Summary
Statins for the primary prevention of cardiovascular disease
Cardiovascular disease (CVD) is ranked as the number one cause of mortality and is a major cause of morbidity world wide. Reducing high blood cholesterol which is a risk factor for CVD events is an important goal of medical treatment. Statins are the first-choice agents. Since the early statin trials were reported, several reviews of the effects of statins have been published highlighting their benefits particularly in people with a past history of CVD. However for people without a past history of CVD (primary prevention), the evidence is less clear. The aim of this systematic review is to assess the effects, both in terms of benefits and harms of statins for the primary prevention of CVD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE until 2007. We found 14 randomised control trials with 16 trial arms (34,272 patients) dating from 1994 to 2006. All were randomised control trials comparing statins with usual care or placebo. Duration of treatment was minimum one year and with follow up of a minimum of six months. All cause mortality. coronary heart disease and stroke events were reduced with the use of statins as was the need for revascularisations. Statin treatment reduced blood cholesterol. Taking statins did not increase the risk of adverse effects such as cancer. and few trials reported on costs or quality of life. This current systematic review highlights the shortcomings in the published trials and we recommend that caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.
This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2011 Issue 1, Copyright © 2011 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X).
This record should be cited as: Taylor F, Ward K, Moore THM, Burke M, Davey Smith G, Casas J-P, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD004816. DOI: 10.1002/14651858.CD004816.pub4
Editorial Group: Heart Group
This version first published online: January 19. 2011
Last assessed as up-to-date: September 8. 2007
Abstract
Background
Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of coronary heart disease (CHD) is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with coronary artery disease. The case for primary prevention, however, is less clear.
Objectives
To assess the effects, both harms and benefits, of statins in people with no history of CVD.
Search strategy
To avoid duplication of effort, we checked reference lists of previous systematic reviews. We searched the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (2001 to March 2007) and EMBASE (2003 to March 2007). There were no language restrictions.
Selection criteria
Randomised controlled trials of statins with minimum duration of one year and follow-up of six months, in adults with no restrictions on their total low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD, were included.
Data collection and analysis
Two authors independently selected studies for inclusion and extracted data. Outcomes included all cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), change in blood total cholesterol concentration, revascularisation, adverse events, quality of life and costs. Relative risk (RR) was calculated for dichotomous data, and for continuous data pooled weighted mean differences (with 95% confidence intervals) were calculated.
Main results
Fourteen randomised control trials (16 trial arms; 34,272 participants) were included. Eleven trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (RR 0.83, 95% CI 0.73 to 0.95) as was combined fatal and non-fatal CVD endpoints (RR 0.70, 95% CI 0.61 to 0.79). Benefits were also seen in the reduction of revascularisation rates (RR 0.66, 95% CI 0.53 to 0.83). Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no clear evidence of any significant harm caused by statin prescription or of effects on patient quality of life.
Authors' conclusions
Although reductions in all-cause mortality, composite endpoints and revascularisations were found with no excess of adverse events, there was evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.
Wednesday, January 26, 2011
Aspirin for Primary Prevention in Diabetes
Previous guidelines recommended low-dose aspirin therapy for the primary prevention of stroke in patients with type 1 or type 2 diabetes mellitus who were at increased cardiovascular (CV) risk. Risk factors included patient age older than 40 years, a family history of CV disease, hypertension, smoking, dyslipidemia, or albuminuria. Aspirin therapy was not recommended for patients younger than 30 years of age because no benefit had been demonstrated, and aspirin was contraindicated in patients under 21 years of age because of associated risk for Reye syndrome.[1]
Since the Antithrombotic Trialists' Collaboration (ATT-C) published their first meta-analysis results in May 2009, questioning the value of low-dose aspirin for primary prevention, confusion has been expressed about when to recommend aspirin for patients with diabetes. The ATT-C performed a meta-analysis of 6 primary prevention trials, including 95,000 individuals with low-average CV risk and 16 secondary prevention trials with 17,000 individuals who had high CV risk. This analysis showed that primary prevention of vascular events with aspirin is of uncertain value, whereas the risk for major episodes of hemorrhage may increase.[2]
The ATT-C updated their recommendations for aspirin in primary prevention after considering the results from the POPADAD (Prevention of Progression of Arterial Disease and Diabetes),[3] JPAD (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes),[4] and AAA (Aspirin for Asymptomatic Atherosclerosis)[5] trials. They concluded that the benefit of aspirin appeared to outweigh its risks when used for secondary, but not primary, prevention.[6]
De Berardis and colleagues conducted a second meta-analysis of 6 studies with 10,117 participants, which suggested that the benefit of aspirin in the primary prevention of major CV events or death in people with diabetes may be lower than in other high-risk populations.[7] Evidence demonstrating that low-dose aspirin is beneficial was lacking in this analysis, and the benefits were not found to exceed the risk for major bleeding, particularly in patients at low CV risk (< 20% over 10 years) and in older patients (> 70 years of age) at high risk of bleeding.[7]
These recent findings have prompted an evaluation of the current guidelines for aspirin use in primary prevention. The American Diabetes Association (ADA) Standard of Medical Care in Diabetes--2010 guidelines have backed off slightly on recommending aspirin use. The guidelines now recommend the consideration of aspirin therapy 75-162 mg daily as a primary prevention strategy for patients with type 1 or type 2 diabetes mellitus who are at increased CV risk (10-year risk > 10%).
Aspirin should not be recommended for patients at low CV risk, including women younger than 60 years of age, men younger than 50 years of age with no major risk factors, and patients with 10-year CV risk < 5%, because the low benefit is offset by the risk for significant bleeding.
Clinical judgment should be used for patients at intermediate risk or older patients with no risk factors. This generally includes most men older than 50 years of age or women older than 60 years of age who have at least 1 additional major risk factor, such as family history of CV disease, hypertension, smoking, dyslipidemia, or albuminuria.[8] To determine risk factors, 2 assessment tools may be used: the Atherosclerosis Risk in Communities (ARIC) Risk Calculator or the ADA's Risk Assessment Tool, Diabetes Personal Health Decisions.
In summary, it remains questionable how much benefit or risk aspirin confers for primary prevention in patients with diabetes. Currently, 2 trials are under way to answer key questions about the risk/benefit ratio: ASCEND (A Study of Cardiovascular Events iN Diabetes) and ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes). These are large, ongoing studies that will enroll up to 15,000 participants with anticipated completion dates of 2011 and 2013, respectively.
Until results from these studies are in, providers should use clinical judgment, including known approaches, to minimize CV risk, such as smoking cessation, statins, angiotensin-converting enzyme inhibitors, and the achievement of good glucose control before considering aspirin for primary prevention.
Since the Antithrombotic Trialists' Collaboration (ATT-C) published their first meta-analysis results in May 2009, questioning the value of low-dose aspirin for primary prevention, confusion has been expressed about when to recommend aspirin for patients with diabetes. The ATT-C performed a meta-analysis of 6 primary prevention trials, including 95,000 individuals with low-average CV risk and 16 secondary prevention trials with 17,000 individuals who had high CV risk. This analysis showed that primary prevention of vascular events with aspirin is of uncertain value, whereas the risk for major episodes of hemorrhage may increase.[2]
The ATT-C updated their recommendations for aspirin in primary prevention after considering the results from the POPADAD (Prevention of Progression of Arterial Disease and Diabetes),[3] JPAD (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes),[4] and AAA (Aspirin for Asymptomatic Atherosclerosis)[5] trials. They concluded that the benefit of aspirin appeared to outweigh its risks when used for secondary, but not primary, prevention.[6]
De Berardis and colleagues conducted a second meta-analysis of 6 studies with 10,117 participants, which suggested that the benefit of aspirin in the primary prevention of major CV events or death in people with diabetes may be lower than in other high-risk populations.[7] Evidence demonstrating that low-dose aspirin is beneficial was lacking in this analysis, and the benefits were not found to exceed the risk for major bleeding, particularly in patients at low CV risk (< 20% over 10 years) and in older patients (> 70 years of age) at high risk of bleeding.[7]
These recent findings have prompted an evaluation of the current guidelines for aspirin use in primary prevention. The American Diabetes Association (ADA) Standard of Medical Care in Diabetes--2010 guidelines have backed off slightly on recommending aspirin use. The guidelines now recommend the consideration of aspirin therapy 75-162 mg daily as a primary prevention strategy for patients with type 1 or type 2 diabetes mellitus who are at increased CV risk (10-year risk > 10%).
Aspirin should not be recommended for patients at low CV risk, including women younger than 60 years of age, men younger than 50 years of age with no major risk factors, and patients with 10-year CV risk < 5%, because the low benefit is offset by the risk for significant bleeding.
Clinical judgment should be used for patients at intermediate risk or older patients with no risk factors. This generally includes most men older than 50 years of age or women older than 60 years of age who have at least 1 additional major risk factor, such as family history of CV disease, hypertension, smoking, dyslipidemia, or albuminuria.[8] To determine risk factors, 2 assessment tools may be used: the Atherosclerosis Risk in Communities (ARIC) Risk Calculator or the ADA's Risk Assessment Tool, Diabetes Personal Health Decisions.
In summary, it remains questionable how much benefit or risk aspirin confers for primary prevention in patients with diabetes. Currently, 2 trials are under way to answer key questions about the risk/benefit ratio: ASCEND (A Study of Cardiovascular Events iN Diabetes) and ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes). These are large, ongoing studies that will enroll up to 15,000 participants with anticipated completion dates of 2011 and 2013, respectively.
Until results from these studies are in, providers should use clinical judgment, including known approaches, to minimize CV risk, such as smoking cessation, statins, angiotensin-converting enzyme inhibitors, and the achievement of good glucose control before considering aspirin for primary prevention.
Thursday, January 13, 2011
Is acute otitis media treatable?
In children with acute otitis media, two placebo-controlled trials establish that antibiotic treatment with amoxicillin-clavulanate is superior to watchful waiting. The trials appear in the New England Journal of Medicine.
Researchers in Finland and the U.S. separately randomized a total of some 600 children under age 3 years to roughly 10 days of double-blind treatment with either amoxicillin-clavulanate or placebo. All children had been diagnosed with acute otitis media according to strict standards.
In both trials, treatment failure was at least twice as frequent among placebo recipients. Rash and diarrhea were more common among those receiving antibiotics.
An editorialist writes that the trials provide "the best data yet" to answer the question: Is acute otitis media treatable? "The answer is yes," he writes.
Researchers in Finland and the U.S. separately randomized a total of some 600 children under age 3 years to roughly 10 days of double-blind treatment with either amoxicillin-clavulanate or placebo. All children had been diagnosed with acute otitis media according to strict standards.
In both trials, treatment failure was at least twice as frequent among placebo recipients. Rash and diarrhea were more common among those receiving antibiotics.
An editorialist writes that the trials provide "the best data yet" to answer the question: Is acute otitis media treatable? "The answer is yes," he writes.
Friday, January 7, 2011
Echinacea ineffective for the common cold
Echinacea has no effect on the severity or duration of common cold symptoms, according to the results of a recent randomized controlled trial. The trial involved 719 patients (age 12–80 years) with new-onset common cold. Patients were assigned to one of four groups: no pills, placebo pills (blinded), Echinacea pills (blinded) or Echinacea pills (unblinded, open-label). The Echinacea groups received the equivalent of 10.2 g of dried Echinacea root during the first 24 hours and 5.1 g during each of the next four days.
Common cold severity was assessed twice daily by self-reporting, using the short version of the Wisconsin Upper Respiratory Symptom Survey. Secondary outcomes included interleukin-8 levels and neutrophil counts from nasal wash, which were measured at enrolment in the study and two days later.
A total of 713 subjects completed the study. The mean cold severity was 236 for the blinded Echinacea group and 258 for the unblinded Echinacea group, 264 for the blinded placebo group and 286 for the no-pill group. A comparison of the two blinded groups showed a 28-point nonsignificant trend toward benefit for Echinacea. The mean illness duration was 6.34 days in the blinded Echinacea group, 6.76 days in the unblinded Echinacea group, 6.87 days in the blinded placebo group and 7.03 days in the no-pill group. A comparison of the blinded groups showed a nonsignificant 0.53-day benefit for Echinacea. The median changes in interleukin-8 levels and neutrophil counts were not statistically different among the four groups. The frequency of adverse effects was also similar among the four groups.
The authors concluded that statistically significant differences in illness duration and severity were not seen with this dose and formulation of Echinacea compared with placebo. However, a higher-than-expected variability in results limited the study’s power to detect small benefits.
Reference
Barrett B, Brown R, Rakel D, et al. Echinacea for treating the common cold – a randomized trial. Ann Intern Med 2010;153:769-77. www.annals.org/content/153/12/769.full.pdf+html (accessed December 22, 2010).
Common cold severity was assessed twice daily by self-reporting, using the short version of the Wisconsin Upper Respiratory Symptom Survey. Secondary outcomes included interleukin-8 levels and neutrophil counts from nasal wash, which were measured at enrolment in the study and two days later.
A total of 713 subjects completed the study. The mean cold severity was 236 for the blinded Echinacea group and 258 for the unblinded Echinacea group, 264 for the blinded placebo group and 286 for the no-pill group. A comparison of the two blinded groups showed a 28-point nonsignificant trend toward benefit for Echinacea. The mean illness duration was 6.34 days in the blinded Echinacea group, 6.76 days in the unblinded Echinacea group, 6.87 days in the blinded placebo group and 7.03 days in the no-pill group. A comparison of the blinded groups showed a nonsignificant 0.53-day benefit for Echinacea. The median changes in interleukin-8 levels and neutrophil counts were not statistically different among the four groups. The frequency of adverse effects was also similar among the four groups.
The authors concluded that statistically significant differences in illness duration and severity were not seen with this dose and formulation of Echinacea compared with placebo. However, a higher-than-expected variability in results limited the study’s power to detect small benefits.
Reference
Barrett B, Brown R, Rakel D, et al. Echinacea for treating the common cold – a randomized trial. Ann Intern Med 2010;153:769-77. www.annals.org/content/153/12/769.full.pdf+html (accessed December 22, 2010).
Levothyroxine: best taken at bedtime
New study results suggest that levothyroxine improves thyroid hormone levels more when taken at bedtime compared to taking the drug in the morning on an empty stomach. Levothyroxine is one of the most prescribed medications. About 70–80% of the drug is absorbed orally, with absorption occurring in the small intestine. The current consensus is that levothyroxine is best taken before breakfast to prevent interference of its intestinal uptake by food or other medications.
The study was planned when the authors noticed that thyroid hormone levels improved markedly in several patients after switching from morning to bedtime levothyroxine dosing. The six-month, randomized, double-blind crossover trial was conducted in 105 patients with primary hypothyroidism. Patients were instructed to take one capsule in the morning (1/2 hour before breakfast) and one capsule at bedtime (one capsule contained levothyroxine and the other placebo; most patients ate only a small snack or nothing for several hours prior to bedtime). The capsule administration times were then switched after three months. The placebo and levothyroxine capsules were visually identical and patients received the same dose of levothyroxine as before entry into the trial.
Compared to morning levothyroxine intake, bedtime ingestion resulted in a 1.25 mIU/L reduction in thyrotropin level (p < 0.001), a 0.07 ng/dL increase in free thyroxine level (p = 0.01) and a 6.5 ng/dL increase in total triiodothyronine level (p = 0.02). No significant differences were seen between the two treatment groups in any of the secondary outcome measures (creatinine and lipid levels, body mass index, heart rate and quality of life).
The investigators conclude that clinicians should consider prescribing levothyroxine intake at bedtime as an alternative to morning dosing, provided that the bedtime dose is taken on an empty stomach. Although the higher thyroid hormone levels with bedtime administration did not translate into quality of life benefits, bedtime administration may be more convenient than morning intake since patients do not have to postpone breakfast.
Reference
Bolk N, Visser TJ, Nijman J, et al. Effects of evening vs morning levothyroxine intake: a randomized double-blind crossover trial. Arch Intern Med 2010;170:1996-2003. (accessed January 3, 2010).
The study was planned when the authors noticed that thyroid hormone levels improved markedly in several patients after switching from morning to bedtime levothyroxine dosing. The six-month, randomized, double-blind crossover trial was conducted in 105 patients with primary hypothyroidism. Patients were instructed to take one capsule in the morning (1/2 hour before breakfast) and one capsule at bedtime (one capsule contained levothyroxine and the other placebo; most patients ate only a small snack or nothing for several hours prior to bedtime). The capsule administration times were then switched after three months. The placebo and levothyroxine capsules were visually identical and patients received the same dose of levothyroxine as before entry into the trial.
Compared to morning levothyroxine intake, bedtime ingestion resulted in a 1.25 mIU/L reduction in thyrotropin level (p < 0.001), a 0.07 ng/dL increase in free thyroxine level (p = 0.01) and a 6.5 ng/dL increase in total triiodothyronine level (p = 0.02). No significant differences were seen between the two treatment groups in any of the secondary outcome measures (creatinine and lipid levels, body mass index, heart rate and quality of life).
The investigators conclude that clinicians should consider prescribing levothyroxine intake at bedtime as an alternative to morning dosing, provided that the bedtime dose is taken on an empty stomach. Although the higher thyroid hormone levels with bedtime administration did not translate into quality of life benefits, bedtime administration may be more convenient than morning intake since patients do not have to postpone breakfast.
Reference
Bolk N, Visser TJ, Nijman J, et al. Effects of evening vs morning levothyroxine intake: a randomized double-blind crossover trial. Arch Intern Med 2010;170:1996-2003. (accessed January 3, 2010).
Tuesday, January 4, 2011
Colonoscopy Shown to Lower Risk for Right- and Left-Sided Cancers
Colonoscopy is associated with a near-80% reduction in risk for colorectal cancer, according to a population-based case-control study published in the Annals of Internal Medicine.
German investigators ascertained colonoscopy histories of some 1700 patients with a first diagnosis of colorectal cancer and 1900 controls without a history of colorectal cancer. After adjustment for covariates including level of education, smoking status, body-mass index, and use of NSAIDs or hormone replacement, a history of colonoscopy within the preceding 10 years was associated with reduced risk for colorectal cancer on both the left and right sides. Risk reductions were greater for left-sided cancers — at 84% — than for right-sided cancers — at 56%.
The authors say their results reinforce the notion that colonoscopy reduces risks in the community setting as well as in the "highly standardized conditions" of tertiary medical centers. And an editorialist says the results "offer reassurance that colonoscopy can provide substantial protection" against both right- and left-sided disease.
German investigators ascertained colonoscopy histories of some 1700 patients with a first diagnosis of colorectal cancer and 1900 controls without a history of colorectal cancer. After adjustment for covariates including level of education, smoking status, body-mass index, and use of NSAIDs or hormone replacement, a history of colonoscopy within the preceding 10 years was associated with reduced risk for colorectal cancer on both the left and right sides. Risk reductions were greater for left-sided cancers — at 84% — than for right-sided cancers — at 56%.
The authors say their results reinforce the notion that colonoscopy reduces risks in the community setting as well as in the "highly standardized conditions" of tertiary medical centers. And an editorialist says the results "offer reassurance that colonoscopy can provide substantial protection" against both right- and left-sided disease.
Sunday, January 2, 2011
Long-Term Health Risks After Gastroenteritis from Contaminated Drinking Water
Acute gastroenteritis due to E. coli O157:H7 seems associated with increased long-term risk for hypertension and other cardiorenal complications, according to a BMJ study of a large Canadian outbreak.
Researchers tracked some 2000 adults whose well water was contaminated with livestock waste during flooding. About half the cohort reported symptoms compatible with gastroenteritis; both E. coli O157:H7 and Campylobacter species were widely recovered from stool samples taken at the time of the incident.
After a median follow-up of 8 years, those who suffered gastroenteritis were more likely to develop hypertension, structural and functional renal impairment, and cardiovascular disease than those in whom gastroenteritis did not develop or whose illness was mild.
The authors, pointing out that E. coli O157:H7 toxins have receptors in kidney tissue, say it's important for patients infected with this organism to undergo regular blood pressure and kidney-function monitoring "to prevent or reduce silent progressive vascular injury."
Researchers tracked some 2000 adults whose well water was contaminated with livestock waste during flooding. About half the cohort reported symptoms compatible with gastroenteritis; both E. coli O157:H7 and Campylobacter species were widely recovered from stool samples taken at the time of the incident.
After a median follow-up of 8 years, those who suffered gastroenteritis were more likely to develop hypertension, structural and functional renal impairment, and cardiovascular disease than those in whom gastroenteritis did not develop or whose illness was mild.
The authors, pointing out that E. coli O157:H7 toxins have receptors in kidney tissue, say it's important for patients infected with this organism to undergo regular blood pressure and kidney-function monitoring "to prevent or reduce silent progressive vascular injury."
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