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1.  Is statin discontinuation an option in patients who have had a stroke? 
There is clear evidence that long-term statin therapy can prevent the recurrence of vascular events, but in clinical practice, many patients discontinue statin therapy.
To evaluate the effect of statin interruption on clinical outcome in patients discharged after an acute ischemic stroke.
The present study was conducted at an Italian community hospital and enrolled consecutive stroke patients who were discharged from January 2000 to June 2005. Inclusion criteria were absence of any major concurrent illness, absence of any clinical and laboratory evidence of coronary heart disease (CHD) or of any other major cardiac affect or cardiac embolism, and discharge on statin therapy. After exclusions, 631 patients (51% male; mean ± SD age 70.2 ± 7.6 years) were enrolled. All participants were followed up for 12 months. Adherence to prescribed medications was evaluated by telephone interview at 1, 6 and 12 months after discharge. Switching from one cardiovascular agent to another of the same class was considered adherence to the prescribed therapy. Univariate and multivariate Cox proportionalhazards regression analyses were performed to identify risk factors for occurrence of the primary end point, and to identify clinical and demographic variables associated with statin therapy discontinuation during the follow-up period.
The primary end point was death from any cause within 12 months of discharge.
At discharge, 409 (77.6%) patients received a prescription for atorvastatin and 222 (22.4%) patients received a prescription for simvastatin. During the follow-up period, 246 (38.9%) patients discontinued statin therapy; the discontinuation rates were similar for both statins (P=0.544). Seventy-one (28.8%) patients stated mild adverse effects—such as dyspepsia, fatigue, headache and myalgia—as the reason for statin interruption. No instance of major adverse event was reported. In the remaining 175 (71.2%) cases, neither the patient nor the primary care physician could provide any specific medical reason for statin discontinuation. Multivariate analysis identified increasing age (hazard ratio [HR] 1.006 per year, 95% CI 1.004-1.009; P= 0.01) and female sex (HR 1.07, 95% CI 1.03-1.11; P= 0.02) as risk factors for statin discontinuation. By contrast, patients with diabetes were more likely to continue statin therapy (HR 0.86, 95% CI 0.79-0.91; P=0.03). A total of 116 patients died within 1 year of discharge. Ninety-two (79.3%) of these patients had discontinued statin therapy compared with 154 (29.9%) patients who survived (P=0.0001), and statin interruption was identified as an independent predictor of 12-month all-cause mortality (HR 2.78, 95% CI 1.96-3.72; P=0.003). Other independent predictors of death within the first year after the stroke event were increased age, obesity, diabetes, stroke severity on admission, and antiplatelet therapy discontinuation.
A considerable proportion of patients with acute ischemic stroke are at increased risk of death within the first year after the index event because they discontinue statin therapy, often without a specific medical reason.
PMCID: PMC2615565  PMID: 18059384
coronary heart disease; death; statins; stroke; treatment discontinuation
2.  Disentangling the Association between Statins, Cholesterol, and Colorectal Cancer: A Nested Case-Control Study 
PLoS Medicine  2016;13(4):e1002007.
Several prior studies have found an association between statin use and reduced risk of colorectal cancer. We hypothesized that these findings may be due to systematic bias and examined the independent association of colorectal cancer risk with statin use, serum cholesterol, and change in cholesterol concentration.
Methods and Findings
22,163 colorectal cancer cases and 86,538 matched controls between 1995 and 2013 were identified within The Health Improvement Network (THIN) a population-representative database. Conditional logistic regression models estimated colorectal cancer risk with statin use, serum total cholesterol (mmol/L), and change in total cholesterol level. We confirmed a decreased risk of colorectal cancer with statin use (long-term: odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91–0.99; short-term: OR, 0.92; 95% CI, 0.85–0.99). However, to assess whether the observed association may result from indication bias, a subgroup analysis was conducted among patients prescribed a statin. In this subgroup (n = 5,102 cases, n = 19,032 controls), 3.1% of case subjects and 3.1% of controls discontinued therapy. The risk of colorectal cancer was not significantly different among those who continued statin therapy and those who discontinued (OR, 0.98; 95% CI, 0.79–1.22). Increased serum cholesterol was independently associated with decreased risk of colorectal cancer (OR, 0.89 per mmol/L increase; 95% CI, 0.87–0.91); the association was only present if serum cholesterol was measured near the cancer diagnosis (<6 mo: OR, 0.76; 95% CI, 0.47–0.61; >24 mo: OR, 0.98; 95% CI, 0.93–1.03). Decreases in serum total cholesterol >1 mmol/L ≥1 year prior to cancer diagnosis were associated with subsequent colorectal cancer (statin users: OR, 1.25; 95 CI%, 1.03–1.53; nonusers: OR, 2.36; 95 CI%, 1.78–3.12). As an observational study, limitations included incomplete data and residual confounding.
Although the risk of colorectal cancer was lower in statin users versus nonusers, no difference was observed among those who continued versus discontinued statin therapy, suggesting the potential for indication bias. The association between decreased serum cholesterol and colorectal cancer risk suggests a cholesterol-lowering effect of undiagnosed malignancy. Clinical judgment should be used when considering causes of cholesterol reduction in patients, including those on statin therapy.
In a nested case-control study, Ronac Mamtani and colleagues investigate the associations between cholesterol, statin use, and colorectal cancer among primary care patients in the United Kingdom.
Author Summary
In the United States and United Kingdom, cholesterol monitoring is recommended for patients aged 40 years or older, and statins are widely used to treat high cholesterol.
In addition to preventing cardiovascular disease, statins might also potentially have cancer prevention effects.
A number of studies have shown that compared to people not using statins, those receiving statins appear to have a lower colon cancer risk.
Why Was This Study Done?
However, the prior studies that found that statins reduce colon cancer risk did not account for the effect of blood cholesterol level on cancer risk.
If high blood cholesterol (the indication for statins) lowers cancer risk, then the previously reported associations between statins and cancer risk could be biased toward an artificially protective effect of statins (indication bias).
Our study was designed specifically to elucidate the reasons behind the observed association between statin therapy and reduced colon cancer risk.
What Did the Researchers Do and Find?
We performed a case-control study using a computerized database of electronic records from >10 million UK patients in primary care practices (The Health Improvement Network [THIN]).
We identified 22,163 patients with colon cancer (cases) and 86,538 patients without colon cancer (controls), comparing statin use and blood cholesterol level between the two groups.
We confirmed a decreased risk of colon cancer with statin use compared to no use.
After accounting for indication bias by comparing statin-treated patients to those who discontinued statins, we no longer observed a difference in the risk of colorectal cancer.
Rather, higher blood cholesterol level was associated with lower colon cancer risk and lower blood cholesterol level with higher colon cancer risk. For example, decreases in total cholesterol by >1 mmol/L (~38.6 mg/dl) at least a year before the cancer diagnosis were associated with 1.25-fold and 2.36-fold increased risk of colorectal cancer in users and nonusers of statin.
What Do These Findings Mean?
Statins should not be prescribed for the purpose of colon cancer prevention.
Unexplained decreases in blood total cholesterol should alert physicians to consider colon cancer as one potential explanation.
PMCID: PMC4846028  PMID: 27116322
3.  Persistence with Statins and Onset of Rheumatoid Arthritis: A Population-Based Cohort Study 
PLoS Medicine  2010;7(9):e1000336.
In a retrospective cohort study, Gabriel Chodick and colleagues find a significant association between persistence with statin therapy and reduced risk of developing rheumatoid arthritis, but only a modest decrease in risk of osteoarthritis.
The beneficial effects of statins in rheumatoid arthritis (RA) have been suggested previously, but it is unclear whether statins may prevent its development. The aim of this retrospective cohort study was to explore whether persistent use of statins is associated with onset of RA.
Methods and Findings
The computerized medical databases of a large health organization in Israel were used to identify diagnosed RA cases among adults who began statin therapy between 1998 and 2007. Persistence with statins was assessed by calculating the mean proportion of follow-up days covered (PDC) with statins for every study participant. To assess the possible effects of healthy user bias, we also examined the risk of osteoarthritis (OA), a common degenerative joint disease that is unlikely to be affected by use of statins.
A total of 211,627 and 193,770 individuals were eligible for the RA and OA cohort analyses, respectively. During the study follow-up period, there were 2,578 incident RA cases (3.07 per 1,000 person-years) and 17,878 incident OA cases (24.34 per 1,000 person-years). The crude incidence density rate of RA among nonpersistent patients (PDC level of <20%) was 51% higher (3.89 per 1,000 person-years) compared to highly persistent patients who were covered with statins for at least 80% of the follow-up period. After adjustment for potential confounders, highly persistent patients had a hazard ratio of 0.58 (95% confidence interval 0.52–0.65) for RA compared with nonpersistent patients. Larger differences were observed in younger patients and in patients initiating treatment with high efficacy statins. In the OA cohort analysis, high persistence with statins was associated only with a modest decrement in risk ratio (hazard ratio = 0.85; 0.81–0.88) compared to nonadherent patients.
The present study demonstrates an association between persistence with statin therapy and reduced risk of developing RA. The relationship between continuation of statin use and OA onset was weak and limited to patients with short-term follow-up.
Please see later in the article for the Editors' Summary
Editors' Summary
The role of statins in the management of diseases that have an inflammatory component is unclear. There is some evidence that statins may have anti-inflammatory and immunumodulatory properties, demonstrated by reducing the level of C-reactive protein that may play an important role in chronic inflammatory diseases, such as rheumatoid arthritis—a chronic condition that is a major cause of disability. Some small studies have suggested a modest effect of statins in decreasing disease activity in patients with rheumatoid arthritis, but a recent larger study involving over 30,000 patients with rheumatoid arthritis showed no beneficial effect. Furthermore, it has been suggested that statins may have a role in the primary prevention of rheumatoid arthritis, but so far there has been no solid evidence base to support this hypothesis. Before statins can potentially be included in the treatment options for rheumatoid arthritis, or possibly prescribed for the prevention of this condition, there needs to be a much stronger evidence base, such as larger studies with longer follow-up periods, which clearly demonstrates any significant clinical benefits of statin use.
Why Was This Study Done?
This large study (more than 200,000 patients) with a long follow-up period (average of 10 years) was conducted to discover whether there was any kind of association between persistent use of statins and the onset of rheumatoid arthritis.
What Did the Researchers Do and Find?
The researchers conducted a retrospective cohort study among the members of Maccabi Healthcare Services (a health maintenance organization [HMO]) in Israel, which has 1.8-million enrollees and covers every section of the Israeli population, to identify statin users who were at least 18 years of age and did not have RA or a related disease at study entry. The cohort covered the period 1998–2007 and included members who were continuously enrolled in the HMO from 1995 to 1998. The researchers then analyzed the incidence of newly diagnosed rheumatoid arthritis, recording the date of first diagnostic codes (International Classification of Diseases, 9th revision [ICD-9]) associated with rheumatoid arthritis during the study follow-up period. To assess any potential effects of “healthy adherer” bias (good adherence to medication in patients with a chronic illness may be more likely to lead to better health and improved survival), the researchers also examined any possible association between persistent statin use and the development of osteoarthritis, a common degenerative joint disease that is unlikely to be affected by statin use.
During the study follow-up period, there were 2,578 incident cases of rheumatoid arthritis and 17,878 incident cases of osteoarthritis. The crude incidence density rate of rheumatoid arthritis among patients who did not persistently take statins was 51% higher than that of patients who used statins for at least 80% of the follow-up period. Furthermore, patients who persistently used statins had a risk ratio of 0.58 for rheumatoid arthritis compared with patients who did not persistently use statins. In the osteoarthritis cohort analysis, high persistence with statin use was associated with a modest decrement in risk ratio (0.85) compared to patients who did not persist with statins.
What Do These Findings Mean?
This study suggests that there is an association between persistence with statin therapy and reduced risk of developing rheumatoid arthritis. Although the researchers took into account the possibility of healthy adherer bias (by comparing results with the osteoarthritis cohort), this study has other limitations, such as the retrospective design, and the nonrandomization of statin use, which could affect the interpretation of the results. However, the observed associations were greater than those that would be expected from methodological biases alone. Larger, systematic, controlled, prospective studies with high efficacy statins, particularly in younger adults who are at increased risk for rheumatoid arthritis, are needed to confirm these findings and to clarify the exact nature of the biological relationship between adherence to statin therapy and the incidence of rheumatoid arthritis.
Additional Information
Please access these Web sites via the online version of this summary at
Arthritis Research UK provides a wide range of information on arthritis research
The American College of Rheumatology provides information on rheumatology research
Patient information on rheumatoid arthritis is available at Patient UK
Extensive information about statins is available at statin answers
PMCID: PMC2935457  PMID: 20838658
4.  Statins do not prevent acute organ failure in ventilated ICU patients: single-centre retrospective cohort study 
Critical Care  2011;15(1):R74.
Observational studies suggest statin therapy reduces incident sepsis, but few studies have examined the impact on new organ failure. We tested the hypothesis that statin therapy, administered for standard clinical indications to ventilated intensive care unit patients, prevents acute organ failure without harming the liver.
We performed a retrospective, single-centre cohort study in a tertiary mixed medical/surgical intensive care unit. Mechanically ventilated patients without nonrespiratory organ failure within 24 hours after admission were assessed (during the first 15 days) for new acute organ failure (defined as Sequential Organ Failure Assessment (SOFA) score 3 or 4), liver failure (defined as new hepatic SOFA ≥3, or a 1.5 times increase of bilirubin from baseline to a value ≥20 mmol/l), and alanine transferase (ALT) > 165 IU/l. The effect of statin administration was explored in generalised linear mixed models.
A total of 1,397 patients were included. Two hundred and nineteen patients received a median (interquartile range) of three (two, eight) statin doses. Patients receiving statins were older (67.4 vs. 55.5 years, P < 0.0001), less likely female (25.1% vs. 37.9%, P = 0.0003) and sicker (Acute Physiology and Chronic Health Evaluation (APACHE) II score 20.3 vs. 17.8, P < 0.0001). Considering outcome events at least 1 day after statin administration, statin patients were equally likely to develop acute organ failure (28.4% vs. 22.3%, P = 0.29) and hepatic failure (9.5% vs. 7.6%, P = 0.34), but were more likely to experience an ALT increase to > 165 IU/l ((11.2% vs. 4.8%, P = 0.0005). Multivariable analysis showed that APACHE II score (odds ratio (OR) = 1.05 per point; 95% confidence interval (CI) = 1.03 to 1.07) and APACHE II admission category (P < 0.0001), but not statin administration (OR = 1.21; 95% CI = 0.92 to 1.62), were significantly associated with acute organ failure occurring on or after the day of first statin administration. Statin administration was not associated with liver impairment (OR = 1.08; 95% CI = 0.66 to 1.77) but was associated with a rise in ALT > 165 IU/l (OR = 2.25; 95% CI = 1.32 to 3.84), along with APACHE II score (P = 0.016) and admission ALT (P = 0.0001).
Concurrent statin therapy does not appear to protect against the development of new acute organ failure in critically ill, ventilated patients. The lack of effect may be due to residual confounding, a relatively low number of doses received, or an absence of true effect. Randomised controlled trials are needed to confirm a protective effect.
PMCID: PMC3222007  PMID: 21356051
5.  A cluster randomized trial to assess the impact of opinion leader endorsed evidence summaries on improving quality of prescribing for patients with chronic cardiovascular disease: rationale and design [ISRCTN26365328] 
Although much has been written about the influence of local opinion leaders on clinical practice, there have been few controlled studies of their effect, and almost none have attempted to change prescribing in the community for chronic conditions such as heart failure (HF) or ischemic heart disease (IHD). These two conditions are common and there is very good evidence about how to best prevent morbidity and mortality – and good evidence that quality of care is, in general, suboptimal. Practice audits have demonstrated that about one-half of eligible HF patients are prescribed ACE inhibitors (with fewer still reaching appropriate target doses) and less than one-third of patients with established IHD are prescribed statins (with many fewer reaching recommended cholesterol targets). It is apparent that interventions to improve quality of prescribing are urgently needed. We hypothesized that an intervention that consisted of patient-specific one-page evidence summaries, generated and then endorsed by local opinion leaders, would be able to change prescribing practices of community-based primary care physicians.
Methods (study design)
A pragmatic single-centre cluster randomized controlled trial comparing an opinion leader-based intervention to usual care for patients with HF or IHD. Randomization will be clustered at the level of the primary care physician; as the design effect is anticipated to be negligible, the unit of analysis will be the patient. Patients with HF or IHD (not receiving ACE inhibitors or statins, respectively) will be recruited from community pharmacies and allocated to intervention or usual care based on the randomization status of their primary care physician. The primary outcome is improvement in prescription of proven efficacious therapies for HF (ACE inhibitors) or IHD (statins) within 6 months of the intervention.
If the methods used in this intervention are found to improve prescribing practices, similar interventions could be designed for other chronic conditions dealt with in the outpatient setting.
PMCID: PMC1175844  PMID: 15982421
6.  Glycaemic control in Australia and New Zealand before and after the NICE-SUGAR trial: a translational study 
Critical Care  2013;17(5):R215.
There is no information on the uptake of Intensive Insulin Therapy (IIT) before the Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR) trial in Australia and New Zealand (ANZ) and on the bi-national response to the trial, yet such data would provide important information on the evolution of ANZ practice in this field. We aimed to study ANZ glycaemic control before and after the publication of the results of the NICE-SUGAR trial.
We analysed glucose control in critically ill patients across Australia and New Zealand during a two-year period before and after the publication of the NICE-SUGAR study. We used the mean first day glucose (Glu1) (a validated surrogate of ICU glucose control) to define practice. The implementation of an IIT protocol was presumed if the median of Glu1 measurements was <6.44 mmol/L for a given ICU. Hypoglycaemia was categorised as severe (glucose ≤2.2 mmol/L) or moderate (glucose ≤3.9 mmol/L).
We studied 49 ICUs and 176,505 patients. No ICU practiced IIT before or after NICE-SUGAR. Overall, Glu1 increased from 7.96 (2.95) mmol/L to 8.03 (2.92) mmol/L (P <0.0001) after NICE-SUGAR. Similar increases were noted in all patient subgroups studied (surgical, medical, insulin dependent diabetes mellitus, ICU stay >48/<48 hours). The rate of severe and moderate hypoglycaemia before and after NICE-SUGAR study were 0.59% vs. 0.55% (P =0.33) and 6.62% vs. 5.68% (P <0.0001), respectively. Both crude and adjusted mortalities declined over the study period.
IIT had not been adopted in ANZ before the NICE-SUGAR study and glycaemic control corresponded to that delivered in the control arm of NICE-SUGAR trial. There were only minor changes in practice after the trial toward looser glycaemic control. The rate of moderate hypoglycaemia and mortality decreased along with such changes.
PMCID: PMC4056083  PMID: 24088368
7.  Statins in the Treatment of Chronic Heart Failure: A Systematic Review 
PLoS Medicine  2006;3(8):e333.
The efficacy of statin therapy in patients with established chronic heart failure (CHF) is a subject of much debate.
Methods and Findings
We conducted three systematic literature searches to assess the evidence supporting the prescription of statins in CHF. First, we investigated the participation of CHF patients in randomized placebo-controlled clinical trials designed to evaluate the efficacy of statins in reducing major cardiovascular events and mortality. Second, we assessed the association between serum cholesterol and outcome in CHF. Finally, we evaluated the ability of statin treatment to modify surrogate endpoint parameters in CHF.
Using validated search strategies, we systematically searched PubMed for our three queries. In addition, we searched the reference lists from eligible studies, used the “see related articles” feature for key publications in PubMed, consulted the Cochrane Library, and searched the ISI Web of Knowledge for papers citing key publications.
Search 1 resulted in the retrieval of 47 placebo-controlled clinical statin trials involving more than 100,000 patients. CHF patients had, however, been systematically excluded from these trials. Search 2 resulted in the retrieval of eight studies assessing the relationship between cholesterol levels and outcome in CHF patients. Lower serum cholesterol was consistently associated with increased mortality. Search 3 resulted in the retrieval of 18 studies on the efficacy of statin treatment in CHF. On the whole, these studies reported favorable outcomes for almost all surrogate endpoints.
Since CHF patients have been systematically excluded from randomized, controlled clinical cholesterol-lowering trials, the effect of statin therapy in these patients remains to be established. Currently, two large, randomized, placebo-controlled statin trials are under way to evaluate the efficacy of statin treatment in terms of reducing clinical endpoints in CHF patients in particular.
A systematic review found that patients with heart failure have been excluded from randomised controlled trials on the use of statins. Evidence from other studies on the effectiveness of statins for patients with heart failure is weak and conflicting.
Editors' Summary
When medical researchers test a drug—or some other treatment—for a particular medical condition, they often decide not to include in their study anyone who has, in addition to the disease they are interested in, certain other health problems. This is because including patients with two or more conditions can complicate the analysis of the results and make it hard to reach firm conclusions. However, excluding patients in this way can result in uncertainty as to whether treatments are effective for anyone who suffers from the disease in question, or just for people like those who took part in the research.
A great deal of research has been conducted with drugs known as statins, which lower cholesterol levels in the blood. (A raised level of cholesterol is known to be a major risk factor for cardiovascular disease, which causes heart attacks and strokes.) As a result of this research, statins have been accepted as effective and safe. They are now, in consequence, among the most commonly prescribed medicines. Heart failure, however, is not the same thing as a heart attack. It is the name given to the condition where the muscles of the heart have become weakened, most often as a result of aging, and the heart becomes gradually less efficient at pumping blood around the body. (Some people with heart failure live for many years, but 70% of those with the condition die within ten years.) It is common for people with cardiovascular disease also to have heart failure. Nevertheless, some researchers who have studied the effects of statins have made the decision not to include in their studies any patients with cardiovascular disease who, in addition, have heart failure.
Why Was This Study Done?
The researchers in this study were aware that patients with heart failure have often been excluded from statin trials. They felt it was important to assess the available evidence supporting the prescription of statins for such patients. Specifically, they wanted to find out the following: how often have patients with heart failure been included in statin trials, what evidence is available as to whether it is beneficial for patients with heart failure to have low cholesterol, and what evidence is there that prescribing statins helps these patients?
What Did the Researchers Do and Find?
They did not do any new work involving patients. Instead, they did a very thorough search for all relevant studies of good quality that had already been published and they reviewed the results. “Randomized clinical trials” (RCTs) are the most reliable type of medical research. The researchers found there had been 47 such trials (involving over 100,000 patients) on the use of statins for treating cardiovascular disease, but all these trials had excluded heart failure patients. They found eight studies (which were not RCTs) looking at cholesterol levels and heart failure. These studies found, perhaps surprisingly, that death rates were higher in those patients with heart failure who had low cholesterol. However, they also found 18 studies (again not RCTs) on the use of statins in patients with heart failure. These 18 studies seemed to suggest that statins were of benefit to the patients who received them.
What Do These Findings Mean?
The evidence for or against prescribing statins for people with heart failure is limited, conflicting, and unclear. Further research involving RTCs is necessary. (Two such trials are known to be in progress.)
Additional Information.
Please access these Web sites via the online version of this summary at
General information about statins is available from the Web site of Patient UK
The American Heart Association Web site is a good source of information about all types of heart disease, including heart attacks and heart failure
For a definition of randomized controlled trials see Wikipedia, a free online encyclopedia that anyone can edit
More detailed information about the quality of evidence from medical research may be found in the James Lind Library
PMCID: PMC1551909  PMID: 16933967
8.  Personalized Prediction of Lifetime Benefits with Statin Therapy for Asymptomatic Individuals: A Modeling Study 
PLoS Medicine  2012;9(12):e1001361.
In a modeling study conducted by Myriam Hunink and colleagues, a population-based cohort from Rotterdam is used to predict the possible lifetime benefits of statin therapy, on a personalized basis.
Physicians need to inform asymptomatic individuals about personalized outcomes of statin therapy for primary prevention of cardiovascular disease (CVD). However, current prediction models focus on short-term outcomes and ignore the competing risk of death due to other causes. We aimed to predict the potential lifetime benefits with statin therapy, taking into account competing risks.
Methods and Findings
A microsimulation model based on 5-y follow-up data from the Rotterdam Study, a population-based cohort of individuals aged 55 y and older living in the Ommoord district of Rotterdam, the Netherlands, was used to estimate lifetime outcomes with and without statin therapy. The model was validated in-sample using 10-y follow-up data. We used baseline variables and model output to construct (1) a web-based calculator for gains in total and CVD-free life expectancy and (2) color charts for comparing these gains to the Systematic Coronary Risk Evaluation (SCORE) charts. In 2,428 participants (mean age 67.7 y, 35.5% men), statin therapy increased total life expectancy by 0.3 y (SD 0.2) and CVD-free life expectancy by 0.7 y (SD 0.4). Age, sex, smoking, blood pressure, hypertension, lipids, diabetes, glucose, body mass index, waist-to-hip ratio, and creatinine were included in the calculator. Gains in total and CVD-free life expectancy increased with blood pressure, unfavorable lipid levels, and body mass index after multivariable adjustment. Gains decreased considerably with advancing age, while SCORE 10-y CVD mortality risk increased with age. Twenty-five percent of participants with a low SCORE risk achieved equal or larger gains in CVD-free life expectancy than the median gain in participants with a high SCORE risk.
We developed tools to predict personalized increases in total and CVD-free life expectancy with statin therapy. The predicted gains we found are small. If the underlying model is validated in an independent cohort, the tools may be useful in discussing with patients their individual outcomes with statin therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD) affects the heart and/or the blood vessels and is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Established risk factors for CVD include smoking, high blood pressure, obesity, and high blood levels of a fat called low-density lipoprotein (“bad cholesterol”). Because many of these risk factors can be modified by lifestyle changes and by drugs, CVD can be prevented. Thus, physicians can assess a healthy individual's risk of developing CVD using a CVD prediction model (equations that take into account the CVD risk factors to which the individual is exposed) and can then recommend lifestyle changes and medications to reduce that individual's CVD risk.
Why Was This Study Done?
Current guidelines recommend that asymptomatic (healthy) individuals whose likely CVD risk is high should be encouraged to take statins—cholesterol-lowering drugs—as a preventative measure. Statins help to prevent CVD in healthy people with a high predicted risk of CVD, but, like all medicines, they have some unwanted side effects, so it is important that physicians can communicate both the benefits and drawbacks of statins to their patients in a way that allows them to make an informed decision about taking these drugs. Telling a patient that statins will reduce his or her short-term risk of CVD is not always helpful—patients really need to know the potential lifetime benefits of statin therapy. That is, they need to know how much longer they might live if they take statins. Here, the researchers use a mathematical model to predict the personalized lifetime benefits (increased total and CVD-free life expectancy) of statin therapy for individuals without a history of CVD.
What Did the Researchers Do and Find?
The researchers used the Rotterdam Ischemic Heart Disease & Stroke Computer Simulation (RISC) model, which simulates the life courses of individuals through six health states, from well through to CVD or non-CVD death, to estimate lifetime outcomes with and without statin therapy in a population of healthy elderly individuals. They then used these outcomes and information on baseline risk factors to develop a web-based calculator suitable for personalized prediction of the lifetime benefits of statins in routine clinical practice. The model estimated that statin therapy increases average life expectancy in the study population by 0.3 years and average CVD-free life expectancy by 0.7 years. The gains in total and CVD-free life expectancy associated with statin therapy increased with blood pressure, unfavorable cholesterol levels, and body mass index (an indicator of body fat) but decreased with age. Notably, the web-based calculator predicted that some individuals with a low ten-year CVD risk might achieve a similar or larger gain in CVD-free life expectancy with statin therapy than some individuals with a high ten-year risk. So, for example, both a 55-year-old non-smoking woman with a ten-year CVD mortality risk of 2% (a two in a hundred chance of dying of CVD within ten years) and a 65-year-old male smoker with a ten-year CVD mortality risk of 15% might both gain one year of CVD-free life expectancy with statin therapy.
What Do These Findings Mean?
These findings suggest that statin therapy can lead on average to small gains in total life expectancy and slightly larger gains in CVD-free life expectancy among healthy individuals, and show that life expectancy benefits can be predicted using an individual's risk factor profile. The accuracy and generalizability of these findings is limited by the assumptions included in the model (in particular, the model did not allow for the known side effects of statin therapy) and by the data fed into it—importantly, the risk prediction model needs to be validated using an independent dataset. If future research confirms the findings of this study, the researchers' web-based calculator could provide complementary information to the currently recommended ten-year CVD mortality risk assessment. Whether communication of personalized outcomes will ultimately result in better clinical outcomes remains to be seen, however, because patients may be less likely to choose statin therapy when provided with more information about its likely benefits.
Additional Information
Please access these websites via the online version of this summary at
The web-based calculator for personalized prediction of lifetime benefits with statin therapy is available (after agreement to software license)
The American Heart Association provides information about many types of cardiovascular disease for patients, carers, and professionals, including information about drug therapy for cholesterol and a heart attack risk calculator
The UK National Health Service Choices website provides information about cardiovascular disease and about statins
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy; information is also available on statins, including personal stories about deciding to take statins
The US National Heart Lung and Blood Institute provides information on a wide range of cardiovascular diseases
The European Society of Cardiology's cardiovascular disease risk assessment model (SCORE) is available
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, stroke, and statins (in English and Spanish)
PMCID: PMC3531501  PMID: 23300388
9.  Factors Associated with Findings of Published Trials of Drug–Drug Comparisons: Why Some Statins Appear More Efficacious than Others 
PLoS Medicine  2007;4(6):e184.
Published pharmaceutical industry–sponsored trials are more likely than non-industry-sponsored trials to report results and conclusions that favor drug over placebo. Little is known about potential biases in drug–drug comparisons. This study examined associations between research funding source, study design characteristics aimed at reducing bias, and other factors that potentially influence results and conclusions in randomized controlled trials (RCTs) of statin–drug comparisons.
Methods and Findings
This is a cross-sectional study of 192 published RCTs comparing a statin drug to another statin drug or non-statin drug. Data on concealment of allocation, selection bias, blinding, sample size, disclosed funding source, financial ties of authors, results for primary outcomes, and author conclusions were extracted by two coders (weighted kappa 0.80 to 0.97). Univariate and multivariate logistic regression identified associations between independent variables and favorable results and conclusions. Of the RCTs, 50% (95/192) were funded by industry, and 37% (70/192) did not disclose any funding source. Looking at the totality of available evidence, we found that almost all studies (98%, 189/192) used only surrogate outcome measures. Moreover, study design weaknesses common to published statin–drug comparisons included inadequate blinding, lack of concealment of allocation, poor follow-up, and lack of intention-to-treat analyses. In multivariate analysis of the full sample, trials with adequate blinding were less likely to report results favoring the test drug, and sample size was associated with favorable conclusions when controlling for other factors. In multivariate analysis of industry-funded RCTs, funding from the test drug company was associated with results (odds ratio = 20.16 [95% confidence interval 4.37–92.98], p < 0.001) and conclusions (odds ratio = 34.55 [95% confidence interval 7.09–168.4], p < 0.001) that favor the test drug when controlling for other factors. Studies with adequate blinding were less likely to report statistically significant results favoring the test drug.
RCTs of head-to-head comparisons of statins with other drugs are more likely to report results and conclusions favoring the sponsor's product compared to the comparator drug. This bias in drug–drug comparison trials should be considered when making decisions regarding drug choice.
Lisa Bero and colleagues found published trials comparing one statin with another were more likely to report results and conclusions favoring the sponsor's product than the comparison drug.
Editors' Summary
Randomized controlled trials are generally considered to be the most reliable type of experimental study for evaluating the effectiveness of different treatments. Randomization involves the assignment of participants in the trial to different treatment groups by the play of chance. Properly done, this procedure means that the different groups are comparable at outset, reducing the chance that outside factors could be responsible for treatment effects seen in the trial. When done properly, randomization also ensures that the clinicians recruiting participants into the trial cannot know the treatment group to which a patient will end up being assigned. However, despite these advantages, a large number of factors can still result in bias creeping in. Bias comes about when the findings of research appear to differ in some systematic way from the true result. Other research studies have suggested that funding is a source of bias; studies sponsored by drug companies seem to more often favor the sponsor's drug than trials not sponsored by drug companies
Why Was This Study Done?
The researchers wanted to more precisely understand the impact of different possible sources of bias in the findings of randomized controlled trials. In particular, they wanted to study the outcomes of “head-to-head” drug comparison studies for one particular class of drugs, the statins. Drugs in this class are commonly prescribed to reduce the levels of cholesterol in blood amongst people who are at risk of heart and other types of disease. This drug class is a good example for studying the role of bias in drug–drug comparison trials, because these trials are extensively used in decision making by health-policy makers.
What Did the Researchers Do and Find?
This research study was based on searching PubMed, a biomedical literature database, with the aim of finding all randomized controlled trials of statins carried out between January 1999 and May 2005 (reference lists also were searched). Only trials which compared one statin to another statin or one statin to another type of drug were included. The researchers extracted the following information from each article: the study's source of funding, aspects of study design, the overall results, and the authors' conclusions. The results were categorized to show whether the findings were favorable to the test drug (the newer statin), inconclusive, or not favorable to the test drug. Aspects of each study's design were also categorized in relation to various features, such as how well the randomization was done (in particular, the degree to which the processes used would have prevented physicians from knowing which treatment a patient was likely to receive on enrollment); whether all participants enrolled in the trial were eventually analyzed; and whether investigators or participants knew what treatment an individual was receiving.
One hundred and ninety-two trials were included in this study, and of these, 95 declared drug company funding; 23 declared government or other nonprofit funding while 74 did not declare funding or were not funded. Trials that were properly blinded (where participants and investigators did not know what treatment an individual received) were less likely to have conclusions favoring the test drug. However, large trials were more likely to favor the test drug than smaller trials. When looking specifically at the trials funded by drug companies, the researchers found various factors that predicted whether a result or conclusion favored the test drug. These included the impact of the journal publishing the results; the size of the trial; and whether funding came from the maker of the test drug. However, properly blinded trials were less likely to produce results favoring the test drug. Even once all other factors were accounted for, the funding source for the study was still linked with results and conclusions that favored the maker of the test drug.
What Do These Findings Mean?
This study shows that the type of sponsorship available for randomized controlled trials of statins was strongly linked to the results and conclusions of those studies, even when other factors were taken into account. However, it is not clear from this study why sponsorship has such a strong link to the overall findings. There are many possible reasons why this might be. Some people have suggested that drug companies may deliberately choose lower dosages for the comparison drug when they carry out “head-to-head” trials; this tactic is likely to result in the company's product doing better in the trial. Others have suggested that trials which produce unfavorable results are not published, or that unfavorable outcomes are suppressed. Whatever the reasons for these findings, the implications are important, and suggest that the evidence base relating to statins may be substantially biased.
Additional Information.
Please access these Web sites via the online version of this summary at
The James Lind Library has been created to help people understand fair tests of treatments in health care by illustrating how fair tests have developed over the centuries
The International Committee of Medical Journal Editors has provided guidance regarding sponsorship, authorship, and accountability
The CONSORT statement is a research tool that provides an evidence-based approach for reporting the results of randomized controlled trials
Good Publication Practice guidelines provide standards for responsible publication of research sponsored by pharmaceutical companies
Information from Wikipedia on Statins. Wikipedia is an internet encyclopedia anyone can edit
PMCID: PMC1885451  PMID: 17550302
10.  Variations in statin prescribing for primary cardiovascular disease prevention: cross-sectional analysis 
Statins are an important intervention for primary and secondary cardiovascular disease (CVD) prevention. We aimed to establish the variation in primary preventive treatment for CVD with statins in the English population.
Cross sectional analyses of 6155 English primary care practices with 40,017,963 patients in 2006/7. Linear regression was used to model prescribing rates of statins for primary CVD prevention as a function of IMD (index of multiple deprivation) quintile, proportion of population from an ethnic minority, and age over 65 years. Defined Daily Doses (DDD) were used to calculate the numbers of patients receiving a statin. Statin prescriptions were allocated to primary and secondary prevention based on the prevalence of CVD and stroke.
We estimated that 10.5% (s.d.3.7%) of the registered population were dispensed a statin for any indication and that 6.3% (s.d. 3.0%) received a statin for primary CVD prevention. The regression model explained 21.2% of the variation in estimates of prescribing for primary prevention. Practices with higher prevalence of hypertension (β co-efficient 0.299 p <0.001) and diabetes (β co-efficient 0.566 p < 0.001) prescribed more statins for primary prevention. Practices with higher levels of ethnicity (β co-efficient-0.026 p <0.001), greater deprivation (β co-efficient −0.152 p < 0.001) older patients (β co-efficient −0.032 p 0.002), larger lists (β co-efficient −0.085, p < 0.001) and were more rural (β co-efficient −0.121, p0.026) prescribed fewer statins. In a small proportion of practices (0.5%) estimated prescribing rates for statins were so low that insufficient prescriptions were issued to meet the predicted secondary prevention requirements of their registered population.
Absolute estimated prescribing rates for primary prevention of CVD were 6.3% of the population. There was evidence of social inequalities in statin prescribing for primary prevention. These findings support the recent introduction of a financial incentive for primary prevention of CVD in England.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6963-14-414) contains supplementary material, which is available to authorized users.
PMCID: PMC4263070  PMID: 25240604
Hydroxymethylglutaryl-CoA reductase inhibitors; Primary health care; Cardiovascular diseases
11.  Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials 
PLoS Medicine  2012;9(9):e1001310.
A systematic review and meta-analysis conducted by Kazem Rahimi and colleagues re-evaluates the hypothesis, generated in previous studies, that statins may reduce the risk of venous thromboembolic events. Their meta-analysis does not support the previous findings.
It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins.
Methods and Findings
We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78–1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72–1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76–1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82–1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80–1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out.
Please see later in the article for the Editors' Summary.
The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out.
Editors' Summary
Blood normally flows smoothly throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Occasionally, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood towards the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the leg) include pain, swelling, and redness in the affected limb. DVT is treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a pulmonary embolism (PE), a life-threatening condition characterized by chest pain, breathlessness, coughing, and dizziness. Little is known about how to prevent DVTs and PEs but risk factors for these venous thromboembolic events include having an inherited blood clotting disorder, oral contraceptive use, having surgery, and prolonged inactivity (on long-haul plane flights, for example).
Why Was This Study Done?
In 2009, a secondary (add-on) analysis of data from a randomized controlled trial (RCT, a study that randomly assigns individuals to receive different treatments and compares the outcomes associated with each treatment) called the JUPITER trial reported that rosuvastatin—a cholesterol-lowering drug (statin)—halved the risk of venous thromboembolic events among apparently healthy adults. The JUPITER trial was initiated to test whether statins reduce the risk of strokes, heart attacks, and other cardiovascular diseases (conditions that involve the heart and the blood vessels) among adults with raised levels of a predictor for these diseases called C-reactive protein; statins reduce the levels of this protein as well as those of cholesterol. Because fewer than 100 of the participants in the JUPITER trial developed a DVT or PE, the reduction in the risk of a venous thromboembolic event among the participants who took rosuvastatin could have happened by chance. In this systematic review and meta-analysis of 29 RCTs of statins that collected information on many more venous thromboembolic events, the researchers test the hypothesis that statins substantially reduce the risk of such events. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 RCTs (105,759 participants) that compared the effects of statins with control (dummy) tablets and seven (40,594 participants) that compared an intensive statin regimen with a standard regimen. They then obtained largely unpublished information about the venous thromboembolic events that occurred during these trials (about 1,000 DVTs and PEs) from the original investigators. In the trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events. Thus, although events occurred in 465 participants who were given statins (0.9% of the participants) and in 521 participants who were given control tablets (1% of the participants), this difference in outcomes was not statistically significant—it could have happened by chance. Exclusion of the JUPITER trial results from the meta-analysis did not alter this finding. The researchers also found no evidence that intensive statin therapy reduced the risk of venous thromboembolic events compared to standard therapy.
What Do These Findings Mean?
The findings of this meta-analysis do not support the suggestion that statins, either at the standard dose or at higher doses, reduce the risk of venous thromboembolic events substantially among healthy adults. It is possible that the effect of statins has been underestimated in this meta-analysis because of missing data or because of some other source of bias. Furthermore, because the total number of events in this meta-analysis is still relatively modest, these findings do not rule out the possibility that statins may reduce the risk of venous thromboembolic events by up to about one-fifth in some or all individuals. Additional large RCTs are now needed to investigate whether statin treatment does in fact reduce the risk of venous thromboembolic events in adults and, if it does, whether all statins have a similar effect and whether statin treatment is beneficial in everyone or only in specific subgroups of people.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Frits Rosendaal
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolisms), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, on pulmonary embolism, and on statins; a Behind the Headlines article describes the JUPITER trial and its implications
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and statins (in English and Spanish)
PMCID: PMC3445446  PMID: 23028261
12.  Discontinuation of statin therapy in older people: does a cancer diagnosis make a difference? An observational cohort study using data linkage 
BMJ Open  2012;2(3):e000880.
The aim was to examine statin discontinuation rates in a cohort of elderly Australians with newly diagnosed cancer using population-based secondary health data.
Observational cohort study.
New South Wales, the largest jurisdiction in Australia. The Pharmaceutical Benefits and Repatriation Pharmaceutical Benefits Schemes are national programmes subsidising prescription drugs to the Australian population and Australian Government Department of Veterans' Affairs clients.
The cohort comprised 1731 cancer patients aged ≥65 years with evidence of statin use in the 90 days prior to diagnosis. They were matched to 3462 non-cancer patients prescribed statins in the same period.
Main outcome measure
The authors compared statin discontinuation rates up to 4 years post-diagnosis and examined the factors associated with statin discontinuation.
The proportion of cancer patients discontinuing statin therapy at 4 years (27%) was comparable to the comparison cohort; however, significantly higher proportions of the cancer cohort discontinued statins than the comparison cohort at 3, 6 and 12 months of follow-up (9.7% vs 7.4% at 12 months, respectively). More than 30% of cancer patients who died were dispensed statins within 30 days of death. Discontinuation of statin therapy in cancer patients was associated with regionalised and distant disease spread at diagnosis (p<0.001), older age (p=0.006), upper gastrointestinal organs and liver cancer (aHR 2.95, 95% CI 1.92 to 4.53) and cancer of the lung, bronchus and trachea (aHR 1.99, 95% CI 1.32 to 3.00) and poorer survival.
Medications should be rationalised at the time of a cancer diagnosis, especially in the setting of a poor prognosis. At least for some patients in our cohort, statin therapy may be inappropriately continued which adds unnecessarily to therapeutic burden.
Article summary
Article focus
There is limited clinical guidance on managing comorbid conditions after the diagnosis of life-threatening illness.
Some medications may be continued unnecessarily and may even cause harm after a cancer diagnosis.
The aim of this study is to examine the rates of statin discontinuation in a cohort of older cancer patients compared with their peers with no cancer diagnosis.
Key messages
In the setting of cancer, statins may be continued unnecessarily in some patients.
A high proportion of cancer patients are dispensed statins 30 days before death.
Reassessment of existing treatments is recommended after a cancer diagnosis so as to minimised therapeutic burden.
Strengths and limitations of this study
This is a large retrospective cohort study of elderly Australians using population data set linkage.
We were unable to establish if statin therapy had been reviewed subsequent to a cancer diagnosis nor the reasons for discontinuation.
PMCID: PMC3358623  PMID: 22614172
13.  A UK general practice population cohort study investigating the association between lipid lowering drugs and 30-day mortality following medically attended acute respiratory illness 
PeerJ  2016;4:e1902.
Background. Cholesterol lowering drugs HMG-CoA reductase inhibitors (statins) and PPARα activators (fibrates) have been shown to reduce host inflammation via non-disease specific immunomodulatory mechanisms. Recent studies suggest that commonly prescribed drugs in general practice, statins and fibrates, may be beneficial in influenza-like illness related mortality. This retrospective cohort study examines the association between two lipid lowering drugs, statins and fibrates, and all-cause 30-day mortality following a medically attended acute respiratory illness (MAARI).
Methods. Primary care patient data were retrospectively extracted from the UK Clinical Practice Research Datalink (CPRD) database. The sample comprised 201,179 adults aged 30 years or older experiencing a MAARI episode. Patient exposure to statins or fibrates was coded as separate dichotomous variables and deemed current if the most recent GP prescription was issued in the 30 days prior to MAARI diagnosis. Multivariable logistic regression and Cox regression were used for analyses. Adjustment was carried out for chronic lung disease, heart failure, metformin and glitazones, comorbidity burden, socio-demographic and lifestyle variables such as smoking status and body mass index (BMI). Statistical interaction tests were carried out to check for effect modification by gender, body mass index, smoking status and comorbidity.
Results. A total of 1,096 (5%) patients died within the 30-day follow up period. Of this group, 213 (19.4%) were statin users and 4 (0.4%) were fibrate users. After adjustment, a significant 35% reduction in odds [adj OR; 0.65 (95% CI [0.52–0.80])] and a 33% reduction in the hazard [adj HR: 0.67 (95% CI [0.55–0.83])] of all-cause 30-day mortality following MAARI was observed in statin users. A significant effect modification by comorbidity burden was observed for the association between statin use and MAARI-related mortality. Fibrate use was associated with a non-significant reduction in 30-day MAARI-related mortality.
Conclusion. This study suggests that statin use may be associated with a reduction in 30-day mortality following acute respiratory illness that is severe enough to merit medical consultation. Findings from this study support and strengthen similar observational research while providing a strong rationale for a randomised controlled trial investigating the potential role of statins in acute respiratory infections.
PMCID: PMC4841228  PMID: 27114868
Fibrates; Lipid lowering drugs; statins; mortality; MAARI; Acute respiratory illness; Cohort study; CPRD
14.  Evaluating an implementation strategy in cardiovascular prevention to improve prescribing of statins in Germany: an intention to treat analysis 
BMC Public Health  2013;13:623.
The prescription of statins is an evidence-based treatment to reduce the risk of cardiovascular events in patients with elevated cardiovascular risk or with a cardiovascular disorder (CVD). In spite of this, many of these patients do not receive statins.
We evaluated the impact of a brief educational intervention in cardiovascular prevention in primary care physicians’ prescribing behaviour regarding statins beyond their participation in a randomised controlled trial (RCT). For this, prescribing data of all patients > 35 years who were counselled before and after the study period were analysed (each n > 75000). Outcome measure was prescription of Hydroxymethylglutaryl-CoA Reductase Inhibitors (statins) corresponding to patients’ overall risk for CVD. Appropriateness of prescribing was examined according to different risk groups based on the Anatomical Therapeutic Chemical Classification System (ATC codes).
There was no consistent association between group allocation and statin prescription controlling for risk status in each risk group before and after study participation. However, we found a change to more significant drug configurations predicting the prescription of statins in the intervention group, which can be regarded as a small intervention effect.
Our results suggest that an active implementation of a brief evidence-based educational intervention does not lead to prescription modifications in everyday practice. Physician’s prescribing behaviour is affected by an established health care system, which is not easy to change.
Trial registration
PMCID: PMC3716622  PMID: 23819600
Evaluation studies; Intention to treat analysis; Cardiovascular diseases; Drug prescriptions; Hydroxymethylglutaryl-CoA Reductase Inhibitors
15.  Education and practice gaps on atrial fibrillation and anticoagulation: a survey of cardiovascular nurses 
Patients’ knowledge of their atrial fibrillation (AF) and anticoagulation therapy are determinants of the efficacy of thromboprophylaxis. Nurses may be well placed to provide counselling and education to patients on all aspects of anticoagulation, including self-management. It is important that nurses are well informed to provide optimal education to patients. Current practice and knowledge of cardiovascular nurses on AF and anticoagulation in the Australian and New Zealand (ANZ) context is not well reported.
This study aimed to; 1) Explore the nurse’s role in clinical decision making in anticoagulation in the setting of AF; 2) Describe perceived barriers and enablers to anticoagulation in AF; 3) Investigate practice patterns in the management of anticoagulation in the ANZ setting; 4) Assess cardiovascular nurses’ knowledge of anticoagulation.
A paper-based survey on current practices and knowledge of AF and anticoagulation was distributed during the Australian Cardiovascular Nursing College (ACNC) Annual Scientific Meeting, February 2014. This survey was also emailed to Cardiovascular Trials Nurses throughout New South Wales, Australia and nursing members of the Cardiac Society of Australia and New Zealand (CSANZ).
There were 41/73 (56 %) respondents to the paper-based survey. A further 14 surveys were completed online via nurse members of the CSANZ, and via an investigator developed NSW cardiovascular trials nurse email distribution list. A total of 55 surveys were completed and included in analyses. Prior education levels on AF, stroke risk, anticoagulation and health behaviour modification were mixed. The CHA2DS2VASc and HAS-BLED risk stratification tools were reported to be underused by this group of clinicians. Reported key barriers to anticoagulation included; fears of patients falling, fears of poor adherence to medication taking and routine monitoring. Patient self-monitoring and self-management were reported as underutilised. ANZ cardiovascular nurses reported their key role to be counselling and advising patients on therapy regimens. Anticoagulant-drug interaction knowledge was generally poor.
This study identified poor knowledge and practice in the areas of AF and anticoagulation. There is scope for improvement for cardiovascular nurses in ANZ in relation to AF and anticoagulation knowledge and practice.
PMCID: PMC4709951  PMID: 26758627
Clinical practice; Anticoagulant knowledge; Anticoagulation; Atrial fibrillation; Education; Survey methods; Patient education; Self-management
16.  Statin use and the risk of herpes zoster: a nested case–control study using primary care data from the U.K. Clinical Research Practice Datalink 
The British Journal of Dermatology  2016;175(6):1183-1194.
Statins are commonly prescribed worldwide and recent evidence suggests that they may increase the risk of herpes zoster (HZ).
To quantify the effect of statin exposure on the risk of HZ in the U.K.
A matched case–control study was conducted using data from U.K. primary care and hospital records. Patients > 18 years with an incident diagnosis of HZ were matched to up to four controls for age, sex and general practice. Patients were included in the statin exposure group if they had ever used a statin, and the daily dosage of the most recent statin prescription and the time since the most recent statin prescription were also recorded. The primary outcome was an incident diagnosis of HZ. Odds ratios (ORs) were estimated from conditional logistic regression and adjusted for potential confounders.
A total of 144 959 incident cases of HZ were matched to 549 336 controls. Adjusted analysis suggested strong evidence for an increase in the risk of HZ related to statin exposure (OR 1·13, 95% confidence interval 1·11–1·15). There was also an increased risk when dosages were increased for patients who were currently or had recently been receiving statin treatment (P trend < 0·001), and we found an attenuation of the increased risk of HZ in previous statin users as the time since last statin exposure increased (P trend < 0·001).
These findings are consistent with the hypothesis that statin therapy leads to an increase in the risk of HZ.
What's already known about this topic?
Studies in both Canada and Taiwan have recently reported a small but significantly increased risk of herpes zoster (HZ) in patients receiving statin treatment.As statins are one of the most widely prescribed drugs in the U.K., with around 45 million prescriptions every year, any adverse effects will have substantial public health implications.
What does this study add?
In this large matched case–control study, statin exposure was associated with a modest increase in the risk of HZ.A dose–response relationship was observed, and there was an attenuation of the increased risk over time among people who stopped statin therapy, indicating that the increased risk is consistent with a causal effect.There may be extra motivation to maximize HZ vaccine uptake among eligible patients receiving a statin.
Linked Comment: Shalom and Cohen. Br J Dermatol 2016; 175:1137–1138.
PMCID: PMC5215701  PMID: 27292233
17.  Patient attitudes towards a new role for pharmacists: continued dispensing 
In Australia, “continued dispensing” (CD) is a new model for supply of prescription medications. Under specific circumstances, community pharmacists are allowed to dispense a further one month supply of prescription only medications without a valid prescription. It allows continuation and treatment adherence when patients run out of statin and/or oral contraceptive (OC) medications, when it is not practical or they fail to plan accordingly to get a new prescription.
The aim of this study was to explore patient attitudes towards a CD model, including any perceived concerns or associated risks with CD prior to its introduction.
An Australia-wide computer-assisted telephone interview survey of statin and OC users aged 18 years or older was conducted in July 2013 prior to implementation of the CD model. A telephone number list was generated via a random number generation function based on a broad breakdown of the Australian population as outlined in the June 2013 Australian Bureau of Statistics data. The sample target for the survey was 300, consisting of 150 statin users and 150 OC users.
There were a total of 301 respondents, comprising 151 statin users and 150 OC users. Approximately 37% of all respondents had experienced running out of their medications in the past 12 months, of whom 35.4% had temporarily stopped treatment and 33.6% requested their medication from a pharmacist without a valid prescription. OC users were more likely to run out of their medications (P=0.021). The majority of respondents had a regular pharmacy (86%) and therefore would be eligible for CD in the future. The majority of those surveyed had no concerns about CD or perceived it as posing no risks. Concerns raised included consultation privacy and the pharmacist’s lack of access to their medical records.
Australian users of statin and OC medications showed a high level of support for CD. Given that a significant proportion of patients temporarily stopped treatment when they ran out of medications and had no valid prescription, implementation of CD may alleviate the negative consequences of therapy interruption in statin and OC users in the short term. Longer-term solutions and opportunities to expand CD require further exploration.
PMCID: PMC4155799  PMID: 25210443
Australia; pharmacists; statins; oral contraceptives; prescription medication
18.  The efficiency of cardiovascular risk assessment: do the right patients get statin treatment? 
Heart  2013;99(21):1597-1602.
To evaluate targeting of statin prescribing for primary prevention to those with high cardiovascular disease (CVD) risk.
Two cohort studies including the general population and initiators of statins aged 35–74 years.
UK primary care records in the Clinical Practice Research Datalink.
3.8 million general population patients and 300 914 statin users.
Statin prescribing.
Main outcome measures
Statin prescribing by CVD risk; observed 5-year CVD risks; variability between practices.
Statin prescribing increased substantially over time to patients with high 10-year CVD risk (≥20%): 7.0% of these received a statin prior to 2007, and 30.4% in 2007 onwards. Prescribing to patients with low risk (<15%) also increased (from 1.9% to 5.0%). Only about half the patients initiating statin treatment were high risk according to CVD risk score. The 5-year CVD risks, as observed during statin treatment, reduced over calendar time (from 17.0% to 7.1%). There was a large variation between general practices in the percentage of high-risk patients prescribed a statin in 2007 onwards, ranging from 8.2% to 61.5%. For low-risk patients, these varied from 2.1% to 29.1%.
There appeared to be substantive overuse in low CVD risk and underuse in high CVD risk (600 000 and 850 000 patients, respectively, in the UK since 2007). There is wide variation between practices in statin prescribing to patients at high CVD risk. There is a clear need for randomised trials for the best strategy to target statin treatment and manage CVD risk for primary prevention.
PMCID: PMC3812879  PMID: 23735939
19.  Discontinuation and restarting in patients on statin treatment: prospective open cohort study using a primary care database 
The BMJ  2016;353:i3305.
Objectives To estimate rates of discontinuation and restarting of statins, and to identify patient characteristics associated with either discontinuation or restarting.
Design Prospective open cohort study.
Setting 664 general practices contributing to the Clinical Practice Research Datalink in the United Kingdom. Data extracted in October 2014.
Participants Incident statin users aged 25-84 years identified between January 2002 and September 2013. Patients with statin prescriptions divided into two groups: primary prevention and secondary prevention (those already diagnosed with cardiovascular disease). Patients with statin prescriptions in the 12 months before study entry were excluded.
Main outcome measures Discontinuation of statin treatment (first 90 day gap after the estimated end date of a statin prescription), and restarting statin treatment for those who discontinued (defined as any subsequent prescription between discontinuation and study end).
Results Of 431 023 patients prescribed statins as primary prevention with a median follow-up time of 137 weeks, 47% (n=204 622) discontinued treatment and 72% (n=147 305) of those who discontinued restarted. Of 139 314 patients prescribed statins as secondary prevention with median follow-up time of 182 weeks, 41% (n=57 791) discontinued treatment and 75% (43 211) of those who discontinued restarted. Younger patients (aged ≤50 years), older patients (≥75 years), women, and patients with chronic liver disease were more likely to discontinue statins and less likely to restart. However, patients in ethnic minority groups, current smokers, and patients with type 1 diabetes were more likely to discontinue treatment but then were more likely to restart, whereas patients with hypertension and type 2 diabetes were less likely to discontinue treatment and more likely to restart if they did discontinue. These results were mainly consistent in the primary prevention and secondary prevention groups.
Conclusions Although a large proportion of statin users discontinue, many of them restart. For many patient groups previously considered as “stoppers,” the problem of statin treatment “stopping” could be part of the wider issue of poor adherence. Identification of patient groups associated with completely stopping or stop-starting behaviour has positive implications for patients and doctors as well as suggesting areas for future research.
PMCID: PMC4925919  PMID: 27353261
20.  Genetically Guided Statin Therapy on Statin Perceptions, Adherence, and Cholesterol Lowering: A Pilot Implementation Study in Primary Care Patients 
Journal of Personalized Medicine  2014;4(2):147-162.
Statin adherence is often limited by side effects. The SLCO1B1*5 variant is a risk factor for statin side effects and exhibits statin-specific effects: highest with simvastatin/atorvastatin and lowest with pravastatin/rosuvastatin. The effects of SLCO1B1*5 genotype guided statin therapy (GGST) are unknown. Primary care patients (n = 58) who were nonadherent to statins and their providers received SLCO1B1*5 genotyping and guided recommendations via the electronic medical record (EMR). The primary outcome was the change in Beliefs about Medications Questionnaire, which measured patients’ perceived needs for statins and concerns about adverse effects, measured before and after SLCO1B1*5 results. Concurrent controls (n = 59) were identified through the EMR to compare secondary outcomes: new statin prescriptions, statin utilization, and change in LDL-cholesterol (LDL-c). GGST patients had trends (p = 0.2) towards improved statin necessity and concerns. The largest changes were the “need for statin to prevent sickness” (p < 0.001) and “concern for statin to disrupt life” (p = 0.006). GGST patients had more statin prescriptions (p < 0.001), higher statin use (p < 0.001), and greater decrease in LDL-c (p = 0.059) during follow-up. EMR delivery of SLCO1B1*5 results and recommendations is feasible in the primary care setting. This novel intervention may improve patients’ perceptions of statins and physician behaviors that promote higher statin adherence and lower LDL-c.
PMCID: PMC4263970  PMID: 25563221
pharmacogenetics; personalized medicine; medication adherence; risk assessment; health behavior; hyperlipidemia
21.  Statin Prescribing Patterns in a Cohort of Cancer Patients with Poor Prognosis 
Journal of Palliative Medicine  2013;16(4):412-418.
There are no evidence-based recommendations for statin continuation or discontinuation near the end of life. However, some expert opinion recommends continuing statins prescribed for secondary versus primary prevention of cardiovascular disease.
Our aim was to explore statin prescribing patterns in a longitudinal cohort of individuals with life-limiting illness, and to evaluate differences in these patterns based on secondary versus primary prevention of cardiovascular disease.
Design and setting
This study was a retrospective cohort analysis of 539 persons in an integrated, not-for-profit health maintenance organization (HMO) setting who were receiving statins at diagnosis of a cancer with 0% to 25% predicted 5-year survival. Of the cohort patients, 343 were taking statins for secondary prevention and 196 for primary prevention of cardiovascular disease. Measurements included number and timing of statin refills between diagnosis and date of death, disenrollment, or the end of the observation period.
Four hundred and ninety-six cohort members died within the observation period. Fifty-eight percent of the secondary prevention and 62% of the primary prevention group had at least one statin refill after diagnosis. There were no significant differences between groups for number of days between diagnosis and last refill, or between last refill and death. Two deaths were attributable to cardiovascular causes in each group.
Our retrospective cohort analysis of persons with incident poor-prognosis cancer describes diminished, but persistent statin refills after diagnosis. Neither timing of statin discontinuation nor cardiovascular mortality differed by prescribing indication. There may be an opportunity to reevaluate medication burden in persons taking statins for primary prevention, and it is unclear whether continuing statins prescribed for secondary prevention affects cardiovascular outcomes.
PMCID: PMC3612279  PMID: 23305190
22.  Use of Antiepileptic Drugs and Lipid-Lowering Agents in The United States 
Epilepsy & behavior : E&B  2014;34:105-108.
The extent to which enzyme-inducing antiepileptic drugs (EIAEDs) are used as first-line treatment in the United States remains unknown. Studies suggest that EIAEDs produce elevation of serum lipids, which could require additional treatment. We assessed the current use of EIAED in monotherapy for epilepsy in the U.S., as well as the correlation between use of EIAEDs and subsequent new prescriptions for HMG-CoA reductase inhibitors (“statins”) for hyperlipidemia.
We queried the MarketScan® databases between July 2009 to January 2013, covering 66 million patients with commercial or supplemental Medicare insurance. We identified individuals who had a diagnosis of seizures, continuous enrollment in the database from 6 months prior to 24 months after the epilepsy diagnosis, no utilization of an AED or a statin prior to that diagnosis, and at least 1 new AED prescription. We tabulated the fraction who were prescribed EIAEDs (phenytoin, carbamazepine, barbiturates) and those prescribed all other AEDs. Rates of new statin prescription between 1 and 24 months after AED prescription were assessed among the two groups, restricted to those with no prior history of vascular disease who had lipid serology obtained subsequent to the new AED prescription.
Of the 11,893 patients with newly-treated epilepsy, 2425 (20.4%) were started on an EIAED, and 9468 (79.6%) were started on a non-inducing AED. There was a consistent and significant trend for EIAEDs to be increasingly prescribed with increasing age (p<0.0001).
Among patients meeting the criteria, a statin was newly prescribed in 66 of 496 (13.3%) EIAED-treated patients, and in 178 of 1930 (9.2%) non-inducing AED patients (p < 0.007). This difference remained significant after accounting for age and gender (p=0.015). A patient starting an EIAED was 46% more likely to be subsequently prescribed a statin than a patient started on a non-inducing AED (95% CI 1.08–1.98).
EIAED prescription for epilepsy appears to increase with increasing age in the U.S. despite the absence of a cogent rationale for this practice, suggesting a failure to appreciate the complications of EIAED therapy among U.S. physicians. Statins were more often started in those newly-prescribed EIAEDs than to those given non-inducing AEDs. These preliminary data provides further evidence suggesting that EIAEDs elevate lipids in a clinically meaningful manner.
PMCID: PMC4046904  PMID: 24735835
antiepileptic drugs; enzyme induction; lipid-lowering agents; United States
23.  Statin non-adherence: clinical consequences and proposed solutions 
F1000Research  2016;5:F1000 Faculty Rev-714.
Large controlled clinical trials have demonstrated reductions with statin therapy in cardiovascular events in patients presenting with acute coronary syndromes and stable coronary heart disease and individuals at high risk of a cardiovascular event. In trials of acute coronary syndromes and stable coronary heart disease, high-intensity statin therapy is more effective in the prevention of recurrent cardiovascular events than low-intensity statin therapy. Thus, evidence-based guidelines recommend in-hospital initiation of high-intensity statin therapy for all acute coronary syndrome patients. Clinical trials report high adherence to and low discontinuation of high-intensity statin therapy; however, in clinical practice, high-intensity statins are prescribed to far fewer patients, who often discontinue their statin after the first refill. A coordinated effort among the patient, provider, pharmacist, health system, and insurer is necessary to improve utilization and persistence of prescribed medications. The major cause for statin discontinuations reported by patients is perceived adverse events. Evaluation of potential adverse events requires validated tools to distinguish between statin-associated adverse events versus non-specific complaints. Treatment options for statin-intolerant patients include the use of a different statin, often at a lower dose or frequency. In order to lower LDL cholesterol, lower doses of statins may be combined with ezetimibe or bile acid sequestrants. Newer treatment options for patients with statin-associated muscle symptoms may include proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors.
PMCID: PMC4841191  PMID: 27134737
statin therapy; cardiovascular events; coronary heart disease; acute coronary syndromes; statin therapy adherence
24.  Doctors’ knowledge, attitudes, and compliance with 2013 ACC/AHA guidelines for prevention of atherosclerotic cardiovascular disease in Singapore 
There is an unmet need for strategies to prevent atherosclerotic cardiovascular disease in Singapore. The main objective of this study was to investigate Singapore physicians’ response to the 2013 American College of Cardiology and American Heart Association (ACC/AHA) guidelines for treatment of cholesterol and their impact on clinical practice.
This survey was conducted in two stages, qualitative and quantitative. Physicians were initially screened on the basis of an initial screener questionnaire, and eligible physicians were then included in the study.
Qualitative (n=19) and quantitative (n=66) surveys were completed by eligible physicians from Singapore. Physicians were less familiar with the 2013 ACC/AHA guidelines (35%) as compared with the Singapore Ministry of Health (MoH) lipid guidelines 2006 (49%). Of the physicians whose opinion was sought on the ACC/AHA guidelines, more than 50% disagreed with the definition of high-, moderate-, and low-intensity statin therapy; recommendation of atorvastatin 40–80 mg and rosuvastatin 20–40 mg as medications for high-intensity statin therapy; and classification of individuals who would benefit from moderate- to high-intensity statin therapy. Most physicians assumed that Asians may be intolerant to high-intensity statin therapy.
Although embracing the 2013 ACC/AHA guidelines in clinical practice is expected to provide better clinical care to patients, our study revealed high reluctance by physicians, especially in the use of high-dose statins. However, ACC/AHA guidelines can be easily adopted in Asia as there is a wealth of data available for atorvastatin in primary and secondary prevention of atherosclerotic cardiovascular disease with similar efficacy and safety profiles in the white and Asian populations.
PMCID: PMC4461017  PMID: 26082642
cholesterol treatment; cardiovascular disease; statin therapy; CVD risk factors; LDL target levels
25.  Preadmission statin use and one-year mortality among patients in intensive care - A cohort study 
Critical Care  2010;14(2):R29.
Statins reduce risk of cardiovascular events and have beneficial pleiotropic effects; both may reduce mortality in critically ill patients. We examined whether statin use was associated with risk of death in general intensive care unit (ICU) patients.
Cohort study of 12,483 critically ill patients > 45 yrs of age with a first-time admission to one of three highly specialized ICUs within the Aarhus University Hospital network, Denmark, between 2001 and 2007. Statin users were identified through population-based prescription databases. We computed cumulative mortality rates 0-30 days and 31-365 days after ICU admission and mortality rate ratios (MRRs), using Cox regression analysis controlling for potential confounding factors (demographics, use of other cardiovascular drugs, comorbidity, markers of social status, diagnosis, and surgery).
1882 (14.3%) ICU patients were current statin users. Statin users had a reduced risk of death within 30 days of ICU admission [users: 22.1% vs. non-users 25.0%; adjusted MRR = 0.76 (95% confidence interval (CI): 0.69 to 0.86)]. Statin users also had a reduced risk of death within one year after admission to the ICU [users: 36.4% vs. non-users 39.9%; adjusted MRR = 0.79 (95% CI: 0.73 to 0.86)]. Reduced risk of death associated with current statin use remained robust in various subanalyses and in an analysis using propensity score matching. Former use of statins and current use of non-statin lipid-lowering drugs were not associated with reduced risk of death.
Preadmission statin use was associated with reduced risk of death following intensive care. The associations seen could be a pharmacological effect of statins, but unmeasured differences in characteristics of statin users and non-users cannot be entirely ruled out.
PMCID: PMC2887131  PMID: 20214779

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