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James J. Stevermer is in the Department of Family and Community Medicine at the University of Missouri–Columbia.
Treatment of high LDL saves lives of those with diabetes or cardiovascular disease
Hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy that effectively reduces low-density lipoprotein (LDL) cholesterol increases life expectancy at least as much among those with diabetes mellitus without cardiovascular disease as among those with established cardiovascular disease alone.
While this result is only based on a validated theoretical model, it was extrapolated to the entire American population, and is consistent with randomized clinical trials. Public health programs and health care providers should give as much emphasis to treating elevated LDL among those with diabetes who are still free of cardiovascular disease as among those with already established cardiovascular disease.
Hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy that effectively reduces low-density lipoprotein (LDL) cholesterol increases life expectancy at least as much among those with diabetes mellitus without cardiovascular disease as among those with established cardiovascular disease alone.
While this result is only based on a validated theoretical model, it was extrapolated to the entire American population, and is consistent with randomized clinical trials. Public health programs and health care providers should give as much emphasis to treating elevated LDL among those with diabetes who are still free of cardiovascular disease as among those with already established cardiovascular disease.
Hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy that effectively reduces low-density lipoprotein (LDL) cholesterol increases life expectancy at least as much among those with diabetes mellitus without cardiovascular disease as among those with established cardiovascular disease alone.
While this result is only based on a validated theoretical model, it was extrapolated to the entire American population, and is consistent with randomized clinical trials. Public health programs and health care providers should give as much emphasis to treating elevated LDL among those with diabetes who are still free of cardiovascular disease as among those with already established cardiovascular disease.
Taper proton pump inhibitor to once daily for GERD
For patients with gastroesophageal reflux disease (GERD) who take proton pump inhibitors (PPIs) more than once daily, an attempt to reduce dosing to once daily will be successful in over 80%, with little change in quality of life.
Given the expense of these medications, clinicians should undertake a trial of once-daily dosing for patients on higher doses, after their initial symptoms are controlled for at least 8 weeks. Though dose reduction is harder to achieve when patients have been taking a PPI long-term, 84% of such patients who could not tolerate an initial dose reduction were able to do so on a subsequent attempt.
For patients with gastroesophageal reflux disease (GERD) who take proton pump inhibitors (PPIs) more than once daily, an attempt to reduce dosing to once daily will be successful in over 80%, with little change in quality of life.
Given the expense of these medications, clinicians should undertake a trial of once-daily dosing for patients on higher doses, after their initial symptoms are controlled for at least 8 weeks. Though dose reduction is harder to achieve when patients have been taking a PPI long-term, 84% of such patients who could not tolerate an initial dose reduction were able to do so on a subsequent attempt.
For patients with gastroesophageal reflux disease (GERD) who take proton pump inhibitors (PPIs) more than once daily, an attempt to reduce dosing to once daily will be successful in over 80%, with little change in quality of life.
Given the expense of these medications, clinicians should undertake a trial of once-daily dosing for patients on higher doses, after their initial symptoms are controlled for at least 8 weeks. Though dose reduction is harder to achieve when patients have been taking a PPI long-term, 84% of such patients who could not tolerate an initial dose reduction were able to do so on a subsequent attempt.
Nebulized epinephrine does not help bronchiolitis
Nebulized epinephrine does not improve clinical status or reduce the length of the hospital stay in infants aged <1 year with acute bronchiolitis. It also does not reduce clinical scores during or shortly after medication administration.
In this study, infants requiring oxygen and intravenous fluids—presumably the sickest infants in the study—required longer hospital stays if they received epinephrine. A wheezing infant may be presenting with a first episode of asthma, so a trial of bronchodilators would seem reasonable; however, it appears that the primary intervention for bronchiolitis is supportive treatment, with supplemental oxygen, intravenous fluids, and ventilatory support when needed.
Nebulized epinephrine does not improve clinical status or reduce the length of the hospital stay in infants aged <1 year with acute bronchiolitis. It also does not reduce clinical scores during or shortly after medication administration.
In this study, infants requiring oxygen and intravenous fluids—presumably the sickest infants in the study—required longer hospital stays if they received epinephrine. A wheezing infant may be presenting with a first episode of asthma, so a trial of bronchodilators would seem reasonable; however, it appears that the primary intervention for bronchiolitis is supportive treatment, with supplemental oxygen, intravenous fluids, and ventilatory support when needed.
Nebulized epinephrine does not improve clinical status or reduce the length of the hospital stay in infants aged <1 year with acute bronchiolitis. It also does not reduce clinical scores during or shortly after medication administration.
In this study, infants requiring oxygen and intravenous fluids—presumably the sickest infants in the study—required longer hospital stays if they received epinephrine. A wheezing infant may be presenting with a first episode of asthma, so a trial of bronchodilators would seem reasonable; however, it appears that the primary intervention for bronchiolitis is supportive treatment, with supplemental oxygen, intravenous fluids, and ventilatory support when needed.
Does finasteride prevent prostate cancer?
Treatment with finasteride will, over 7 years, decrease the prevalence of prostate cancer but increase the likelihood of developing a high-grade cancer. For every 1000 men given finasteride for prostate cancer, 62 will not develop prostate cancer. In addition, 35 men will not develop benign prostatic hypertrophy, 27 will have less urinary urgency or frequency, and 21 will report less urinary retention.
However, of those that develop prostate cancer, 13 will have higher-grade cancer (Gleason score 7 or higher), 59 will have erec-tile dysfunction, 58 will have a loss of libido, and 131 will have reduced volume of ejaculate. This study provides no information on the clinical significance of reducing the overall rate of cancer, while increasing higher-grade tumors. Since it is unclear whether finasteride reduces morbidity or mortality, it cannot be recommended for the routine prevention of prostate cancer.
Treatment with finasteride will, over 7 years, decrease the prevalence of prostate cancer but increase the likelihood of developing a high-grade cancer. For every 1000 men given finasteride for prostate cancer, 62 will not develop prostate cancer. In addition, 35 men will not develop benign prostatic hypertrophy, 27 will have less urinary urgency or frequency, and 21 will report less urinary retention.
However, of those that develop prostate cancer, 13 will have higher-grade cancer (Gleason score 7 or higher), 59 will have erec-tile dysfunction, 58 will have a loss of libido, and 131 will have reduced volume of ejaculate. This study provides no information on the clinical significance of reducing the overall rate of cancer, while increasing higher-grade tumors. Since it is unclear whether finasteride reduces morbidity or mortality, it cannot be recommended for the routine prevention of prostate cancer.
Treatment with finasteride will, over 7 years, decrease the prevalence of prostate cancer but increase the likelihood of developing a high-grade cancer. For every 1000 men given finasteride for prostate cancer, 62 will not develop prostate cancer. In addition, 35 men will not develop benign prostatic hypertrophy, 27 will have less urinary urgency or frequency, and 21 will report less urinary retention.
However, of those that develop prostate cancer, 13 will have higher-grade cancer (Gleason score 7 or higher), 59 will have erec-tile dysfunction, 58 will have a loss of libido, and 131 will have reduced volume of ejaculate. This study provides no information on the clinical significance of reducing the overall rate of cancer, while increasing higher-grade tumors. Since it is unclear whether finasteride reduces morbidity or mortality, it cannot be recommended for the routine prevention of prostate cancer.
Low-dose doxycycline moderately effective for acne
The authors propose that moderate acne may be treated with doxycycline in subantimicrobial doses (20-mg tablets taken twice daily). This regimen was well-tolerated, moderately effective in reducing skin lesions, and did not have a detectable effect on the antibiotic resistance of skin flora.
The cost of Periostat (the only form of doxycycline 20 mg available in the US) is about $55 per month, while generic doxycycline 100 mg is about $10.1 This study has some significant flaws, but a trial of low-dose doxycycline in an adult with acne severe enough to warrant antibiotics would still seem a reasonable, albeit expensive, option.
The authors propose that moderate acne may be treated with doxycycline in subantimicrobial doses (20-mg tablets taken twice daily). This regimen was well-tolerated, moderately effective in reducing skin lesions, and did not have a detectable effect on the antibiotic resistance of skin flora.
The cost of Periostat (the only form of doxycycline 20 mg available in the US) is about $55 per month, while generic doxycycline 100 mg is about $10.1 This study has some significant flaws, but a trial of low-dose doxycycline in an adult with acne severe enough to warrant antibiotics would still seem a reasonable, albeit expensive, option.
The authors propose that moderate acne may be treated with doxycycline in subantimicrobial doses (20-mg tablets taken twice daily). This regimen was well-tolerated, moderately effective in reducing skin lesions, and did not have a detectable effect on the antibiotic resistance of skin flora.
The cost of Periostat (the only form of doxycycline 20 mg available in the US) is about $55 per month, while generic doxycycline 100 mg is about $10.1 This study has some significant flaws, but a trial of low-dose doxycycline in an adult with acne severe enough to warrant antibiotics would still seem a reasonable, albeit expensive, option.
Does C-reactive protein predict cardiovascular events in women better than LDL?
C-reactive protein (CRP) is an independent predictor of a first cardiovascular event in women and appears to be a stronger predictor than low-density lipoprotein (LDL) cholesterol levels.
Unfortunately, this information does not lead directly to a therapeutic intervention. As an accompanying editorial stated, low carotenoid levels also predict cardiovascular events, but supplementation with beta carotene does not reduce an individual’s risk.1
This study does not clarify whether CRP is a causative agent, a marker, or a result of cardiovascular disease. Our focus should remain on identifying and treating conventional risk factors until we better understand the exact role CRP has in therapeutic decisions regarding cardiovascular disease.
C-reactive protein (CRP) is an independent predictor of a first cardiovascular event in women and appears to be a stronger predictor than low-density lipoprotein (LDL) cholesterol levels.
Unfortunately, this information does not lead directly to a therapeutic intervention. As an accompanying editorial stated, low carotenoid levels also predict cardiovascular events, but supplementation with beta carotene does not reduce an individual’s risk.1
This study does not clarify whether CRP is a causative agent, a marker, or a result of cardiovascular disease. Our focus should remain on identifying and treating conventional risk factors until we better understand the exact role CRP has in therapeutic decisions regarding cardiovascular disease.
C-reactive protein (CRP) is an independent predictor of a first cardiovascular event in women and appears to be a stronger predictor than low-density lipoprotein (LDL) cholesterol levels.
Unfortunately, this information does not lead directly to a therapeutic intervention. As an accompanying editorial stated, low carotenoid levels also predict cardiovascular events, but supplementation with beta carotene does not reduce an individual’s risk.1
This study does not clarify whether CRP is a causative agent, a marker, or a result of cardiovascular disease. Our focus should remain on identifying and treating conventional risk factors until we better understand the exact role CRP has in therapeutic decisions regarding cardiovascular disease.
Early invasive strategy for acute cardiac ischemia is cost effective
In patients with unstable angina and non–ST segment myocardial infarction treated with aspirin, heparin, and tirofiban, an early invasive strategy with routine angiography and appropriate revascularization has better clinical outcomes, at a relatively minimal increase in cost.
In patients with unstable angina and non–ST segment myocardial infarction treated with aspirin, heparin, and tirofiban, an early invasive strategy with routine angiography and appropriate revascularization has better clinical outcomes, at a relatively minimal increase in cost.
In patients with unstable angina and non–ST segment myocardial infarction treated with aspirin, heparin, and tirofiban, an early invasive strategy with routine angiography and appropriate revascularization has better clinical outcomes, at a relatively minimal increase in cost.
What is the target for low-density lipoprotein cholesterol in patients with heart disease?
EVIDENCE-BASED ANSWER
Large published randomized controlled trials (RCTs) show that pravastatin and simvastatin are well-tolerated and reduce major coronary events such as death, myocardial infarction, and revascularization by about 25%. The Heart Protection Study suggested this benefit is noted even among individuals with pretreatment low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL. Fluvastatin reduces major coronary events, but current studies are too small to prove reduced overall mortality. The best evidence to date suggests that most patients at significant risk for major coronary events should be given pravastatin or simvastatin 40 mg daily, without concern for the initial or follow-up LDL levels. (Grade of recommendation: A, based on large randomized trials.)
Evidence summary
The evidence is solid to support the use of HMG–CoA reductase inhibitors (statins) for patients with coronary artery disease (CAD). The Scandinavian Simvastatin Survival study used simvastatin 20 mg daily unless total cholesterol levels did not decrease to less than 200 mg/dL.1 The Long-Term Intervention with Pravastatin in Ischaemic Disease study randomized patients to pravastatin 40 mg daily or placebo, without titration.2 The intervention arm in the Cholesterol and Recurrent Events trial was also pravastatin 40 mg daily, with cholestyramine added if the LDL level remained higher than 175 mg/dL.3 The Lescol Intervention Prevention study randomized patients after angioplasty to fluvastatin 40 mg twice daily or placebo.4 The Heart Protection Study used simvastatin 40 mg daily, without titration.5 No RCTs have evaluated the clinical benefit of adding medications to adequate doses of statins to lower LDL to less than 175 mg/dL. See Table of major RCTs with clinical outcomes.
Subgroup analyses of earlier major RCTs had suggested that patients with CAD and low initial LDL levels (< 125 mg/dL) have little to gain from pravastatin.2,3 However, the Heart Protection Study enrolled 20,000 people with CAD or equivalent (diabetes, peripheral vascular disease, stroke, etc).5 The study demonstrated a reduction of major coronary events with simvastatin, with numbers needed to treat (NNT) of 19 (P < .0001); the NNT for reduction in all-cause mortality was 55 (P = .0003). The benefit of simvastatin was noted in virtually every predefined subgroup, including individuals older than 70 years, women, and patients without known CAD (but with CAD equivalents). Notably, no difference in benefit was found between patients with different pretreatment LDL levels. A significant reduction in major vascular events was noted even for the 3400 subjects with pretreatment LDL levels of less than 100 mg/dL (NNT = 22, P = .0006). A greater percentage reduction in LDL with medication did not predict better clinical outcomes.5
TABLE
LDL levels and relative risk of major coronary events after treatment
| Study, year | N | Intervention medication | LDL level, mg/dL | Relative risk of major coronary events | |
|---|---|---|---|---|---|
| Control group | Intervention group | ||||
| 4S,1 1994 | 4444 | Simvastatin 20 mg/d* | 190 | 122 | 0.66 (0.59–0.85) |
| CARE,3 1996 | 4159 | Pravastatin 40 mg/d | 139 | 97 | 0.76 (0.64–0.91) |
| LIPID,2 1998 | 9014 | Pravastatin 40 mg/d | 150 | 113 | 0.76 (0.68–0.85) |
| LIPS,4 2002 | 1677 | Fluvastatin 80 mg/d | 132 | 100 | 0.78 (0.64–0.95) |
| HPS,5 2002 | 20,536 | Simvastatin 40 mg/d | 127 | 89 | 0.76 (0.72–0.81) |
| *Increased to 40 mg/d if total cholesterol did not drop to less than 200 mg/dL. | |||||
| 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events trial; HPS, Heart Protection Study; LDL, low-density lipoprotein; LIPID, Long-Term Intervention with Pravastatin in Ischaemic Disease study; LIPS, Lescol Intervention Prevention Study. | |||||
Recommendations from others
The National Cholesterol Education Project (NCEP) recommends that patients with CAD and an LDL of more than 130 mg/dL adopt therapeutic lifestyle changes and start LDL-lowering medication, usually a statin. For patients with LDL between 100 and 130 mg/dL, the NCEP recommends therapeutic lifestyle changes, with the option of adding a statin. For patients with LDL less than 100 mg/dL, maintenance of LDL control is recommended with therapeutic lifestyle changes. For patients with high initial LDL levels that stay above 100 mg/dL on statin therapy, the NCEP recommends that additional medications, such as nicotinic acid or fibrates, as well as intensive therapeutic lifestyle changes, be considered.6
Clinical Commentary by William Chavey, MD, at http://www.fpin.org.
1. The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.
2. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57.
3. Sacks FM, Pfeffer MA, Moye LA, et al. N Engl J Med 1996;335:1001-9.
4. Serruys PW, De Feyter P, Macaya C, et al. JAMA 2002;287:3215-22.
5. Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.
6. National Cholesterol Education Program. Adult Treatment Panel III Report. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.pdf. Accessed June 3, 2002.
EVIDENCE-BASED ANSWER
Large published randomized controlled trials (RCTs) show that pravastatin and simvastatin are well-tolerated and reduce major coronary events such as death, myocardial infarction, and revascularization by about 25%. The Heart Protection Study suggested this benefit is noted even among individuals with pretreatment low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL. Fluvastatin reduces major coronary events, but current studies are too small to prove reduced overall mortality. The best evidence to date suggests that most patients at significant risk for major coronary events should be given pravastatin or simvastatin 40 mg daily, without concern for the initial or follow-up LDL levels. (Grade of recommendation: A, based on large randomized trials.)
Evidence summary
The evidence is solid to support the use of HMG–CoA reductase inhibitors (statins) for patients with coronary artery disease (CAD). The Scandinavian Simvastatin Survival study used simvastatin 20 mg daily unless total cholesterol levels did not decrease to less than 200 mg/dL.1 The Long-Term Intervention with Pravastatin in Ischaemic Disease study randomized patients to pravastatin 40 mg daily or placebo, without titration.2 The intervention arm in the Cholesterol and Recurrent Events trial was also pravastatin 40 mg daily, with cholestyramine added if the LDL level remained higher than 175 mg/dL.3 The Lescol Intervention Prevention study randomized patients after angioplasty to fluvastatin 40 mg twice daily or placebo.4 The Heart Protection Study used simvastatin 40 mg daily, without titration.5 No RCTs have evaluated the clinical benefit of adding medications to adequate doses of statins to lower LDL to less than 175 mg/dL. See Table of major RCTs with clinical outcomes.
Subgroup analyses of earlier major RCTs had suggested that patients with CAD and low initial LDL levels (< 125 mg/dL) have little to gain from pravastatin.2,3 However, the Heart Protection Study enrolled 20,000 people with CAD or equivalent (diabetes, peripheral vascular disease, stroke, etc).5 The study demonstrated a reduction of major coronary events with simvastatin, with numbers needed to treat (NNT) of 19 (P < .0001); the NNT for reduction in all-cause mortality was 55 (P = .0003). The benefit of simvastatin was noted in virtually every predefined subgroup, including individuals older than 70 years, women, and patients without known CAD (but with CAD equivalents). Notably, no difference in benefit was found between patients with different pretreatment LDL levels. A significant reduction in major vascular events was noted even for the 3400 subjects with pretreatment LDL levels of less than 100 mg/dL (NNT = 22, P = .0006). A greater percentage reduction in LDL with medication did not predict better clinical outcomes.5
TABLE
LDL levels and relative risk of major coronary events after treatment
| Study, year | N | Intervention medication | LDL level, mg/dL | Relative risk of major coronary events | |
|---|---|---|---|---|---|
| Control group | Intervention group | ||||
| 4S,1 1994 | 4444 | Simvastatin 20 mg/d* | 190 | 122 | 0.66 (0.59–0.85) |
| CARE,3 1996 | 4159 | Pravastatin 40 mg/d | 139 | 97 | 0.76 (0.64–0.91) |
| LIPID,2 1998 | 9014 | Pravastatin 40 mg/d | 150 | 113 | 0.76 (0.68–0.85) |
| LIPS,4 2002 | 1677 | Fluvastatin 80 mg/d | 132 | 100 | 0.78 (0.64–0.95) |
| HPS,5 2002 | 20,536 | Simvastatin 40 mg/d | 127 | 89 | 0.76 (0.72–0.81) |
| *Increased to 40 mg/d if total cholesterol did not drop to less than 200 mg/dL. | |||||
| 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events trial; HPS, Heart Protection Study; LDL, low-density lipoprotein; LIPID, Long-Term Intervention with Pravastatin in Ischaemic Disease study; LIPS, Lescol Intervention Prevention Study. | |||||
Recommendations from others
The National Cholesterol Education Project (NCEP) recommends that patients with CAD and an LDL of more than 130 mg/dL adopt therapeutic lifestyle changes and start LDL-lowering medication, usually a statin. For patients with LDL between 100 and 130 mg/dL, the NCEP recommends therapeutic lifestyle changes, with the option of adding a statin. For patients with LDL less than 100 mg/dL, maintenance of LDL control is recommended with therapeutic lifestyle changes. For patients with high initial LDL levels that stay above 100 mg/dL on statin therapy, the NCEP recommends that additional medications, such as nicotinic acid or fibrates, as well as intensive therapeutic lifestyle changes, be considered.6
Clinical Commentary by William Chavey, MD, at http://www.fpin.org.
EVIDENCE-BASED ANSWER
Large published randomized controlled trials (RCTs) show that pravastatin and simvastatin are well-tolerated and reduce major coronary events such as death, myocardial infarction, and revascularization by about 25%. The Heart Protection Study suggested this benefit is noted even among individuals with pretreatment low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL. Fluvastatin reduces major coronary events, but current studies are too small to prove reduced overall mortality. The best evidence to date suggests that most patients at significant risk for major coronary events should be given pravastatin or simvastatin 40 mg daily, without concern for the initial or follow-up LDL levels. (Grade of recommendation: A, based on large randomized trials.)
Evidence summary
The evidence is solid to support the use of HMG–CoA reductase inhibitors (statins) for patients with coronary artery disease (CAD). The Scandinavian Simvastatin Survival study used simvastatin 20 mg daily unless total cholesterol levels did not decrease to less than 200 mg/dL.1 The Long-Term Intervention with Pravastatin in Ischaemic Disease study randomized patients to pravastatin 40 mg daily or placebo, without titration.2 The intervention arm in the Cholesterol and Recurrent Events trial was also pravastatin 40 mg daily, with cholestyramine added if the LDL level remained higher than 175 mg/dL.3 The Lescol Intervention Prevention study randomized patients after angioplasty to fluvastatin 40 mg twice daily or placebo.4 The Heart Protection Study used simvastatin 40 mg daily, without titration.5 No RCTs have evaluated the clinical benefit of adding medications to adequate doses of statins to lower LDL to less than 175 mg/dL. See Table of major RCTs with clinical outcomes.
Subgroup analyses of earlier major RCTs had suggested that patients with CAD and low initial LDL levels (< 125 mg/dL) have little to gain from pravastatin.2,3 However, the Heart Protection Study enrolled 20,000 people with CAD or equivalent (diabetes, peripheral vascular disease, stroke, etc).5 The study demonstrated a reduction of major coronary events with simvastatin, with numbers needed to treat (NNT) of 19 (P < .0001); the NNT for reduction in all-cause mortality was 55 (P = .0003). The benefit of simvastatin was noted in virtually every predefined subgroup, including individuals older than 70 years, women, and patients without known CAD (but with CAD equivalents). Notably, no difference in benefit was found between patients with different pretreatment LDL levels. A significant reduction in major vascular events was noted even for the 3400 subjects with pretreatment LDL levels of less than 100 mg/dL (NNT = 22, P = .0006). A greater percentage reduction in LDL with medication did not predict better clinical outcomes.5
TABLE
LDL levels and relative risk of major coronary events after treatment
| Study, year | N | Intervention medication | LDL level, mg/dL | Relative risk of major coronary events | |
|---|---|---|---|---|---|
| Control group | Intervention group | ||||
| 4S,1 1994 | 4444 | Simvastatin 20 mg/d* | 190 | 122 | 0.66 (0.59–0.85) |
| CARE,3 1996 | 4159 | Pravastatin 40 mg/d | 139 | 97 | 0.76 (0.64–0.91) |
| LIPID,2 1998 | 9014 | Pravastatin 40 mg/d | 150 | 113 | 0.76 (0.68–0.85) |
| LIPS,4 2002 | 1677 | Fluvastatin 80 mg/d | 132 | 100 | 0.78 (0.64–0.95) |
| HPS,5 2002 | 20,536 | Simvastatin 40 mg/d | 127 | 89 | 0.76 (0.72–0.81) |
| *Increased to 40 mg/d if total cholesterol did not drop to less than 200 mg/dL. | |||||
| 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events trial; HPS, Heart Protection Study; LDL, low-density lipoprotein; LIPID, Long-Term Intervention with Pravastatin in Ischaemic Disease study; LIPS, Lescol Intervention Prevention Study. | |||||
Recommendations from others
The National Cholesterol Education Project (NCEP) recommends that patients with CAD and an LDL of more than 130 mg/dL adopt therapeutic lifestyle changes and start LDL-lowering medication, usually a statin. For patients with LDL between 100 and 130 mg/dL, the NCEP recommends therapeutic lifestyle changes, with the option of adding a statin. For patients with LDL less than 100 mg/dL, maintenance of LDL control is recommended with therapeutic lifestyle changes. For patients with high initial LDL levels that stay above 100 mg/dL on statin therapy, the NCEP recommends that additional medications, such as nicotinic acid or fibrates, as well as intensive therapeutic lifestyle changes, be considered.6
Clinical Commentary by William Chavey, MD, at http://www.fpin.org.
1. The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.
2. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57.
3. Sacks FM, Pfeffer MA, Moye LA, et al. N Engl J Med 1996;335:1001-9.
4. Serruys PW, De Feyter P, Macaya C, et al. JAMA 2002;287:3215-22.
5. Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.
6. National Cholesterol Education Program. Adult Treatment Panel III Report. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.pdf. Accessed June 3, 2002.
1. The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.
2. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57.
3. Sacks FM, Pfeffer MA, Moye LA, et al. N Engl J Med 1996;335:1001-9.
4. Serruys PW, De Feyter P, Macaya C, et al. JAMA 2002;287:3215-22.
5. Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.
6. National Cholesterol Education Program. Adult Treatment Panel III Report. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.pdf. Accessed June 3, 2002.
Evidence-based answers from the Family Physicians Inquiries Network
In children hospitalized for asthma exacerbations, does adding ipratropium bromide to albuterol and corticosteroids improve outcome?
ABSTRACT
BACKGROUND: Adding 2 to 3 doses of ipratropium bromide (Atrovent) to conventional therapy with inhaled β-agonists and systemic corticosteroids improves lung function and decreases hospital admissions when given in the emergency department (ED). This study evaluated whether ipratropium bromide administration improves outcomes in children who require subsequent hospitalization.
POPULATION STUDIED: The authors enrolled 80 children aged 1 to 18 years with a history of asthma admitted to the pediatric inpatient unit of a tertiary-care urban hospital. Children had to have moderate to severe symptoms upon admission, defined as requiring inhaled β2-agonists at least every 2 hours, having a forced expiratory volume in 1 second (FEV1) of 25% to 80% of predicted, or having a clinical asthma score of 3 to 9 out of a possible 10. The clinical asthma score is a total of 5 items—respiratory rate, wheezing, inspiratory–expiratory ratio, retracting, and observed dyspnea—scored on a 3-point scale. Excluded patients had coexisting cardiac, neurologic, immunosuppressive, or other chronic pulmonary disease, hypersensitivity to the study drugs, or known ocular abnormalities. Children were excluded if their asthma score was 10, if they needed airway intervention, or if more than 12 hours had elapsed between the first nebulizer treatment and admission.
STUDY DESIGN AND VALIDITY: This was a double-blind randomized controlled trial. Study patients received frequent nebulized albuterol at 0.15 mg/kg as well as either IV hydrocortisone at 4 to 6 mg/kg every 6 hours or oral prednisone 1 mg/kg once daily. Attending physicians determined nebulizer treatment frequency, ranging from 30 minutes to 4 hours. Subjects were randomized to receive either ipratropium bromide or normal saline, matched to the albuterol dosing interval. Participants were stratified by age (less than 5 years vs 5 years or more) and by the number of ipratropium bromide doses they received in the ED (3 or less vs more than 3). Investigators used an intention-to-treat analysis and allocation was concealed.
OUTCOMES MEASURED: The primary outcome was the clinical asthma score, measured at baseline and every 6 hours until discharge. The clinical score is reproducible, valid, and predictive. Secondary outcomes included oxygen saturation, FEV1, length of stay, time to a 4-hour albuterol dosing interval, and readmission to the hospital or ED within 72 hours of discharge.
RESULTS: Of the 212 patients assessed for the trial, only 99 were eligible. Of these, 84 parents consented to enroll their children (4 children were later determined not to meet inclusion criteria and were excluded). The ipratropium and placebo groups were essentially the same. There was no difference in the asthma score between treatment and control groups in 3 of the 4 subgroups. In one subgroup—those who had fewer than 3 doses of ipratropium bromide in the ED—ipratropium provided a slight benefit. The difference in change in scores was 0.5 on the clinical asthma score, a statistically but not clinically important change. There were no differences in the secondary outcomes. The average heart rate was 6 to 10 beats per minute greater in the ipratropium group. The authors noted no transient anisocoria, a potential adverse effect of ipratropium bromide in children.
Giving ipratropium bromide to children with moderate to severe asthma exacerbations reduces admissions and asthma symptoms when given with appropriate β-agonists and corticosteroids in the ED. Ipratropium bromide provides no further benefit for children who require hospitalization after receiving the drug in the ED; therefore, adding ipratropium bromide to standard in-hospital care is not beneficial.
ABSTRACT
BACKGROUND: Adding 2 to 3 doses of ipratropium bromide (Atrovent) to conventional therapy with inhaled β-agonists and systemic corticosteroids improves lung function and decreases hospital admissions when given in the emergency department (ED). This study evaluated whether ipratropium bromide administration improves outcomes in children who require subsequent hospitalization.
POPULATION STUDIED: The authors enrolled 80 children aged 1 to 18 years with a history of asthma admitted to the pediatric inpatient unit of a tertiary-care urban hospital. Children had to have moderate to severe symptoms upon admission, defined as requiring inhaled β2-agonists at least every 2 hours, having a forced expiratory volume in 1 second (FEV1) of 25% to 80% of predicted, or having a clinical asthma score of 3 to 9 out of a possible 10. The clinical asthma score is a total of 5 items—respiratory rate, wheezing, inspiratory–expiratory ratio, retracting, and observed dyspnea—scored on a 3-point scale. Excluded patients had coexisting cardiac, neurologic, immunosuppressive, or other chronic pulmonary disease, hypersensitivity to the study drugs, or known ocular abnormalities. Children were excluded if their asthma score was 10, if they needed airway intervention, or if more than 12 hours had elapsed between the first nebulizer treatment and admission.
STUDY DESIGN AND VALIDITY: This was a double-blind randomized controlled trial. Study patients received frequent nebulized albuterol at 0.15 mg/kg as well as either IV hydrocortisone at 4 to 6 mg/kg every 6 hours or oral prednisone 1 mg/kg once daily. Attending physicians determined nebulizer treatment frequency, ranging from 30 minutes to 4 hours. Subjects were randomized to receive either ipratropium bromide or normal saline, matched to the albuterol dosing interval. Participants were stratified by age (less than 5 years vs 5 years or more) and by the number of ipratropium bromide doses they received in the ED (3 or less vs more than 3). Investigators used an intention-to-treat analysis and allocation was concealed.
OUTCOMES MEASURED: The primary outcome was the clinical asthma score, measured at baseline and every 6 hours until discharge. The clinical score is reproducible, valid, and predictive. Secondary outcomes included oxygen saturation, FEV1, length of stay, time to a 4-hour albuterol dosing interval, and readmission to the hospital or ED within 72 hours of discharge.
RESULTS: Of the 212 patients assessed for the trial, only 99 were eligible. Of these, 84 parents consented to enroll their children (4 children were later determined not to meet inclusion criteria and were excluded). The ipratropium and placebo groups were essentially the same. There was no difference in the asthma score between treatment and control groups in 3 of the 4 subgroups. In one subgroup—those who had fewer than 3 doses of ipratropium bromide in the ED—ipratropium provided a slight benefit. The difference in change in scores was 0.5 on the clinical asthma score, a statistically but not clinically important change. There were no differences in the secondary outcomes. The average heart rate was 6 to 10 beats per minute greater in the ipratropium group. The authors noted no transient anisocoria, a potential adverse effect of ipratropium bromide in children.
Giving ipratropium bromide to children with moderate to severe asthma exacerbations reduces admissions and asthma symptoms when given with appropriate β-agonists and corticosteroids in the ED. Ipratropium bromide provides no further benefit for children who require hospitalization after receiving the drug in the ED; therefore, adding ipratropium bromide to standard in-hospital care is not beneficial.
ABSTRACT
BACKGROUND: Adding 2 to 3 doses of ipratropium bromide (Atrovent) to conventional therapy with inhaled β-agonists and systemic corticosteroids improves lung function and decreases hospital admissions when given in the emergency department (ED). This study evaluated whether ipratropium bromide administration improves outcomes in children who require subsequent hospitalization.
POPULATION STUDIED: The authors enrolled 80 children aged 1 to 18 years with a history of asthma admitted to the pediatric inpatient unit of a tertiary-care urban hospital. Children had to have moderate to severe symptoms upon admission, defined as requiring inhaled β2-agonists at least every 2 hours, having a forced expiratory volume in 1 second (FEV1) of 25% to 80% of predicted, or having a clinical asthma score of 3 to 9 out of a possible 10. The clinical asthma score is a total of 5 items—respiratory rate, wheezing, inspiratory–expiratory ratio, retracting, and observed dyspnea—scored on a 3-point scale. Excluded patients had coexisting cardiac, neurologic, immunosuppressive, or other chronic pulmonary disease, hypersensitivity to the study drugs, or known ocular abnormalities. Children were excluded if their asthma score was 10, if they needed airway intervention, or if more than 12 hours had elapsed between the first nebulizer treatment and admission.
STUDY DESIGN AND VALIDITY: This was a double-blind randomized controlled trial. Study patients received frequent nebulized albuterol at 0.15 mg/kg as well as either IV hydrocortisone at 4 to 6 mg/kg every 6 hours or oral prednisone 1 mg/kg once daily. Attending physicians determined nebulizer treatment frequency, ranging from 30 minutes to 4 hours. Subjects were randomized to receive either ipratropium bromide or normal saline, matched to the albuterol dosing interval. Participants were stratified by age (less than 5 years vs 5 years or more) and by the number of ipratropium bromide doses they received in the ED (3 or less vs more than 3). Investigators used an intention-to-treat analysis and allocation was concealed.
OUTCOMES MEASURED: The primary outcome was the clinical asthma score, measured at baseline and every 6 hours until discharge. The clinical score is reproducible, valid, and predictive. Secondary outcomes included oxygen saturation, FEV1, length of stay, time to a 4-hour albuterol dosing interval, and readmission to the hospital or ED within 72 hours of discharge.
RESULTS: Of the 212 patients assessed for the trial, only 99 were eligible. Of these, 84 parents consented to enroll their children (4 children were later determined not to meet inclusion criteria and were excluded). The ipratropium and placebo groups were essentially the same. There was no difference in the asthma score between treatment and control groups in 3 of the 4 subgroups. In one subgroup—those who had fewer than 3 doses of ipratropium bromide in the ED—ipratropium provided a slight benefit. The difference in change in scores was 0.5 on the clinical asthma score, a statistically but not clinically important change. There were no differences in the secondary outcomes. The average heart rate was 6 to 10 beats per minute greater in the ipratropium group. The authors noted no transient anisocoria, a potential adverse effect of ipratropium bromide in children.
Giving ipratropium bromide to children with moderate to severe asthma exacerbations reduces admissions and asthma symptoms when given with appropriate β-agonists and corticosteroids in the ED. Ipratropium bromide provides no further benefit for children who require hospitalization after receiving the drug in the ED; therefore, adding ipratropium bromide to standard in-hospital care is not beneficial.
Does losartan (Cozaar) slow the progression of renal disease in patients with type 2 diabetes and nephropathy?
BACKGROUND: Interruption of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors is renoprotective both in patients with type 1 diabetes and in patients without diabetes who have overt nephropathy. This study evaluates the effectiveness of losartan, an angiotensin-receptor blocker (ARB), in slowing the progression of nephropathy in type 2 diabetes.
POPULATION STUDIED: The Reduction of Endpoints in Non-insulin– dependent diabetes with the Angiotensin II Antagonist Losartan (RENAAL) study included 1513 people with type 2 diabetes and nephropathy, ranging in age from 31 to 70 years. Nephropathy was defined as urinary protein excretion of at least 500 mg daily and a serum creatinine of 1.3 to 3.0 mg per dL. Patients were excluded if they had a diagnosis of nondiabetic nephropathy; had experienced a recent myocardial infarction, transient ischemic attack, or stroke; had recently undergone coronary artery bypass grafting or percutaneous coronary angioplasty; or had ever had heart failure.
STUDY DESIGN AND VALIDITY: The RENAAL study was a double-blind randomized placebo-controlled trial in which patients were assigned to receive either losartan 50 to 100 mg or placebo. All patients received other antihypertensive therapy (excluding ACE inhibitors and ARBs) as necessary to maintain a blood pressure level of less than 140/90 mm Hg. The groups were similar at baseline, with a mean serum creatinine was 1.9 mg per dL (standard deviation = 0.5). The patients were followed up for a mean of 3.4 years, and an intention-to-treat analysis was reported. The study methods appeared valid, although concealment of allocation was not described.
OUTCOMES MEASURED: The primary outcome was the combined outcomes of a doubling of the baseline serum creatinine concentration, end-stage renal disease, and death.
RESULTS: Treatment with losartan resulted in a 16% reduction in the primary composite end point (95% confidence interval [CI], 2%-28%; P =.02; number needed to treat [NNT]=28). The risk for doubling of serum creatinine concentration was reduced by 25% (95% CI, 8-39; P =.006; NNT=23). The likelihood of reaching end-stage renal disease was reduced by 28% (95% CI, 11-42; P =.002; NNT=17). Losartan also decreased the level of proteinuria by 35% (P < .001) and the rate of decline of renal function by 18% (P =.01). A 32% reduction in a patient’s first hospitalization for heart failure was observed (P =.005). There was no difference in the composite end point of morbidity and mortality due to cardiovascular causes, adverse events, or overall mortality.
Losartan showed significant renal benefits in patients with type 2 diabetes and nephropathy. Two other recent papers support this finding. In one, irbesartan (Avapro) protected against the progression of nephropathy in patients with type 2 diabetes compared with either amlodipine (Norvasc) or placebo.1 Treatment with irbesartan also reduced the rate of progression to overt nephropathy in hypertensive patients with type 2 diabetes and microalbuminuria.1
It is unknown whether ACE inhibitors induce the same degree of renoprotection as ARBs in patients with type 2 diabetes. However, ACE inhibitors slow progression of nephropathy due to type 1 diabetes and have significant cardiovascular benefits for patients with type 2 diabetes and hypertension. Interestingly, the RENAAL study was stopped early because of a recently published analysis of the Heart Outcome Prevention Evaluation study,2 which focused on the effects of an ACE inhibitor on patients with diabetes and mild renal insufficiency (serum creatinine = 1.4-2.3 mg/dL). That analysis showed that ramipril reduced a combined end point of cardiovascular death, myocardial infarction, or stroke by a hazard ratio of 0.48 (95% CI, 0.26-0.86). Although ARBs are clearly renoprotective in patients with type 2 diabetes, the data do not yet provide a rationale for sacrificing the cardiovascular protection of an ACE inhibitor in this high-risk population. For now, ACE inhibitors should be the first agent for patients with diabetes who have hypertension and renal disease, reserving ARBs for those who cannot tolerate the ACE inhibitors.
BACKGROUND: Interruption of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors is renoprotective both in patients with type 1 diabetes and in patients without diabetes who have overt nephropathy. This study evaluates the effectiveness of losartan, an angiotensin-receptor blocker (ARB), in slowing the progression of nephropathy in type 2 diabetes.
POPULATION STUDIED: The Reduction of Endpoints in Non-insulin– dependent diabetes with the Angiotensin II Antagonist Losartan (RENAAL) study included 1513 people with type 2 diabetes and nephropathy, ranging in age from 31 to 70 years. Nephropathy was defined as urinary protein excretion of at least 500 mg daily and a serum creatinine of 1.3 to 3.0 mg per dL. Patients were excluded if they had a diagnosis of nondiabetic nephropathy; had experienced a recent myocardial infarction, transient ischemic attack, or stroke; had recently undergone coronary artery bypass grafting or percutaneous coronary angioplasty; or had ever had heart failure.
STUDY DESIGN AND VALIDITY: The RENAAL study was a double-blind randomized placebo-controlled trial in which patients were assigned to receive either losartan 50 to 100 mg or placebo. All patients received other antihypertensive therapy (excluding ACE inhibitors and ARBs) as necessary to maintain a blood pressure level of less than 140/90 mm Hg. The groups were similar at baseline, with a mean serum creatinine was 1.9 mg per dL (standard deviation = 0.5). The patients were followed up for a mean of 3.4 years, and an intention-to-treat analysis was reported. The study methods appeared valid, although concealment of allocation was not described.
OUTCOMES MEASURED: The primary outcome was the combined outcomes of a doubling of the baseline serum creatinine concentration, end-stage renal disease, and death.
RESULTS: Treatment with losartan resulted in a 16% reduction in the primary composite end point (95% confidence interval [CI], 2%-28%; P =.02; number needed to treat [NNT]=28). The risk for doubling of serum creatinine concentration was reduced by 25% (95% CI, 8-39; P =.006; NNT=23). The likelihood of reaching end-stage renal disease was reduced by 28% (95% CI, 11-42; P =.002; NNT=17). Losartan also decreased the level of proteinuria by 35% (P < .001) and the rate of decline of renal function by 18% (P =.01). A 32% reduction in a patient’s first hospitalization for heart failure was observed (P =.005). There was no difference in the composite end point of morbidity and mortality due to cardiovascular causes, adverse events, or overall mortality.
Losartan showed significant renal benefits in patients with type 2 diabetes and nephropathy. Two other recent papers support this finding. In one, irbesartan (Avapro) protected against the progression of nephropathy in patients with type 2 diabetes compared with either amlodipine (Norvasc) or placebo.1 Treatment with irbesartan also reduced the rate of progression to overt nephropathy in hypertensive patients with type 2 diabetes and microalbuminuria.1
It is unknown whether ACE inhibitors induce the same degree of renoprotection as ARBs in patients with type 2 diabetes. However, ACE inhibitors slow progression of nephropathy due to type 1 diabetes and have significant cardiovascular benefits for patients with type 2 diabetes and hypertension. Interestingly, the RENAAL study was stopped early because of a recently published analysis of the Heart Outcome Prevention Evaluation study,2 which focused on the effects of an ACE inhibitor on patients with diabetes and mild renal insufficiency (serum creatinine = 1.4-2.3 mg/dL). That analysis showed that ramipril reduced a combined end point of cardiovascular death, myocardial infarction, or stroke by a hazard ratio of 0.48 (95% CI, 0.26-0.86). Although ARBs are clearly renoprotective in patients with type 2 diabetes, the data do not yet provide a rationale for sacrificing the cardiovascular protection of an ACE inhibitor in this high-risk population. For now, ACE inhibitors should be the first agent for patients with diabetes who have hypertension and renal disease, reserving ARBs for those who cannot tolerate the ACE inhibitors.
BACKGROUND: Interruption of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors is renoprotective both in patients with type 1 diabetes and in patients without diabetes who have overt nephropathy. This study evaluates the effectiveness of losartan, an angiotensin-receptor blocker (ARB), in slowing the progression of nephropathy in type 2 diabetes.
POPULATION STUDIED: The Reduction of Endpoints in Non-insulin– dependent diabetes with the Angiotensin II Antagonist Losartan (RENAAL) study included 1513 people with type 2 diabetes and nephropathy, ranging in age from 31 to 70 years. Nephropathy was defined as urinary protein excretion of at least 500 mg daily and a serum creatinine of 1.3 to 3.0 mg per dL. Patients were excluded if they had a diagnosis of nondiabetic nephropathy; had experienced a recent myocardial infarction, transient ischemic attack, or stroke; had recently undergone coronary artery bypass grafting or percutaneous coronary angioplasty; or had ever had heart failure.
STUDY DESIGN AND VALIDITY: The RENAAL study was a double-blind randomized placebo-controlled trial in which patients were assigned to receive either losartan 50 to 100 mg or placebo. All patients received other antihypertensive therapy (excluding ACE inhibitors and ARBs) as necessary to maintain a blood pressure level of less than 140/90 mm Hg. The groups were similar at baseline, with a mean serum creatinine was 1.9 mg per dL (standard deviation = 0.5). The patients were followed up for a mean of 3.4 years, and an intention-to-treat analysis was reported. The study methods appeared valid, although concealment of allocation was not described.
OUTCOMES MEASURED: The primary outcome was the combined outcomes of a doubling of the baseline serum creatinine concentration, end-stage renal disease, and death.
RESULTS: Treatment with losartan resulted in a 16% reduction in the primary composite end point (95% confidence interval [CI], 2%-28%; P =.02; number needed to treat [NNT]=28). The risk for doubling of serum creatinine concentration was reduced by 25% (95% CI, 8-39; P =.006; NNT=23). The likelihood of reaching end-stage renal disease was reduced by 28% (95% CI, 11-42; P =.002; NNT=17). Losartan also decreased the level of proteinuria by 35% (P < .001) and the rate of decline of renal function by 18% (P =.01). A 32% reduction in a patient’s first hospitalization for heart failure was observed (P =.005). There was no difference in the composite end point of morbidity and mortality due to cardiovascular causes, adverse events, or overall mortality.
Losartan showed significant renal benefits in patients with type 2 diabetes and nephropathy. Two other recent papers support this finding. In one, irbesartan (Avapro) protected against the progression of nephropathy in patients with type 2 diabetes compared with either amlodipine (Norvasc) or placebo.1 Treatment with irbesartan also reduced the rate of progression to overt nephropathy in hypertensive patients with type 2 diabetes and microalbuminuria.1
It is unknown whether ACE inhibitors induce the same degree of renoprotection as ARBs in patients with type 2 diabetes. However, ACE inhibitors slow progression of nephropathy due to type 1 diabetes and have significant cardiovascular benefits for patients with type 2 diabetes and hypertension. Interestingly, the RENAAL study was stopped early because of a recently published analysis of the Heart Outcome Prevention Evaluation study,2 which focused on the effects of an ACE inhibitor on patients with diabetes and mild renal insufficiency (serum creatinine = 1.4-2.3 mg/dL). That analysis showed that ramipril reduced a combined end point of cardiovascular death, myocardial infarction, or stroke by a hazard ratio of 0.48 (95% CI, 0.26-0.86). Although ARBs are clearly renoprotective in patients with type 2 diabetes, the data do not yet provide a rationale for sacrificing the cardiovascular protection of an ACE inhibitor in this high-risk population. For now, ACE inhibitors should be the first agent for patients with diabetes who have hypertension and renal disease, reserving ARBs for those who cannot tolerate the ACE inhibitors.