 min five d/wk) but wonder whether a low-fat or a Mediterranean diet would be more effective in reducing her risk.

Cardiovascular disease (CVD), including heart disease and stroke, is the leading cause of mortality in the United States. CVD accounts for one in every three deaths,² and stroke is a leading cause of long-term disability.² The direct cost of treating CVD is estimated at $312.6 billion annually.²

Many modifiable risk factors contribute to CVD, including smoking, sedentary lifestyle, obesity, alcohol consumption, and poorly controlled chronic disease, as well as an unhealthy diet. A recent report from the American Heart Association suggests that 13% of deaths from CVD can be attributed to poor diet.²

Focus counseling on at-risk patients

Primary care providers (PCPs) often struggle to effectively counsel patients on behavioral change strategies, facing many barriers. Chief among them are the lack of time, training, and confidence in their counseling techniques, as well as a lack of patient motivation and readiness to change.³ In recognition of these barriers, the US Preventive Services Task Force recently recommended that PCPs focus behavioral counseling efforts on patients at high risk for heart disease.⁴

Large observational studies have found an association between trans fat and increased risk for CVD, as well as decreased risk for CVD in patients adhering to a Mediterranean diet.^5-11 This type of diet typically includes a high intake of olive oil, fruit, nuts, vegetables, and cereals; moderate intake of fish and poultry; and low intake of dairy products, red meat, processed meats, and sweets. It also includes wine in moderation, consumed with meals.

Data on the physiologic properties of olive oil, including its antioxidant, vasodilating, and antiplatelet effects—as well as its effects on LDL cholesterol that may inhibit atherogenesis—support the link between a Mediterranean diet and a decreased risk for CVD found in the observational studies.^12,13 Until recently, however, no randomized controlled trial (RCT) had compared the effect of a Mediterranean diet with that of a low-fat diet for primary prevention of CVD.

STUDY SUMMARY

Mediterranean diet significantly lowers risk

Prevencion con Dieta Mediterranea (PREDIMED) was a large RCT (N = 7,447) comparing two variations of a Mediterranean diet with a low-fat diet for primary prevention of CVD. This Spanish study enrolled men ages 55 to 80 and women ages 60 to 80 who were at high risk for CVD. The risk was based on either a diagnosis of type 2 diabetes or the presence of ≥ 3 major risk factors, including smoking, hypertension, elevated LDL cholesterol, low HDL cholesterol, overweight or obesity, and a family history of early heart disease.

Participants were randomly assigned to one of three dietary groups: One group followed a Mediterranean diet supplemented with ≥ 4 Tb of extra virgin olive oil per day; a second group was put on a Mediterranean diet supplemented by 30 g (about 1/3 cup) of mixed nuts daily; a third group (the controls) was advised to follow a low-fat diet. The majority of baseline characteristics and medications taken throughout the study were similar among all three groups.

Those in both Mediterranean diet groups were followed for a median of 4.8 years, during which they received quarterly dietary classes and individual and group counseling. The controls received baseline training, plus a leaflet about low-fat diets annually. In year 3, however, the researchers began giving the control group the same level of counseling as those in the Mediterranean diet groups to avoid confounding ­results.

Adherence to the diets was determined by a self-reported 14-item dietary screening questionnaire, plus urinary hydroxytyrosol and serum alpha-linoleic acid levels to assess for olive oil and mixed nut compliance. Self-reporting⁵ and biometric data indicated good compliance with the Mediterranean diets, and there was no difference found in levels of exercise among the groups.

After five years, those in the Mediterranean diet groups had consumed significantly more olive oil, nuts, vegetables, fruits, wine, legumes, seafood, and sofrito sauce (a popular tomato-based sauce) than the control group. Participants in the low-fat diet group had decreased their fat intake by 2%, while those in the Mediterranean groups had increased fat intake (by 2.03% for the olive oil group and 2.1% for the nut group). Overall, 37% of energy intake by those in the low-fat diet group came from fat (exceeding the < 30% of calories derived from fat intake that defines a low-fat diet), compared with 39% fat intake for those in both Mediterranean diet groups.

The primary outcome was a composite of MI, stroke, and death from cardiovascular causes, and there were clinically meaningful and statistically significant differences between the Mediterranean diet groups and the controls. The primary outcome rate for the supplemental olive oil group was 3.8%; 3.4% for the extra nuts group; and 4.4% for the controls. This represents a 30% reduction in risk for combined stroke, MI, and death due to cardiovascular causes for the Mediterranean diet groups (hazard ratio [HR], 0.7 and number needed to treat [NNT], 148 for the olive oil group; HR, 0.7 and NNT, 100 for the group consuming extra nuts). Similar benefits were found in the multivariable adjusted analyses. The results correspond to three fewer events (stroke, MI, or ­cardiovascular death) per 1,000 person-years for this high-risk population.

The only individual outcome that showed a significant decrease was stroke, with an NNT of 125 in both Mediterranean diet groups. Outcomes for the controls were similar before and after they began receiving quarterly counseling.

WHAT’S NEW?

Mediterranean diet is better than a lower-fat regimen

This study indicates that a Mediterranean diet, with increased intake of either olive oil or mixed nuts, is more protective against CVD than a recommended low-fat diet. It also shows that advising patients at high risk to follow a Mediterranean diet, providing dietary counseling, and monitoring them for adherence, rather than simply recommending a low-fat diet, can significantly decrease the risk for stroke.

Rates of CVD are higher in the US than in Spain, so implementing a Mediterranean diet on a large scale in this country has the potential to produce a greater response than that seen in this study.

CAVEATS

Would a true low-fat diet be a better comparison?

Although the control group’s diet was meant to be low fat, the participants did not achieve this, possibly due to the relatively low level of dietary education and personalized counseling at the start of the study. Their inability to reach the < 30% fat target could also reflect the difficulty patients have, in general, in decreasing fat content in their diet, which may mean the diet they maintained was a more realistic comparison.

This study used one brand of olive oil and a particular mixture of nuts (walnuts, hazelnuts, and almonds); it is possible that variations on either of these could affect the benefits of the diet.

CHALLENGES TO IMPLEMENTATION

Fitting a Mediterranean diet into an American lifestyle

The typical US diet is significantly different from that of most Spaniards. Americans may find it difficult to add either ≥ 4 Tb of olive oil or 30 g (1/3 cup) of nuts daily, for example, due to both cost and availability. Limited access to both individual and group counseling could be a barrier, as well.

On the other hand, this practice changer has the potential to simplify dietary counseling by allowing clinicians to focus on just one type of diet, for which there are many resources available both online and in print. We believe it makes sense to recommend a Mediterranean diet, while continuing to recommend increased exercise, smoking cessation, and improved control of chronic disease to lower patients’ risk for poor outcomes from CVD.

REFERENCES

1. Estruch R, Ros F, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368: 1279-1290.

2. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127:e6-e245.

3. Kushner RF. Barriers to providing nutrition counseling by physicians: a survey of primary care practitioners. Prev Med. 1995;24:546-552.

4. USPSTF. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults. www.uspreventiveservicestaskforce.org/uspstf/usp sphys.htm. Accessed December 18, 2013.

5. Hu FB, Stampfer MJ, Manson JE, et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med. 1997;337:1491-1499.

6. Oomen C, Ocké MC, Feskens JM, et al. Association between trans fatty acid intake and 10-year risk of coronary heart disease in the Zutphen Elderly Study: a prospective population-based study. Lancet. 2001;357:746-751.

7. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction. Final report of the Lyon Diet Heart Study. Circulation. 1999;99:779-785.

8. Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA. 2004;292: 1433-1439.

9. Kris-Etherton P, Eckel RH, Howard BV, et al; Nutrition Committee Population Science Committee and Clinical Science Committee of the American Heart Association. Lyon Diet Heart Study. Benefits of a Mediterranean-style, National Education Program/AHA Step 1 Dietary Pattern on cardiovascular disease. Circulation. 2001;103:1823-1825.

10. Panagiotakos DB, Chrysohoou C, Pitsavos C, et al. The association of Mediterranean diet with lower risk of acute coronary syndromes, in hypertensive subjects. Int J Cardiol. 2002; 82:141-147.

11. Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. The role of traditional Mediterranean-type of diet and lifestyle, in the development of acute coronary syndromes: preliminary results from CARDIO 2000 study. Centr Eur J Public Health. 2002;10:11-15.

12. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004;292:1440-1446.

13. Vincent-Baudry S, Defoort C, Gerber M, et al. The Medi-RIVAGE study: reduction of cardiovascular disease risk factors after a 3-mo intervention with a Mediterranean-type diet or a low-fat diet. Am J Clin Nutr. 2005;82: 964-971.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL 1RR 024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2013. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2013;62(12):745-746, 748.

PRACTICE CHANGER

Counsel patients at high risk for cardiovascular disease and stroke to follow a Mediterranean diet, which is associated with a 30% risk reduction.¹

STRENGTH OF RECOMMENDATION

B: Based on one well-designed randomized controlled trial.¹

ILLUSTRATIVE CASE

A 62-year-old patient with diabetes, obesity, and a family history of early-onset coronary artery disease is motivated to make significant lifestyle changes. You recommend moderate aerobic exercise (30 min five d/wk) but wonder whether a low-fat or a Mediterranean diet would be more effective in reducing her risk.

Cardiovascular disease (CVD), including heart disease and stroke, is the leading cause of mortality in the United States. CVD accounts for one in every three deaths,² and stroke is a leading cause of long-term disability.² The direct cost of treating CVD is estimated at $312.6 billion annually.²

Many modifiable risk factors contribute to CVD, including smoking, sedentary lifestyle, obesity, alcohol consumption, and poorly controlled chronic disease, as well as an unhealthy diet. A recent report from the American Heart Association suggests that 13% of deaths from CVD can be attributed to poor diet.²

Focus counseling on at-risk patients

Primary care providers (PCPs) often struggle to effectively counsel patients on behavioral change strategies, facing many barriers. Chief among them are the lack of time, training, and confidence in their counseling techniques, as well as a lack of patient motivation and readiness to change.³ In recognition of these barriers, the US Preventive Services Task Force recently recommended that PCPs focus behavioral counseling efforts on patients at high risk for heart disease.⁴

Large observational studies have found an association between trans fat and increased risk for CVD, as well as decreased risk for CVD in patients adhering to a Mediterranean diet.^5-11 This type of diet typically includes a high intake of olive oil, fruit, nuts, vegetables, and cereals; moderate intake of fish and poultry; and low intake of dairy products, red meat, processed meats, and sweets. It also includes wine in moderation, consumed with meals.

Data on the physiologic properties of olive oil, including its antioxidant, vasodilating, and antiplatelet effects—as well as its effects on LDL cholesterol that may inhibit atherogenesis—support the link between a Mediterranean diet and a decreased risk for CVD found in the observational studies.^12,13 Until recently, however, no randomized controlled trial (RCT) had compared the effect of a Mediterranean diet with that of a low-fat diet for primary prevention of CVD.

STUDY SUMMARY

Mediterranean diet significantly lowers risk

Prevencion con Dieta Mediterranea (PREDIMED) was a large RCT (N = 7,447) comparing two variations of a Mediterranean diet with a low-fat diet for primary prevention of CVD. This Spanish study enrolled men ages 55 to 80 and women ages 60 to 80 who were at high risk for CVD. The risk was based on either a diagnosis of type 2 diabetes or the presence of ≥ 3 major risk factors, including smoking, hypertension, elevated LDL cholesterol, low HDL cholesterol, overweight or obesity, and a family history of early heart disease.

Participants were randomly assigned to one of three dietary groups: One group followed a Mediterranean diet supplemented with ≥ 4 Tb of extra virgin olive oil per day; a second group was put on a Mediterranean diet supplemented by 30 g (about 1/3 cup) of mixed nuts daily; a third group (the controls) was advised to follow a low-fat diet. The majority of baseline characteristics and medications taken throughout the study were similar among all three groups.

Those in both Mediterranean diet groups were followed for a median of 4.8 years, during which they received quarterly dietary classes and individual and group counseling. The controls received baseline training, plus a leaflet about low-fat diets annually. In year 3, however, the researchers began giving the control group the same level of counseling as those in the Mediterranean diet groups to avoid confounding ­results.

Adherence to the diets was determined by a self-reported 14-item dietary screening questionnaire, plus urinary hydroxytyrosol and serum alpha-linoleic acid levels to assess for olive oil and mixed nut compliance. Self-reporting⁵ and biometric data indicated good compliance with the Mediterranean diets, and there was no difference found in levels of exercise among the groups.

After five years, those in the Mediterranean diet groups had consumed significantly more olive oil, nuts, vegetables, fruits, wine, legumes, seafood, and sofrito sauce (a popular tomato-based sauce) than the control group. Participants in the low-fat diet group had decreased their fat intake by 2%, while those in the Mediterranean groups had increased fat intake (by 2.03% for the olive oil group and 2.1% for the nut group). Overall, 37% of energy intake by those in the low-fat diet group came from fat (exceeding the < 30% of calories derived from fat intake that defines a low-fat diet), compared with 39% fat intake for those in both Mediterranean diet groups.

The primary outcome was a composite of MI, stroke, and death from cardiovascular causes, and there were clinically meaningful and statistically significant differences between the Mediterranean diet groups and the controls. The primary outcome rate for the supplemental olive oil group was 3.8%; 3.4% for the extra nuts group; and 4.4% for the controls. This represents a 30% reduction in risk for combined stroke, MI, and death due to cardiovascular causes for the Mediterranean diet groups (hazard ratio [HR], 0.7 and number needed to treat [NNT], 148 for the olive oil group; HR, 0.7 and NNT, 100 for the group consuming extra nuts). Similar benefits were found in the multivariable adjusted analyses. The results correspond to three fewer events (stroke, MI, or ­cardiovascular death) per 1,000 person-years for this high-risk population.

The only individual outcome that showed a significant decrease was stroke, with an NNT of 125 in both Mediterranean diet groups. Outcomes for the controls were similar before and after they began receiving quarterly counseling.

WHAT’S NEW?

Mediterranean diet is better than a lower-fat regimen

This study indicates that a Mediterranean diet, with increased intake of either olive oil or mixed nuts, is more protective against CVD than a recommended low-fat diet. It also shows that advising patients at high risk to follow a Mediterranean diet, providing dietary counseling, and monitoring them for adherence, rather than simply recommending a low-fat diet, can significantly decrease the risk for stroke.

Rates of CVD are higher in the US than in Spain, so implementing a Mediterranean diet on a large scale in this country has the potential to produce a greater response than that seen in this study.

CAVEATS

Would a true low-fat diet be a better comparison?

Although the control group’s diet was meant to be low fat, the participants did not achieve this, possibly due to the relatively low level of dietary education and personalized counseling at the start of the study. Their inability to reach the < 30% fat target could also reflect the difficulty patients have, in general, in decreasing fat content in their diet, which may mean the diet they maintained was a more realistic comparison.

This study used one brand of olive oil and a particular mixture of nuts (walnuts, hazelnuts, and almonds); it is possible that variations on either of these could affect the benefits of the diet.

CHALLENGES TO IMPLEMENTATION

Fitting a Mediterranean diet into an American lifestyle

The typical US diet is significantly different from that of most Spaniards. Americans may find it difficult to add either ≥ 4 Tb of olive oil or 30 g (1/3 cup) of nuts daily, for example, due to both cost and availability. Limited access to both individual and group counseling could be a barrier, as well.

On the other hand, this practice changer has the potential to simplify dietary counseling by allowing clinicians to focus on just one type of diet, for which there are many resources available both online and in print. We believe it makes sense to recommend a Mediterranean diet, while continuing to recommend increased exercise, smoking cessation, and improved control of chronic disease to lower patients’ risk for poor outcomes from CVD.

REFERENCES

1. Estruch R, Ros F, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368: 1279-1290.

2. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127:e6-e245.

3. Kushner RF. Barriers to providing nutrition counseling by physicians: a survey of primary care practitioners. Prev Med. 1995;24:546-552.

4. USPSTF. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults. www.uspreventiveservicestaskforce.org/uspstf/usp sphys.htm. Accessed December 18, 2013.

5. Hu FB, Stampfer MJ, Manson JE, et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med. 1997;337:1491-1499.

6. Oomen C, Ocké MC, Feskens JM, et al. Association between trans fatty acid intake and 10-year risk of coronary heart disease in the Zutphen Elderly Study: a prospective population-based study. Lancet. 2001;357:746-751.

7. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction. Final report of the Lyon Diet Heart Study. Circulation. 1999;99:779-785.

8. Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA. 2004;292: 1433-1439.

9. Kris-Etherton P, Eckel RH, Howard BV, et al; Nutrition Committee Population Science Committee and Clinical Science Committee of the American Heart Association. Lyon Diet Heart Study. Benefits of a Mediterranean-style, National Education Program/AHA Step 1 Dietary Pattern on cardiovascular disease. Circulation. 2001;103:1823-1825.

10. Panagiotakos DB, Chrysohoou C, Pitsavos C, et al. The association of Mediterranean diet with lower risk of acute coronary syndromes, in hypertensive subjects. Int J Cardiol. 2002; 82:141-147.

11. Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. The role of traditional Mediterranean-type of diet and lifestyle, in the development of acute coronary syndromes: preliminary results from CARDIO 2000 study. Centr Eur J Public Health. 2002;10:11-15.

12. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004;292:1440-1446.

13. Vincent-Baudry S, Defoort C, Gerber M, et al. The Medi-RIVAGE study: reduction of cardiovascular disease risk factors after a 3-mo intervention with a Mediterranean-type diet or a low-fat diet. Am J Clin Nutr. 2005;82: 964-971.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL 1RR 024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2013. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2013;62(12):745-746, 748.

PRACTICE CHANGER

Counsel patients at high risk for cardiovascular disease and stroke to follow a Mediterranean diet, which is associated with a 30% risk reduction.¹

STRENGTH OF RECOMMENDATION

B: Based on one well-designed randomized controlled trial.¹

ILLUSTRATIVE CASE

A 62-year-old patient with diabetes, obesity, and a family history of early-onset coronary artery disease is motivated to make significant lifestyle changes. You recommend moderate aerobic exercise (30 min five d/wk) but wonder whether a low-fat or a Mediterranean diet would be more effective in reducing her risk.

Cardiovascular disease (CVD), including heart disease and stroke, is the leading cause of mortality in the United States. CVD accounts for one in every three deaths,² and stroke is a leading cause of long-term disability.² The direct cost of treating CVD is estimated at $312.6 billion annually.²

Many modifiable risk factors contribute to CVD, including smoking, sedentary lifestyle, obesity, alcohol consumption, and poorly controlled chronic disease, as well as an unhealthy diet. A recent report from the American Heart Association suggests that 13% of deaths from CVD can be attributed to poor diet.²

Focus counseling on at-risk patients

Primary care providers (PCPs) often struggle to effectively counsel patients on behavioral change strategies, facing many barriers. Chief among them are the lack of time, training, and confidence in their counseling techniques, as well as a lack of patient motivation and readiness to change.³ In recognition of these barriers, the US Preventive Services Task Force recently recommended that PCPs focus behavioral counseling efforts on patients at high risk for heart disease.⁴

Large observational studies have found an association between trans fat and increased risk for CVD, as well as decreased risk for CVD in patients adhering to a Mediterranean diet.^5-11 This type of diet typically includes a high intake of olive oil, fruit, nuts, vegetables, and cereals; moderate intake of fish and poultry; and low intake of dairy products, red meat, processed meats, and sweets. It also includes wine in moderation, consumed with meals.

Data on the physiologic properties of olive oil, including its antioxidant, vasodilating, and antiplatelet effects—as well as its effects on LDL cholesterol that may inhibit atherogenesis—support the link between a Mediterranean diet and a decreased risk for CVD found in the observational studies.^12,13 Until recently, however, no randomized controlled trial (RCT) had compared the effect of a Mediterranean diet with that of a low-fat diet for primary prevention of CVD.

STUDY SUMMARY

Mediterranean diet significantly lowers risk

Prevencion con Dieta Mediterranea (PREDIMED) was a large RCT (N = 7,447) comparing two variations of a Mediterranean diet with a low-fat diet for primary prevention of CVD. This Spanish study enrolled men ages 55 to 80 and women ages 60 to 80 who were at high risk for CVD. The risk was based on either a diagnosis of type 2 diabetes or the presence of ≥ 3 major risk factors, including smoking, hypertension, elevated LDL cholesterol, low HDL cholesterol, overweight or obesity, and a family history of early heart disease.

Participants were randomly assigned to one of three dietary groups: One group followed a Mediterranean diet supplemented with ≥ 4 Tb of extra virgin olive oil per day; a second group was put on a Mediterranean diet supplemented by 30 g (about 1/3 cup) of mixed nuts daily; a third group (the controls) was advised to follow a low-fat diet. The majority of baseline characteristics and medications taken throughout the study were similar among all three groups.

Those in both Mediterranean diet groups were followed for a median of 4.8 years, during which they received quarterly dietary classes and individual and group counseling. The controls received baseline training, plus a leaflet about low-fat diets annually. In year 3, however, the researchers began giving the control group the same level of counseling as those in the Mediterranean diet groups to avoid confounding ­results.

Adherence to the diets was determined by a self-reported 14-item dietary screening questionnaire, plus urinary hydroxytyrosol and serum alpha-linoleic acid levels to assess for olive oil and mixed nut compliance. Self-reporting⁵ and biometric data indicated good compliance with the Mediterranean diets, and there was no difference found in levels of exercise among the groups.

After five years, those in the Mediterranean diet groups had consumed significantly more olive oil, nuts, vegetables, fruits, wine, legumes, seafood, and sofrito sauce (a popular tomato-based sauce) than the control group. Participants in the low-fat diet group had decreased their fat intake by 2%, while those in the Mediterranean groups had increased fat intake (by 2.03% for the olive oil group and 2.1% for the nut group). Overall, 37% of energy intake by those in the low-fat diet group came from fat (exceeding the < 30% of calories derived from fat intake that defines a low-fat diet), compared with 39% fat intake for those in both Mediterranean diet groups.

The primary outcome was a composite of MI, stroke, and death from cardiovascular causes, and there were clinically meaningful and statistically significant differences between the Mediterranean diet groups and the controls. The primary outcome rate for the supplemental olive oil group was 3.8%; 3.4% for the extra nuts group; and 4.4% for the controls. This represents a 30% reduction in risk for combined stroke, MI, and death due to cardiovascular causes for the Mediterranean diet groups (hazard ratio [HR], 0.7 and number needed to treat [NNT], 148 for the olive oil group; HR, 0.7 and NNT, 100 for the group consuming extra nuts). Similar benefits were found in the multivariable adjusted analyses. The results correspond to three fewer events (stroke, MI, or ­cardiovascular death) per 1,000 person-years for this high-risk population.

The only individual outcome that showed a significant decrease was stroke, with an NNT of 125 in both Mediterranean diet groups. Outcomes for the controls were similar before and after they began receiving quarterly counseling.

WHAT’S NEW?

Mediterranean diet is better than a lower-fat regimen

This study indicates that a Mediterranean diet, with increased intake of either olive oil or mixed nuts, is more protective against CVD than a recommended low-fat diet. It also shows that advising patients at high risk to follow a Mediterranean diet, providing dietary counseling, and monitoring them for adherence, rather than simply recommending a low-fat diet, can significantly decrease the risk for stroke.

Rates of CVD are higher in the US than in Spain, so implementing a Mediterranean diet on a large scale in this country has the potential to produce a greater response than that seen in this study.

CAVEATS

Would a true low-fat diet be a better comparison?

Although the control group’s diet was meant to be low fat, the participants did not achieve this, possibly due to the relatively low level of dietary education and personalized counseling at the start of the study. Their inability to reach the < 30% fat target could also reflect the difficulty patients have, in general, in decreasing fat content in their diet, which may mean the diet they maintained was a more realistic comparison.

This study used one brand of olive oil and a particular mixture of nuts (walnuts, hazelnuts, and almonds); it is possible that variations on either of these could affect the benefits of the diet.

CHALLENGES TO IMPLEMENTATION

Fitting a Mediterranean diet into an American lifestyle

The typical US diet is significantly different from that of most Spaniards. Americans may find it difficult to add either ≥ 4 Tb of olive oil or 30 g (1/3 cup) of nuts daily, for example, due to both cost and availability. Limited access to both individual and group counseling could be a barrier, as well.

On the other hand, this practice changer has the potential to simplify dietary counseling by allowing clinicians to focus on just one type of diet, for which there are many resources available both online and in print. We believe it makes sense to recommend a Mediterranean diet, while continuing to recommend increased exercise, smoking cessation, and improved control of chronic disease to lower patients’ risk for poor outcomes from CVD.

REFERENCES

1. Estruch R, Ros F, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368: 1279-1290.

2. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127:e6-e245.

3. Kushner RF. Barriers to providing nutrition counseling by physicians: a survey of primary care practitioners. Prev Med. 1995;24:546-552.

4. USPSTF. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults. www.uspreventiveservicestaskforce.org/uspstf/usp sphys.htm. Accessed December 18, 2013.

5. Hu FB, Stampfer MJ, Manson JE, et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med. 1997;337:1491-1499.

6. Oomen C, Ocké MC, Feskens JM, et al. Association between trans fatty acid intake and 10-year risk of coronary heart disease in the Zutphen Elderly Study: a prospective population-based study. Lancet. 2001;357:746-751.

7. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction. Final report of the Lyon Diet Heart Study. Circulation. 1999;99:779-785.

8. Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA. 2004;292: 1433-1439.

9. Kris-Etherton P, Eckel RH, Howard BV, et al; Nutrition Committee Population Science Committee and Clinical Science Committee of the American Heart Association. Lyon Diet Heart Study. Benefits of a Mediterranean-style, National Education Program/AHA Step 1 Dietary Pattern on cardiovascular disease. Circulation. 2001;103:1823-1825.

10. Panagiotakos DB, Chrysohoou C, Pitsavos C, et al. The association of Mediterranean diet with lower risk of acute coronary syndromes, in hypertensive subjects. Int J Cardiol. 2002; 82:141-147.

11. Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. The role of traditional Mediterranean-type of diet and lifestyle, in the development of acute coronary syndromes: preliminary results from CARDIO 2000 study. Centr Eur J Public Health. 2002;10:11-15.

12. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004;292:1440-1446.

13. Vincent-Baudry S, Defoort C, Gerber M, et al. The Medi-RIVAGE study: reduction of cardiovascular disease risk factors after a 3-mo intervention with a Mediterranean-type diet or a low-fat diet. Am J Clin Nutr. 2005;82: 964-971.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL 1RR 024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2013. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2013;62(12):745-746, 748.

ILLUSTRATIVE CASE

A 60-year-old patient with moderate COPD and a history of frequent exacerbations comes in for a follow-up visit. She has been using albuterol and ipratropium intermittently. you want to add a longer-acting bronchodilator and wonder if tiotropium or salmeterol is more effective for reducing exacerbations.

COPD is the fourth leading cause of death in the United States.² More than 12 million Americans have been diagnosed with COPD, and it is estimated that another 12 million would have a COPD diagnosis if all smokers older than 45 years underwent spirometry.² The disorder accounts for some 16 million physician visits each year and costs the US health care system approximately $19 billion annually, with acute exacerbations and hospitalizations representing 58% of the total.^2,3

Despite guidelines, COPD is often undertreated
One of the main goals of COPD treatment is to reduce the frequency and intensity of acute exacerbations, both to improve patients’ quality of life and reduce health care costs. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has developed guidelines for effective management of COPD, which recommend long-acting bronchodilators as first-line maintenance therapy for patients whose disease is moderate to very severe.⁴

Evidence suggests that physicians frequently undertreat moderate to severe COPD, however, following national guidelines only about a quarter of the time.⁵ This is, in part, because many clinicians doubt the efficacy of COPD treatment for improving symptoms or decreasing exacerbations.^5,6 Yet studies have shown that the long-acting broncho dilators tiotropium (an anticholinergic agent) and salmeterol (a beta2-adrenergic agonist), used with or without inhaled corticosteroids, are effective in reducing the frequency of COPD exacerbations, improving quality of life and lung function, and reducing the number of hospitalizations.^7-10

Long-acting bronchodilators are therefore clearly indicated but, until recently, there was little evidence as to which one is better.

STUDY SUMMARY: Tiotropium group had fewer exacerbations…

The Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial compared tiotropium with salmeterol for their ability to prevent exacerbations.¹ This was a randomized double-blind trial of 7376 patients with moderate to very severe COPD diagnosed by spirometry. Participants were recruited from 725 medical centers in 25 countries. To be eligible, they had to be ≥40 years, with at least a 10 pack-year history of smoking, a forced expiratory volume in 1 second (FEV1) <70% predicted, an FEV1/forced vital capacity (FVC ) <70%, and at least one exacerbation in the previous year.

Patients were randomly assigned to either the tiotropium or the salmeterol group. Those on tiotropium received a daily dose of 18 mcg through a HandiHaler device, plus a placebo with a metered-dose inhaler twice a day. Patients in the other group received 50 mcg salmeterol through a metered-dose inhaler twice daily, plus a placebo with a HandiHaler once a day. These medications were in addition to patients’ current medication regimens, including inhaled corticosteroids, with this exception: Use of anticholinergics and long-acting beta-agonists was discontinued for the course of the trial.

All participants were followed for one year, with clinic visits at 2, 4, 8, and 12 months to assess for medication adherence and symptoms of exacerbation. The primary endpoint was the time to first exacerbation. This was defined as an increase in, or a new onset of, more than one symptom of COPD (ie, cough, sputum production, wheezing, dyspnea, and chest tightness), with at least one symptom lasting ≥3 days and leading to treatment with glucocorticoids and/or antibiotics, or hospitalization. Secondary outcomes were times to first moderate and severe exacerbations and use of steroids and antibiotics.

There were significant differences in several outcomes. The time to first exacerbation was 187 days for tiotropium vs 145 days for salmeterol, a difference of 42 days (hazard ratio [HR]=0.83; 95% confidence interval [CI], 0.77-0.90; P<.001). In addition, tiotropium reduced the annual number of exacerbations compared with salmeterol (rate ratio=0.89; 95% CI, 0.83-0.96; P=.002), with a number needed to treat (NNT) of 24 patients to prevent one moderate to severe exacerbation per year.

…and used fewer drugs

Compared with salmeterol, there was a 14% reduction in risk of a moderate exacerbation associated with tiotropium (HR=0.86; 95% CI, 0.79-0.93; P<.001; NNT=32) and a 28% reduction in risk of a severe exacerbation (HR=0.72; 95% CI, 0.61-0.85; P<.001; NNT=48). In addition, the tiotropium group had a 23% risk reduction in the use of systemic glucocorticoids (HR=0.77; 95% CI, 0.69-0.85; P<.001; NNT=26) compared with the salmeterol group, and a 15% risk reduction in the use of antibiotics (HR=0.85; 95% CI, 0.78-0.92; P<0.001; NNT=31). The difference in reduction in death rates between the 2 groups was not statistically significant.

The observed differences were consistent across all major subgroups (age, sex, smoking status, and severity of COPD) of patients studied. Interestingly, patients with low BMI or very severe COPD appeared to benefit the most from tiotropium.

WHAT’S NEW: The difference between 2 agents is clear

Although national guidelines recommend long-acting bronchodilators for COPD that is moderate or worse, there have been few data to guide clinicians in determining which one to use. The findings of this study suggest that tiotropium should be our first choice. Tiotropium’s once-a-day dosing is an additional benefit, as patients using it will likely have better compliance than those using twice-daily salmeterol. The data may also prompt development of a once-daily inhaled corticosteroid/ long-acting anticholinergic combination.

CAVEATS: Cost, funding source

Cost may be an issue. Spiriva and Serevent, the brand names for tiotropium and salmeterol, respectively, are second-tier medications on several formularies, and tiotropium is about 45% more expensive (tiotropium=$262, salmeterol=$181 for one month’s supply; www.drugstore.com, accessed January 19, 2012). There are also several long-acting beta-agonists in development that will be dosed once daily; once they’re approved, tiotropium’s once-a-day dosing may no longer be seen as an advantage.

It is also worth noting that this trial was supported by Boehringer Ingelheim and Pfizer, which jointly market Spiriva.

Finally, smoking must be addressed. Strongly encouraging patients to kick the habit is still the most important intervention we can make in helping to improve the quality of life, and survival, of patients with COPD.

CHALLENGES TO IMPLEMENTATION: COPD guidelines need updating

There are no major challenges to incorporating this recommendation into clinical practice; the key challenge lies in diagnosing COPD and adequately monitoring and helping patients manage the disease.

Current guidelines do not distinguish between the efficacy of long-acting bronchodilators, but findings from this study are important enough to change future versions of national guidelines. The GOLD committee is due to release a new guideline report soon, and will likely update its recommendations at that time.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 60-year-old patient with moderate COPD and a history of frequent exacerbations comes in for a follow-up visit. She has been using albuterol and ipratropium intermittently. you want to add a longer-acting bronchodilator and wonder if tiotropium or salmeterol is more effective for reducing exacerbations.

COPD is the fourth leading cause of death in the United States.² More than 12 million Americans have been diagnosed with COPD, and it is estimated that another 12 million would have a COPD diagnosis if all smokers older than 45 years underwent spirometry.² The disorder accounts for some 16 million physician visits each year and costs the US health care system approximately $19 billion annually, with acute exacerbations and hospitalizations representing 58% of the total.^2,3

Despite guidelines, COPD is often undertreated
One of the main goals of COPD treatment is to reduce the frequency and intensity of acute exacerbations, both to improve patients’ quality of life and reduce health care costs. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has developed guidelines for effective management of COPD, which recommend long-acting bronchodilators as first-line maintenance therapy for patients whose disease is moderate to very severe.⁴

Evidence suggests that physicians frequently undertreat moderate to severe COPD, however, following national guidelines only about a quarter of the time.⁵ This is, in part, because many clinicians doubt the efficacy of COPD treatment for improving symptoms or decreasing exacerbations.^5,6 Yet studies have shown that the long-acting broncho dilators tiotropium (an anticholinergic agent) and salmeterol (a beta2-adrenergic agonist), used with or without inhaled corticosteroids, are effective in reducing the frequency of COPD exacerbations, improving quality of life and lung function, and reducing the number of hospitalizations.^7-10

Long-acting bronchodilators are therefore clearly indicated but, until recently, there was little evidence as to which one is better.

STUDY SUMMARY: Tiotropium group had fewer exacerbations…

The Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial compared tiotropium with salmeterol for their ability to prevent exacerbations.¹ This was a randomized double-blind trial of 7376 patients with moderate to very severe COPD diagnosed by spirometry. Participants were recruited from 725 medical centers in 25 countries. To be eligible, they had to be ≥40 years, with at least a 10 pack-year history of smoking, a forced expiratory volume in 1 second (FEV1) <70% predicted, an FEV1/forced vital capacity (FVC ) <70%, and at least one exacerbation in the previous year.

Patients were randomly assigned to either the tiotropium or the salmeterol group. Those on tiotropium received a daily dose of 18 mcg through a HandiHaler device, plus a placebo with a metered-dose inhaler twice a day. Patients in the other group received 50 mcg salmeterol through a metered-dose inhaler twice daily, plus a placebo with a HandiHaler once a day. These medications were in addition to patients’ current medication regimens, including inhaled corticosteroids, with this exception: Use of anticholinergics and long-acting beta-agonists was discontinued for the course of the trial.

All participants were followed for one year, with clinic visits at 2, 4, 8, and 12 months to assess for medication adherence and symptoms of exacerbation. The primary endpoint was the time to first exacerbation. This was defined as an increase in, or a new onset of, more than one symptom of COPD (ie, cough, sputum production, wheezing, dyspnea, and chest tightness), with at least one symptom lasting ≥3 days and leading to treatment with glucocorticoids and/or antibiotics, or hospitalization. Secondary outcomes were times to first moderate and severe exacerbations and use of steroids and antibiotics.

There were significant differences in several outcomes. The time to first exacerbation was 187 days for tiotropium vs 145 days for salmeterol, a difference of 42 days (hazard ratio [HR]=0.83; 95% confidence interval [CI], 0.77-0.90; P<.001). In addition, tiotropium reduced the annual number of exacerbations compared with salmeterol (rate ratio=0.89; 95% CI, 0.83-0.96; P=.002), with a number needed to treat (NNT) of 24 patients to prevent one moderate to severe exacerbation per year.

…and used fewer drugs

Compared with salmeterol, there was a 14% reduction in risk of a moderate exacerbation associated with tiotropium (HR=0.86; 95% CI, 0.79-0.93; P<.001; NNT=32) and a 28% reduction in risk of a severe exacerbation (HR=0.72; 95% CI, 0.61-0.85; P<.001; NNT=48). In addition, the tiotropium group had a 23% risk reduction in the use of systemic glucocorticoids (HR=0.77; 95% CI, 0.69-0.85; P<.001; NNT=26) compared with the salmeterol group, and a 15% risk reduction in the use of antibiotics (HR=0.85; 95% CI, 0.78-0.92; P<0.001; NNT=31). The difference in reduction in death rates between the 2 groups was not statistically significant.

The observed differences were consistent across all major subgroups (age, sex, smoking status, and severity of COPD) of patients studied. Interestingly, patients with low BMI or very severe COPD appeared to benefit the most from tiotropium.

WHAT’S NEW: The difference between 2 agents is clear

Although national guidelines recommend long-acting bronchodilators for COPD that is moderate or worse, there have been few data to guide clinicians in determining which one to use. The findings of this study suggest that tiotropium should be our first choice. Tiotropium’s once-a-day dosing is an additional benefit, as patients using it will likely have better compliance than those using twice-daily salmeterol. The data may also prompt development of a once-daily inhaled corticosteroid/ long-acting anticholinergic combination.

CAVEATS: Cost, funding source

Cost may be an issue. Spiriva and Serevent, the brand names for tiotropium and salmeterol, respectively, are second-tier medications on several formularies, and tiotropium is about 45% more expensive (tiotropium=$262, salmeterol=$181 for one month’s supply; www.drugstore.com, accessed January 19, 2012). There are also several long-acting beta-agonists in development that will be dosed once daily; once they’re approved, tiotropium’s once-a-day dosing may no longer be seen as an advantage.

It is also worth noting that this trial was supported by Boehringer Ingelheim and Pfizer, which jointly market Spiriva.

Finally, smoking must be addressed. Strongly encouraging patients to kick the habit is still the most important intervention we can make in helping to improve the quality of life, and survival, of patients with COPD.

CHALLENGES TO IMPLEMENTATION: COPD guidelines need updating

There are no major challenges to incorporating this recommendation into clinical practice; the key challenge lies in diagnosing COPD and adequately monitoring and helping patients manage the disease.

Current guidelines do not distinguish between the efficacy of long-acting bronchodilators, but findings from this study are important enough to change future versions of national guidelines. The GOLD committee is due to release a new guideline report soon, and will likely update its recommendations at that time.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 60-year-old patient with moderate COPD and a history of frequent exacerbations comes in for a follow-up visit. She has been using albuterol and ipratropium intermittently. you want to add a longer-acting bronchodilator and wonder if tiotropium or salmeterol is more effective for reducing exacerbations.

COPD is the fourth leading cause of death in the United States.² More than 12 million Americans have been diagnosed with COPD, and it is estimated that another 12 million would have a COPD diagnosis if all smokers older than 45 years underwent spirometry.² The disorder accounts for some 16 million physician visits each year and costs the US health care system approximately $19 billion annually, with acute exacerbations and hospitalizations representing 58% of the total.^2,3

Despite guidelines, COPD is often undertreated
One of the main goals of COPD treatment is to reduce the frequency and intensity of acute exacerbations, both to improve patients’ quality of life and reduce health care costs. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has developed guidelines for effective management of COPD, which recommend long-acting bronchodilators as first-line maintenance therapy for patients whose disease is moderate to very severe.⁴

Evidence suggests that physicians frequently undertreat moderate to severe COPD, however, following national guidelines only about a quarter of the time.⁵ This is, in part, because many clinicians doubt the efficacy of COPD treatment for improving symptoms or decreasing exacerbations.^5,6 Yet studies have shown that the long-acting broncho dilators tiotropium (an anticholinergic agent) and salmeterol (a beta2-adrenergic agonist), used with or without inhaled corticosteroids, are effective in reducing the frequency of COPD exacerbations, improving quality of life and lung function, and reducing the number of hospitalizations.^7-10

Long-acting bronchodilators are therefore clearly indicated but, until recently, there was little evidence as to which one is better.

STUDY SUMMARY: Tiotropium group had fewer exacerbations…

The Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial compared tiotropium with salmeterol for their ability to prevent exacerbations.¹ This was a randomized double-blind trial of 7376 patients with moderate to very severe COPD diagnosed by spirometry. Participants were recruited from 725 medical centers in 25 countries. To be eligible, they had to be ≥40 years, with at least a 10 pack-year history of smoking, a forced expiratory volume in 1 second (FEV1) <70% predicted, an FEV1/forced vital capacity (FVC ) <70%, and at least one exacerbation in the previous year.

Patients were randomly assigned to either the tiotropium or the salmeterol group. Those on tiotropium received a daily dose of 18 mcg through a HandiHaler device, plus a placebo with a metered-dose inhaler twice a day. Patients in the other group received 50 mcg salmeterol through a metered-dose inhaler twice daily, plus a placebo with a HandiHaler once a day. These medications were in addition to patients’ current medication regimens, including inhaled corticosteroids, with this exception: Use of anticholinergics and long-acting beta-agonists was discontinued for the course of the trial.

All participants were followed for one year, with clinic visits at 2, 4, 8, and 12 months to assess for medication adherence and symptoms of exacerbation. The primary endpoint was the time to first exacerbation. This was defined as an increase in, or a new onset of, more than one symptom of COPD (ie, cough, sputum production, wheezing, dyspnea, and chest tightness), with at least one symptom lasting ≥3 days and leading to treatment with glucocorticoids and/or antibiotics, or hospitalization. Secondary outcomes were times to first moderate and severe exacerbations and use of steroids and antibiotics.

There were significant differences in several outcomes. The time to first exacerbation was 187 days for tiotropium vs 145 days for salmeterol, a difference of 42 days (hazard ratio [HR]=0.83; 95% confidence interval [CI], 0.77-0.90; P<.001). In addition, tiotropium reduced the annual number of exacerbations compared with salmeterol (rate ratio=0.89; 95% CI, 0.83-0.96; P=.002), with a number needed to treat (NNT) of 24 patients to prevent one moderate to severe exacerbation per year.

…and used fewer drugs

Compared with salmeterol, there was a 14% reduction in risk of a moderate exacerbation associated with tiotropium (HR=0.86; 95% CI, 0.79-0.93; P<.001; NNT=32) and a 28% reduction in risk of a severe exacerbation (HR=0.72; 95% CI, 0.61-0.85; P<.001; NNT=48). In addition, the tiotropium group had a 23% risk reduction in the use of systemic glucocorticoids (HR=0.77; 95% CI, 0.69-0.85; P<.001; NNT=26) compared with the salmeterol group, and a 15% risk reduction in the use of antibiotics (HR=0.85; 95% CI, 0.78-0.92; P<0.001; NNT=31). The difference in reduction in death rates between the 2 groups was not statistically significant.

The observed differences were consistent across all major subgroups (age, sex, smoking status, and severity of COPD) of patients studied. Interestingly, patients with low BMI or very severe COPD appeared to benefit the most from tiotropium.

WHAT’S NEW: The difference between 2 agents is clear

Although national guidelines recommend long-acting bronchodilators for COPD that is moderate or worse, there have been few data to guide clinicians in determining which one to use. The findings of this study suggest that tiotropium should be our first choice. Tiotropium’s once-a-day dosing is an additional benefit, as patients using it will likely have better compliance than those using twice-daily salmeterol. The data may also prompt development of a once-daily inhaled corticosteroid/ long-acting anticholinergic combination.

CAVEATS: Cost, funding source

Cost may be an issue. Spiriva and Serevent, the brand names for tiotropium and salmeterol, respectively, are second-tier medications on several formularies, and tiotropium is about 45% more expensive (tiotropium=$262, salmeterol=$181 for one month’s supply; www.drugstore.com, accessed January 19, 2012). There are also several long-acting beta-agonists in development that will be dosed once daily; once they’re approved, tiotropium’s once-a-day dosing may no longer be seen as an advantage.

It is also worth noting that this trial was supported by Boehringer Ingelheim and Pfizer, which jointly market Spiriva.

Finally, smoking must be addressed. Strongly encouraging patients to kick the habit is still the most important intervention we can make in helping to improve the quality of life, and survival, of patients with COPD.

CHALLENGES TO IMPLEMENTATION: COPD guidelines need updating

There are no major challenges to incorporating this recommendation into clinical practice; the key challenge lies in diagnosing COPD and adequately monitoring and helping patients manage the disease.

Current guidelines do not distinguish between the efficacy of long-acting bronchodilators, but findings from this study are important enough to change future versions of national guidelines. The GOLD committee is due to release a new guideline report soon, and will likely update its recommendations at that time.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ABSTRACT

BACKGROUND: Ambulatory uterine activity monitoring in high-risk women continues despite the results from randomized trials indicating no relationship between monitoring and actual reduction of preterm delivery. The value of uterine contraction frequency as a predictor of preterm delivery, however, remains unclear.

POPULATION STUDIED: A total of 2205 women with a singleton gestation of longer than 22 weeks were screened; 454 met eligibility criteria. Data from 306 women were analyzed, including 254 high-risk women with either a history of preterm delivery (between 20 and 36 weeks’) or bleeding in the 2nd trimester of the current pregnancy, and 52 low-risk women. Exclusion criteria included previous or scheduled use of an ambulatory contraction monitor, use of tocolytic therapy, scheduled cerclage, placenta previa, major fetal anomalies, or no home phone. The mean age of participants was 26.2 years, with a mean parity of 1.8. The majority of participants were black (60%), with at least 12 years of education (74%). Many participants smoked (26%).

STUDY DESIGN AND VALIDITY: The authors used an observational study to determine whether the frequency of contractions could predict spontaneous preterm delivery at less than 35 weeks. Contractions were monitored for at least 30 minutes, twice a day (daytime and nighttime) on 2 or more days per week until 28 weeks, then 4 times per week. Two trained nurses, masked to risk status, analyzed monitor recordings. Contractions were defined as deflections from a clear baseline, with a rounded peak lasting 40 seconds to 120 seconds. Cervical examinations were performed every 2 to 3 weeks, beginning at 22 weeks, up to 6 times, depending on length of gestation. Data collected included cervicovaginal fluid for fetal fibronectin analysis, cervical length by transvaginal ultrasound, and assessment of Bishop score. Assessment of contraction recordings was validated by repeat audits during which samples were re-analyzed. Interpretation discordance occurred in 14% to 28% of recordings, but discrepancies were not greater than 1 contraction per hour.

OUTCOMES MEASURED: The primary outcome was the ability of uterine contraction frequency (daytime and nighttime) to predict spontaneous preterm delivery. In addition, fetal fibronectin, cervical length, and a Bishop score higher than 4 were studied as possible predictors at these same gestational ages.

RESULTS: There was no difference in frequency of contractions between the high-risk and low-risk group and therefore all data were pooled for analysis. The maximal frequency of contractions was inconsistently related to preterm delivery, with the largest association found for nighttime contractions at 27 to 28 weeks (odds ratio [OR] = 1.2; 95% CI, 1.1-1.4). Logistic regression revealed a consistent relationship between ultrasound cervical length and preterm delivery across all gestational age groupings, with statistically significant ORs ranging from 4.0 at 27 to 28 weeks to 7.5 at 31 to 33 weeks. The sensitivity for maximal daytime and nighttime contraction frequency was low, ranging from less than 10% at 22 to 24 weeks to 28% at 27 to 28 weeks and 31 to 33 weeks. Positive PPVs were correspondingly low, with none higher than 25%. Although the sensitivities for fetal fibronectin, ultrasound cervical length assessment, and Bishop scoring were generally somewhat higher (ranging from a low of 19% for fetal fibronectin at 22 to 24 weeks to a high of 82% for cervical length at 31 to 33 weeks) the corresponding PPVs were also low (range = 15% to 37%).

ABSTRACT

BACKGROUND: Ambulatory uterine activity monitoring in high-risk women continues despite the results from randomized trials indicating no relationship between monitoring and actual reduction of preterm delivery. The value of uterine contraction frequency as a predictor of preterm delivery, however, remains unclear.

POPULATION STUDIED: A total of 2205 women with a singleton gestation of longer than 22 weeks were screened; 454 met eligibility criteria. Data from 306 women were analyzed, including 254 high-risk women with either a history of preterm delivery (between 20 and 36 weeks’) or bleeding in the 2nd trimester of the current pregnancy, and 52 low-risk women. Exclusion criteria included previous or scheduled use of an ambulatory contraction monitor, use of tocolytic therapy, scheduled cerclage, placenta previa, major fetal anomalies, or no home phone. The mean age of participants was 26.2 years, with a mean parity of 1.8. The majority of participants were black (60%), with at least 12 years of education (74%). Many participants smoked (26%).

STUDY DESIGN AND VALIDITY: The authors used an observational study to determine whether the frequency of contractions could predict spontaneous preterm delivery at less than 35 weeks. Contractions were monitored for at least 30 minutes, twice a day (daytime and nighttime) on 2 or more days per week until 28 weeks, then 4 times per week. Two trained nurses, masked to risk status, analyzed monitor recordings. Contractions were defined as deflections from a clear baseline, with a rounded peak lasting 40 seconds to 120 seconds. Cervical examinations were performed every 2 to 3 weeks, beginning at 22 weeks, up to 6 times, depending on length of gestation. Data collected included cervicovaginal fluid for fetal fibronectin analysis, cervical length by transvaginal ultrasound, and assessment of Bishop score. Assessment of contraction recordings was validated by repeat audits during which samples were re-analyzed. Interpretation discordance occurred in 14% to 28% of recordings, but discrepancies were not greater than 1 contraction per hour.

OUTCOMES MEASURED: The primary outcome was the ability of uterine contraction frequency (daytime and nighttime) to predict spontaneous preterm delivery. In addition, fetal fibronectin, cervical length, and a Bishop score higher than 4 were studied as possible predictors at these same gestational ages.

RESULTS: There was no difference in frequency of contractions between the high-risk and low-risk group and therefore all data were pooled for analysis. The maximal frequency of contractions was inconsistently related to preterm delivery, with the largest association found for nighttime contractions at 27 to 28 weeks (odds ratio [OR] = 1.2; 95% CI, 1.1-1.4). Logistic regression revealed a consistent relationship between ultrasound cervical length and preterm delivery across all gestational age groupings, with statistically significant ORs ranging from 4.0 at 27 to 28 weeks to 7.5 at 31 to 33 weeks. The sensitivity for maximal daytime and nighttime contraction frequency was low, ranging from less than 10% at 22 to 24 weeks to 28% at 27 to 28 weeks and 31 to 33 weeks. Positive PPVs were correspondingly low, with none higher than 25%. Although the sensitivities for fetal fibronectin, ultrasound cervical length assessment, and Bishop scoring were generally somewhat higher (ranging from a low of 19% for fetal fibronectin at 22 to 24 weeks to a high of 82% for cervical length at 31 to 33 weeks) the corresponding PPVs were also low (range = 15% to 37%).

ABSTRACT

BACKGROUND: Ambulatory uterine activity monitoring in high-risk women continues despite the results from randomized trials indicating no relationship between monitoring and actual reduction of preterm delivery. The value of uterine contraction frequency as a predictor of preterm delivery, however, remains unclear.

POPULATION STUDIED: A total of 2205 women with a singleton gestation of longer than 22 weeks were screened; 454 met eligibility criteria. Data from 306 women were analyzed, including 254 high-risk women with either a history of preterm delivery (between 20 and 36 weeks’) or bleeding in the 2nd trimester of the current pregnancy, and 52 low-risk women. Exclusion criteria included previous or scheduled use of an ambulatory contraction monitor, use of tocolytic therapy, scheduled cerclage, placenta previa, major fetal anomalies, or no home phone. The mean age of participants was 26.2 years, with a mean parity of 1.8. The majority of participants were black (60%), with at least 12 years of education (74%). Many participants smoked (26%).

STUDY DESIGN AND VALIDITY: The authors used an observational study to determine whether the frequency of contractions could predict spontaneous preterm delivery at less than 35 weeks. Contractions were monitored for at least 30 minutes, twice a day (daytime and nighttime) on 2 or more days per week until 28 weeks, then 4 times per week. Two trained nurses, masked to risk status, analyzed monitor recordings. Contractions were defined as deflections from a clear baseline, with a rounded peak lasting 40 seconds to 120 seconds. Cervical examinations were performed every 2 to 3 weeks, beginning at 22 weeks, up to 6 times, depending on length of gestation. Data collected included cervicovaginal fluid for fetal fibronectin analysis, cervical length by transvaginal ultrasound, and assessment of Bishop score. Assessment of contraction recordings was validated by repeat audits during which samples were re-analyzed. Interpretation discordance occurred in 14% to 28% of recordings, but discrepancies were not greater than 1 contraction per hour.

OUTCOMES MEASURED: The primary outcome was the ability of uterine contraction frequency (daytime and nighttime) to predict spontaneous preterm delivery. In addition, fetal fibronectin, cervical length, and a Bishop score higher than 4 were studied as possible predictors at these same gestational ages.

RESULTS: There was no difference in frequency of contractions between the high-risk and low-risk group and therefore all data were pooled for analysis. The maximal frequency of contractions was inconsistently related to preterm delivery, with the largest association found for nighttime contractions at 27 to 28 weeks (odds ratio [OR] = 1.2; 95% CI, 1.1-1.4). Logistic regression revealed a consistent relationship between ultrasound cervical length and preterm delivery across all gestational age groupings, with statistically significant ORs ranging from 4.0 at 27 to 28 weeks to 7.5 at 31 to 33 weeks. The sensitivity for maximal daytime and nighttime contraction frequency was low, ranging from less than 10% at 22 to 24 weeks to 28% at 27 to 28 weeks and 31 to 33 weeks. Positive PPVs were correspondingly low, with none higher than 25%. Although the sensitivities for fetal fibronectin, ultrasound cervical length assessment, and Bishop scoring were generally somewhat higher (ranging from a low of 19% for fetal fibronectin at 22 to 24 weeks to a high of 82% for cervical length at 31 to 33 weeks) the corresponding PPVs were also low (range = 15% to 37%).