Related Articles

Background

Non-invasive stress testing might guide the use of aspirin and statins for primary prevention of coronary heart disease (CHD), but it is unclear if such a strategy would be cost-effective.

Methods and Results

We compared the status quo, in which the current national use of aspirin and statins was simulated, with three other strategies; 1) full implementation of Adult Treatment Panel (ATP III) guidelines, 2) a “treat-all” strategy in which all intermediate-risk persons received statins (men and women) and aspirin (men only) and 3) a “test and treat strategy,” in which all persons with an intermediate-risk of CHD underwent stress testing and those with a positive test were treated with high-intensity statins (men and women) and aspirin (men only). Healthcare costs, CHD events, and quality-adjusted life years from 2011 to 2040 were projected. Under a variety of assumptions, the “treat-all” strategy was the most effective and least expensive strategy. Stress electrocardiography was more effective and less expensive than other “test-and-treat” strategies, but it was less expensive than “treat all” only if statin cost exceeded $3.16/pill or if testing increased adherence from below 22% to above 75%. However, stress electrocardiography could be cost-effective in persons initially non-adherent to the “treat all” strategy if it raised their adherence to 5% and cost-saving if it raised their adherence to 13%.

Conclusions

When generic high-potency statins are available, non-invasive cardiac stress testing to target preventive medications is not cost-effective unless it substantially improves adherence.

Introduction: Statin therapy reduces the rate of coronary heart disease, but high costs in combination with a large population eligible for treatment ask for priority setting. Although trials agree on the size of the benefit, economic analyses of statins report contradictory results. This article reviewed cost effectiveness analyses of statins and sought to synthesise cost effectiveness ratios for categories of risk of coronary heart disease and age.

Methods: The review searched for studies comparing statins with no treatment for the prevention of either cardiovascular or coronary heart disease in men and presenting cost per years of life saved as outcome. Estimates were extracted, standardised for calendar year and currency, and stratified by categories of risk, age, and funding source

Results: 24 studies were included (from 50 retrieved), yielding 216 cost effectiveness ratios. Estimated ratios increase with decreasing risk. After stratification by risk, heterogeneity of ratios is large varying from savings to $59 000 per life year saved in the highest risk category and from $6500 to $490 000 in the lowest category. The pooled estimates show values of $21571 per life year saved for a 10 year coronary heart disease risk of 20% and $16862 per life year saved for 10 year risk of 30%.

Conclusion: Statin therapy is cost effective for high levels of risk, but inconsistencies exist at lower levels. Although the cost effectiveness of statins depends mainly on absolute risk, important heterogeneity remains after adjusting for absolute risk. Economic analyses need to increase their transparency to reduce their vulnerability to bias and increase their reproducibility.

OBJECTIVES--To estimate the cost effectiveness of statins in lowering serum cholesterol concentration in people at varying risk of fatal cardiovascular disease and to explore the implications of changing the criteria for intervention on cost and cost effectiveness for a purchasing authority. DESIGN--A life table method was used to model the effect of treatment with a statin on survival over 10 years in men and women aged 45-64. The costs of intervention were estimated from the direct costs of treatment, offset by savings associated with a reduction in coronary angiographies, non-fatal myocardial infarctions, and revascularisation procedures. The robustness of the model to various assumptions was tested in a sensitivity analysis. SETTING--Population of a typical district health authority. MAIN OUTCOME MEASURE--Cost per life year saved. RESULTS--The average cost effectiveness of treating men aged 45-64 with no history of coronary heart disease and a cholesterol concentration > 6.5 mmol/l for 10 years with a statin was 136,000 pounds per life year saved. The average cost effectiveness for patients with pre-existing coronary heart disease and a cholesterol concentration > 5.4 mmol/l was 32,000 pounds. These averages hide enormous differences in cost effectiveness between groups at different risk, ranging from 6000 pounds per life year in men aged 55-64 who have had a myocardial infarction and whose cholesterol concentration is above 7.2 mmol/l to 361,000 pounds per life year saved in women aged 45-54 with angina and a cholesterol concentration of 5.5-6.0 mmol/l. CONCLUSIONS--Lowering serum cholesterol concentration in patients with and without preexisting coronary heart disease is effective and safe, but treatment for all those in whom treatment is likely to be effective is not sustainable within current NHS resources. Data on cost effectiveness data should be taken into account when assessing who should be eligible for treatment.

Background

The literature on the cost-effectiveness of statin drugs in primary prevention of coronary heart disease is complex. The objective of this study is to compare the disparate results of recent cost-effectiveness analyses of statins.

Findings

We conducted a systematic review of the literature on statin cost-effectiveness. The four studies that met inclusion criteria reported varying conclusions about the cost-effectiveness of statin treatment, without a clear consensus as to whether statins are cost-effective for primary prevention. However, after accounting for each study’s assumptions about statin costs, we found substantial agreement among the studies. Studies that assumed statins to be more expensive found them to be less cost-effective, and vice-versa. Furthermore, treatment of low-risk groups became cost-effective as statins became less expensive.

Conclusions

Drug price is the primary determinant of statin cost-effectiveness within a given risk group. As more statin drugs become generic, patients at low risk for coronary disease may be treated cost-effectively. Though many factors must be weighed in any medical decision, from a cost-effectiveness perspective, statins may now be considered an appropriate therapy for many patients at low risk for heart disease.

Coronary heart disease (CHD) remains the leading cause of death in Germany despite statin use to reduce low-density lipoprotein cholesterol (LDL-C) levels; improving lipids beyond LDL-C may further reduce cardiovascular risk. A fixed-dose combination of extended-release niacin (ERN) with laropiprant (LRPT) provides comprehensive lipid management. We adapted a decision-analytic model to evaluate the economic value (incremental cost-effectiveness ratio [ICER] in terms of costs per life-years gained [LYG]) of ERN/LRPT 2 g over a lifetime in secondary prevention patients in a German setting. Two scenarios were modelled: (1) ERN/LRPT 2 g added to simvastatin 40 mg in patients not at LDL-C goal with simvastatin 40 mg; (2) adding ERN/LRPT 2 g compared with titration to simvastatin 40 mg in patients not at LDL-C goal with simvastatin 20 mg. In both scenarios, adding ERN/LRPT was cost-effective relative to simvastatin monotherapy at a commonly accepted threshold of €30,000 per LYG; ICERs for ERN/LRPT were €13,331 per LYG in scenario 1 and €17,684 per LYG in scenario 2. Subgroup analyses showed that ERN/LRPT was cost-effective in patients with or without diabetes, patients aged ≤65 or >65 years and patients with low baseline high-density lipoprotein cholesterol levels; ICERs ranged from €10,342 to €15,579 in scenario 1, and from €14,081 to €20,462 in scenario 2. In conclusion, comprehensive lipid management with ERN/LRPT 2 g is cost-effective in secondary prevention patients in Germany who have not achieved LDL-C goal with simvastatin monotherapy.

Objective To determine which treatments for preventing coronary heart disease should be offered to which patients by assessing their incremental cost effectiveness.

Design Modelling study

Data sources Cost estimates (for NHS) and estimates of effectiveness obtained for aspirin, antihypertensive drugs, statins and clopidogrel.

Data synthesis Treatment effects were assumed to be independent, and cost per coronary event prevented was calculated for treatments individually and in combination across patients at a range of coronary risks.

Results The most cost effective preventive treatments are aspirin, initial antihypertensive treatment (bendrofluazide and atenolol), and intensive antihypertensive treatment (bendrofluazide, atenolol and enalapril), whereas simvastatin and clopidogrel are the least cost effective (cost per coronary event prevented in a patient at 10% coronary risk over five years is £3500 for aspirin, £12 500 for initial antihypertensives, £18 300 for intensive antihypertensives, £60 000 for clopidogrel, and £61 400 for simvastatin). Aspirin in a patient at 5% five year coronary risk costs less than a fifth as much per event prevented (£7900) as simvastatin in a patient at 30% five year risk (£40 800).

Discussion A cost effective prevention strategy would offer aspirin and initial antihypertensive treatment to all patients at greater than 7.5% five year coronary risk before offering statins or clopidogrel to patients at greater than 15% five year coronary risk. Incremental cost effectiveness analysis of treatments produces robust, practical cost effectiveness rankings that can be used to inform treatment guidelines.

Elderly individuals are at increased risk of coronary heart disease (CHD) and account for a majority of CHD deaths. Several clinical trials have assessed the beneficial effects of statins in individuals with, or at risk of developing, CHD. These trials provide evidence that statins reduce risk and improve clinical outcomes even in older patients; however, statin therapy remains under-utilized among the aged. Atorvastatin has been widely investigated among the older subjects and has the greatest magnitude of favorable effects on clinical outcomes of CHD. The pharmacokinetic properties of atorvastatin allow it to be used every other day, a factor which may decrease adverse events and be especially important in the elderly. The purpose of this article is to review the evidence available from randomized clinical trials regarding the safety and efficacy of atorvastatin in primary and secondary prevention of CHD and stroke in older patients and to discuss issues such as drug interactions, patient compliance and cost-effectiveness, which affect prescription of lipid-lowering therapy among older patients.

Background

Little is known about the cost-effectiveness of secondary prevention after percutaneous coronary intervention (PCI). The aim of this study was to estimate the cost-effectiveness of statin therapy.

Methods

A cost-effectiveness analysis was performed using data from the Lescol Intervention Prevention Study (LIPS). In the LIPS trial, patients with normal-to-moderate hypercholesterolaemia who had undergone a first PCI were randomised to receive either fluvastatin 40 mg twice-daily plus dietary counselling or dietary counselling alone. A Markov model was used to estimate the incremental costs per quality-adjusted life year (QALY) and life year gained (LYG). Costs were based on prices and reimbursed charges, utility data were drawn from literature. Monte Carlo simulations and multivariate analysis were used to assess uncertainty.

Results

Routine statin treatment costs an additional €734 (SD €686) per patient over ten years compared with controls. It resulted in an additional 0.078 (0.047) QALYs or 0.082 (0.041) LYG. The incremental costs per QALY and LYG were €9312 (€14,648) and €8954 (€16,617) respectively. Anticipating a willingness to pay of €20,000 per QALY, there is a 75.1% chance that fluvastatin treatment is cost-effective.

Conclusion

Statin therapy with fluvastatin is economically efficient with regard to reducing heart disease in the Netherlands when given routinely to all patients following PCI.

OBJECTIVE—To assess the cost effectiveness of ramipril treatment in patients at low, medium, and high risk of cardiovascular death.
DESIGN—Population based cost effectiveness analysis from the perspective of the health care provider in the UK. Effectiveness was modelled using data from the HOPE (heart outcome prevention evaluation) trial. The life table method was used to predict mortality in a medium risk cohort, as in the HOPE trial (2.44% annual mortality), and in low and high risk groups (1% and 4.5% annual mortality, respectively).
SETTING—UK population using 1998 government actuary department data.
MAIN OUTCOME MEASURE—Cost per life year gained at five years and lifetime treatment with ramipril.
RESULTS—Cost effectiveness was £36 600, £13 600, and £4000 per life year gained at five years and £5300, £1900, and £100 per life year gained at 20 years (lifetime treatment) in low, medium, and high risk groups, respectively. Cost effectiveness at 20 years remained well below that of haemodialysis (£25 000 per life year gained) over a range of potential drug costs and savings. Treatment of the HOPE population would cost the UK National Health Service (NHS) an additional £360 million but would prevent 12 000 deaths per annum.
CONCLUSIONS—Ramipril is cost effective treatment for cardiovascular risk reduction in patients at medium, high, and low pretreatment risk, with a cost effectiveness comparable with the use of statins. Implementation of ramipril treatment in a medium risk population would result in a major reduction in cardiovascular deaths but would increase annual NHS spending by £360 million.


Keywords: angiotensin converting enzyme inhibitor; cardiovascular risk; cost effectiveness; ramipril

Background:

Although statins have been shown to reduce the risk of cardiovascular events in patients at low cardiovascular risk, their absolute benefit is small in the short term, which may adversely affect cost-effectiveness. We sought to determine the long-term cost-effectiveness (beyond the duration of clinical trials) of low- and high-potency statins in patients at low cardiovascular risk and to estimate the impact on Canada’s publicly funded health care system.

Methods:

Using Markov modelling, we performed a cost-utility analysis in which we compared low-potency statins (fluvastatin, lovastatin, pravastatin and simvastatin) and high-potency statins (atorvastatin and rosuvastatin) with no statins in a simulated cohort of low-risk patients over a lifetime horizon. Model outcomes included costs (in 2010 Canadian dollars), quality-adjusted life-years (QALYs) gained and the cost per QALY gained.

Results:

Over a lifetime horizon, the cost of managing a patient at low cardiovascular risk was estimated to be about $10 100 without statins, $15 200 with low-potency statins and $16 400 with high-potency statins. The cost per QALY gained with high-potency statins (v. no statins) was $21 300; the use of low-potency statins was not considered economically attractive. These results were robust to sensitivity analyses, although their use became economically unattractive when the duration of benefit from statin use was assumed to be less than 10 years.

Interpretation:

Use of high-potency statins in patients at low cardiovascular risk was associated with a cost per QALY gained that was economically attractive by current standards, assuming that the benefit from statin use would continue for at least 10 years. However, the overall expenditure on statins would be substantial, and the ramifications of this practice should be carefully considered by policy-makers.

Ample evidence exists in support of the potent anti-inflammatory properties of statins. In cell studies and animal models statins exert beneficial cardiovascular effects. By inhibiting intracellular isoprenoids formation, statins suppress vascular and myocardial inflammation, favorably modulate vascular and myocardial redox state and improve nitric oxide bioavailability. Randomized clinical trials have demonstrated that further to their lipid lowering effects, statins are useful in the primary and secondary prevention of coronary heart disease (CHD) due to their anti-inflammatory potential. The landmark JUPITER trial suggested that in subjects without CHD, suppression of low-grade inflammation by statins improves clinical outcome. However, recent trials have failed to document any clinical benefit with statins in high risk groups, such in heart failure or chronic kidney disease patients. In this review, we aim to summarize the existing evidence on statins as an anti-inflammatory agent in atherogenesis. We describe the molecular mechanisms responsible for the anti-inflammatory effects of statins, as well as clinical data on the non lipid-lowering, anti-inflammatory effects of statins on cardiovascular outcomes. Lastly, the controversy of the recent large randomized clinical trials and the issue of statin withdrawal are also discussed.

OBJECTIVE--To examine the relative cost effectiveness of a range of screening and intervention strategies for preventing coronary heart disease in primary care. SUBJECTS--7840 patients aged 35-64 years who were participants in a trial of modifying coronary heart disease risk factors in primary care. DESIGN--Effectiveness of interventions assumed and the potential years of life gained estimated from a risk equation calculated from Framingham study data. MAIN OUTCOME MEASURE--The cost per year of life gained. RESULTS--The most cost effective strategy was minimal screening of blood pressure and personal history of vascular disease, which cost 310 pounds-930 pounds per year of life gained for men and 1100 pounds-3460 pounds for women excluding treatment of raised blood pressure. The extra cost per life year gained by adding smoking history to the screening was 400 pounds-6300 pounds in men. All strategies were more cost effective in men than in women and more cost effective in older age groups. Lipid lowering drugs accounted for at least 70% of the estimated costs of all strategies. Cost effectiveness was greatest when drug treatment was limited to those with cholesterol concentrations above 9.5 mmol/l. CONCLUSIONS--Universal screening and intervention strategies are an inefficient approach to reducing the coronary heart disease burden. A basic strategy for screening and intervention, targeted at older men with raised blood pressure and limiting the use of cholesterol lowering drugs to those with very high cholesterol concentrations would be most cost effective.

Background

In a substantial portion of patients (= 25%) with coronary heart disease (CHD), a myocardial infarction or sudden cardiac death without prior symptoms is the first manifestation of disease. The use of new risk predictors for CHD such as the high-sensitivity C-reactive Protein (hs-CRP) in addition to established risk factors could improve prediction of CHD. As a consequence of the altered risk assessment, modified preventive actions could reduce the number of cardiac death and non-fatal myocardial infarction.

Research question

Does the additional information gained through the measurement of hs-CRP in asymptomatic patients lead to a clinically relevant improvement in risk prediction as compared to risk prediction based on traditional risk factors and is this cost-effective?

Methods

A literature search of the electronic databases of the German Institute of Medical Documentation and Information (DIMDI) was conducted. Selection, data extraction, assessment of the study-quality and synthesis of information was conducted according to the methods of evidence-based medicine.

Results

Eight publications about predictive value, one publication on the clinical efficacy and three health-economic evaluations were included. In the seven study populations of the prediction studies, elevated CRP-levels were almost always associated with a higher risk of cardiovascular events and non-fatal myocardial infarctions or cardiac death and severe cardiovascular events. The effect estimates (odds ratio (OR), relative risk (RR), hazard ratio (HR)), once adjusted for traditional risk factors, demonstrated a moderate, independent association between hs-CRP and cardiac and cardiovascular events that fell in the range of 0.7 to 2.47. In six of the seven studies, a moderate increase in the area under the curve (AUC) could be detected by adding hs-CRP as a predictor to regression models in addition to established risk factors though in three cases this was not statistically significant. The difference [in the AUC] between the models with and without hs-CRP fell between 0.00 and 0.023 with a median of 0.003. A decision-analytic modeling study reported a gain in life-expectancy for those using statin therapy for populations with elevated hs-CRP levels and normal lipid levels as compared to statin therapy for those with elevated lipid levels (approximately 6.6 months gain in life-expectancy for 58 year olds). Two decision-analytic models (three publications) on cost-effectiveness reported incremental cost-effectiveness ratios between Euro 8,700 and 50,000 per life year gained for the German context and between 52,000 and 708,000 for the US context. The empirical input data for the model is highly uncertain.

Conclusion

No sufficient evidence is available to support the notion that hs-CRP-values should be measured during the global risk assessment for CAD or cardiovascular disease in addition to the traditional risk factors. The additional measurement of the hs-CRP-level increases the incremental predictive value of the risk prediction. It has not yet been clarified whether this increase is clinically relevant resulting in reduction of cardiovascular morbidity and mortality.

For people with medium cardiovascular risk (5 to 20% in ten years) additional measurement of hs-CRP seems most likely to be clinical relevant to support the decision as to whether or not additional statin therapy should be initiated for primary prevention.

Statin therapy can reduce the occurrence of cardiovascular events for asymptomatic individuals with normal lipid and elevated hs-CRP levels. However, this is not enough to provide evidence for a clinical benefit of hs-CRP-screening. The cost-effectiveness of general hs-CRP-screening as well as screening among only those with normal lipid levels remains unknown at present.

Background

Aspirin reduces myocardial infarction but increases gastrointestinal bleeding. Proton pump inhibitors (PPIs) may reduce upper gastrointestinal bleed. We estimate the cost-utility of aspirin treatment with or without PPI for coronary heart disease (CHD) prevention among men at different risks for CHD and gastrointestinal bleed.

Methods

We updated a Markov model to compare costs and outcomes of low-dose aspirin+PPI (omeprazole 20-mg daily), low-dose aspirin alone, or no treatment for CHD prevention. We performed lifetime analyses in men with different risks for cardiovascular events and gastrointestinal bleed. Aspirin reduced nonfatal myocardial infarction by 30%, increased total stroke by 6%, and increased gastrointestinal bleed risk 2-fold. Adding PPI reduced upper gastrointestinal bleed by 80%. Annual aspirin cost was $13.99; generic PPI was $200.

Results

In 45-year-old men with 10-year CHD risk of 10% and 0.8/1,000 annual gastrointestinal bleed risk, aspirin ($17,571 and 18.67 quality-adjusted life years [QALYs]) was more effective and less costly than no treatment ($18,483 and 18.44 QALYs). Compared with aspirin alone, aspirin+PPI ($21,037 and 18.68 QALYs) had an incremental cost/QALY of $447,077. Results were similar in 55- and 65-year-old men. The incremental cost/QALY of adding PPI was less than $50,000/QALY at annual gastrointestinal bleed probabilities greater than 4–6/1,000.

Conclusion

Aspirin for CHD prevention is less costly and more effective than no treatment in men over 45 with greater than 10-year, 10% CHD risks. Adding PPI is not cost-effective for men with average gastrointestinal bleed risk but may be cost-effective for selected men at increased risk for gastrointestinal bleed.

Background

High homocysteine blood concentrations predispose to coronary artery disease and statins influence homocysteine levels.

Aim

To study whether genes that regulate homocysteine metabolism interact with statins to modify the risk of CHD and other cardiovascular outcomes.

Methods

GenHAT is an ancillary study of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The genotyped population in the lipid lowering trial (LLT) of ALLHAT included 9,624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality and CHD was compared among genotype strata (MTHFR 677 CC, CT and TT, MTHFR 1298 AA, AC, and CC, CBSins DD and I+) by examining an interaction term in a proportional hazards model.

Results

There was no evidence of a pharmacogenetic effect on statins with the MTHFR 1298 A>C genotype for CHD risk. However, in persons with the CC variant for the MTHFR 677 C>T genotype a significantly protective effect against CHD (0.71 (95% CI 0.58–0.87)) was shown. While in the CT (1.25 (95% CI 0.97–1.61) and TT groups (0.80 (95% CI 0.50–1.28) there were no such effects (interaction hazard ratio p=0.004) The CBSins, I+ variant was associated with a significantly reduced risk for CHD among those on statin treatment (0.58 (95% CI 0.44–0.78)) while the DD genotype showed no effect from statin therapy (1.01 (95% CI 0.84–1.20; p=0.002 for interaction). For the endpoint all-cause mortality, no significant differences in efficacy were noted.

Conclusions

Polymorphisms in genes in the homocysteine pathway (MTHFR 677 C>T and CBSins) appear to modify the efficacy of pravastatin in reducing risk of cardiovascular events.

Objective: To assess whether the extent of primary and secondary coronary heart disease (CHD) prevention in older British men and women differs between patients with and without diabetes.

Design: Two prospective cardiovascular cohort studies.

Setting: 24 British towns.

Patients: 4252 men and 4286 women aged 60–79 years examined between 1998 and 2001.

Main outcome measures: Use of aspirin, statin, and blood pressure lowering treatment and risk factor control, examined by diabetic status and history of established CHD.

Results: About 20% of the men and 12% of the women had established CHD at age 60–79 years and 7% of the men and 5% of the women had diabetes. In primary CHD prevention, patients with diabetes were more likely to receive CHD risk reducing medications than those without diabetes, but the proportions receiving preventive treatments in both groups were low. In secondary prevention, diabetic and non-diabetic patients received similar levels of treatment, with the exception of angiotensin converting enzyme inhibitors and (for women only) blood pressure lowering treatment, which were more widely used among diabetic patients. There were no clear differences in blood pressure control or cigarette smoking by diabetic status in primary or secondary prevention. Mean total cholesterol concentrations were lower in diabetic patients independently of treatment with statins.

Conclusions: Despite their exceptionally high CHD risk, many opportunities to reduce CHD risk among patients with diabetes have not been taken.

Background

Little is known about the potential of statin-induced high-density lipoprotein cholesterol (HDL-C) increase to improve renal function in coronary heart disease (CHD) patients.

Methods and Results

In thispost hocanalysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study we investigated the effect of HDL-C increase after statin treatment on renal function. From a total of 1,600 patients, 880 were on various statins (mainly atorvastatin) and 720 were not. Other secondary prevention therapies were similar in the 2 groups. After a 3 year follow up, the lipid profile was unchanged in the statin untreated group and estimated glomerular filtration rate (eGFR) was reduced by 5.1% compared with baseline (P<0.0001). In contrast, in the statin treated group non-HDL-C was reduced by 43%, HDL-C was increased by 7% and there was a significant increase in eGFR compared with baseline by 9.8% (P<0.0001). In multiple regression analysis, the mean 7% increase in HDL-C in the treated arm during the entire study was associated with a 5.6% increase in eGFR recorded after the 6th week of treatment. The odds ratio of eGFR increase with every 5% statin-induced rise in HDL-C was 1.78 (95% confidence interval 1.19-3.34; P=0.001).

Conclusions

Statin treatment significantly improved renal function. Statin-induced HDL-C increase significantly and independently contributed to this improvement. This finding supports the concept that improving lipid variables other than low density lipoprotein cholesterol is also beneficial to preserving renal function.

Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins.

SYNOPSIS

BACKGROUND

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.

OBJECTIVE

To evaluate the effect of statin interruption on clinical outcome in patients discharged after an acute ischemic stroke.

DESIGN AND INTERVENTION

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.

OUTCOME MEASURES

The primary end point was death from any cause within 12 months of discharge.

RESULTS

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.

CONCLUSION

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.

OBJECTIVE—To determine the proportion of the population, firstly, with cholesterol ⩾ 5.0 mmol/l and, secondly, with any cholesterol concentration, who might benefit from statin treatment for the following: secondary prevention of coronary heart disease (CHD); primary prevention at CHD risk 30%, 20%, 15%, and 6% over 10 years; and primary prevention at projected CHD risk 20% over 10 years (CHD risk at age 60 years if actual age < 60 years).
SUBJECTS—Random stratified sample of 3963 subjects aged 35-64 years from the Scottish health survey 1995.
RESULTS—For secondary prevention 7.8% (95% confidence interval (CI) 6.9% to 8.6%) of the population with cholesterol ⩾ 5.0 mmol/l would benefit from statins. For primary prevention, the prevalence of people at CHD risk 30%, 20%, 15%, and 6% over 10 years is 1.5% (95% CI 1.2% to 1.9%), 5.4% (95% CI 4.7% to 6.1%), 9.7% (95% CI 8.8% to 10.6%), and 32.9% (95% CI 31.5% to 34.4%), respectively. At projected CHD risk 20% over 10 years, 12.4% (95% CI 11.4% to 13.5%) would be treated with statins. Removing the 5.0 mmol/l cholesterol threshold makes little difference to population prevalence at high CHD risk.
CONCLUSIONS—Statin treatment would be required for 7.8% of the population for secondary prevention. For primary prevention, among other factors, guidelines should take into account the number of patients needing treatment at different levels of CHD risk when choosing the CHD risk to target. The analysis supports a policy of targeting treatment at CHD risk 30% over 10 years as a minimum, as recommended in current British guidelines, with a move to treating at CHD risk 15% over 10 years as resources permit.


Keywords: statins; coronary risk; secondary prevention; primary prevention

Background

Coronary heart disease (CHD) is a common and potentially fatal malady with a life time prevalence of over 20%. For Germany, the mortality attributable to chronic ischemic heart disease or acute myocardial infarction is estimated at 140,000 deaths per year. An association between prognosis of CHD and lifestyle risk factors has been consistently shown. To positively influence lifestyle risk factors in patients with CHD, non-pharmaceutical secondary prevention strategies are frequently recommended and implemented.

Objectives

The aim of this HTA (HTA = Health Technology Assessment) is to summarise the current literature on strategies for non-pharmaceutical secondary prevention in patients with CHD and to evaluate their medical effectiveness/efficacy and cost-effectiveness as well as the ethical, social and legal implications. In addition, this report aims to compare the effectiveness and efficacy of different intervention components and to evaluate the generalisability with regard to the German context.

Methods

Relevant publications were identified by means of a structured search of databases accessed through the German Institute of Medical Documentation and Information (DIMDI). In addition, a manual search of identified reference lists was conducted. The present report includes German and English literature published between January 2003 and September 2008 targeting adults with CHD. The methodological quality of included studies was assessed according to pre-defined quality criteria, based on the criteria of evidence based medicine.

Results

Among 9,074 publications 43 medical publications met the inclusion criteria. Overall study quality is satisfactory, but only half the studies report overall mortality or cardiac mortality as an outcome, while the remaining studies report less reliable outcome parameters. The follow-up duration varies between twelve and 120 months. Although overall effectiveness of non-pharmaceutical secondary prevention programs shows considerable heterogeneity, there is evidence for the long-term effectiveness concerning mortality, recurrent cardiac events and quality of life. Interventions based on exercise and also multicomponent interventions report more conclusive evidence for reducing mortality, while interventions focusing on psychosocial risk factors seem to be more effective in improving quality of life. Only two studies from Germany fulfill the methodological criteria and are included in this report.

Additionally, 25 economic publications met the inclusion criteria. Both, quantity and quality of publications dealing with combined interventions are higher compared with those investigating single component interventions. However, there are difficulties in transferring the international results into the German health care system, because of its specific structure of the rehabilitation system. While international literature mostly shows a positive cost-effectiveness ratio of combined programs, almost without exception, studies investigate out-of hospital or home-based programs. The examination of publications evaluating the cost-effectiveness of single interventions merely shows a positive trend of exercise-based and smoking cessation programs. Due to a lack of appropriate studies, no conclusive evidence regarding psychosocial and dietary interventions is available.

Altogether eleven publications concerned with ethical or social issues of non-pharmacological secondary prevention strategies are included. These studies are relatively confirm the assumption that patients with a lower socioeconomic background reflect a population at increased risk and therefore have specific needs to participate in rehabilitation programs. However, there currently remains uncertainty, whether these patients participate in rehabilitation more or less often. As barriers, which deter patients from attending, aspects like a lack of motivation, family commitments or the distance between home and rehabilitation centres are identified. Psychological factors like anxiety, depression and uncertainty as well as physical constraints are also pointed out.

Discussion

Non-pharmacological secondary preventive strategies are safe and effective in improving mortality, morbidity and quality of life in patients with CHD. Because of the small number of reliable studies with long term follow up over 60 months, sustainability of observed intervention effects has to be regarded with caution. Due to a lack of suitable studies, it was not possible to determine the effectiveness of interventions in important patient subgroups as well as the comparative effectiveness of different intervention strategies, conclusively. Future research should, amongst others, attempt to investigate these questions in methodologically rigorous studies.

With regard to the cost-effectiveness of non-pharmacological interventions, overall, international studies show positive results. However, there are considerable limitations due to the qualitative and quantitative deficiencies of identified studies. The special characteristics of the German rehabilitation system with its primarily inpatient offers result in further difficulties, when trying to transfer international study results to the German health care system. Both, studies demonstrating the cost-effectiveness of inpatient programs and those investigating the cost-effectiveness of single interventions are currently not available. To examine the German rehabilitation programs concerning their efficiency and their potential for optimisation, there is a need for further research.

Concerning social and ethical issues, a lack of studies addressing the structure of rehabilitation participants in Germany is striking. The same applies to studies examining the reasons for none participation in non-pharmacological secondary prevention programs. Evidence regarding these questions would provide an informative basis for optimising rehabilitation programs in Germany.

Conclusion

Non-pharmacological secondary prevention interventions are safe and able to reduce mortality from CHD and cardiac events, as well as to imporve patient’s quality of life. Nevertheless, there is considerable need for research; especially the effectiveness of interventions for important subgroups of CHD patients has to be evaluated. In addition to intervention effectiveness, there is also some evidence that interventions generate an appropriate cost-effectiveness ratio. However, future research should investigate this further. The same applies to the sustainability of secondary prevention programs and patient’s reasons for not attending them.

Objectives

This report aimed to evaluate the calculation of estimates of effectiveness in cost effectiveness analyses of statins for cardiovascular disease prevention.

Methods

Methodological aspects were reviewed of seven primary studies (based on trial results) and 12 secondary modelling studies (extrapolated) on the cost effectiveness of statin treatment, published between 1995 and 2002. Estimates of life years gained were extracted and compared with estimates calculated using the Dutch male life table of 1996–2000.

Results

Of the seven primary modelling analyses, six showed all the essential data. They estimated that 3 to 5.6 years (average 4.6 years) of statin treatment resulted in 0.15 to 0.41 years (average 0.3 years) saved over a lifetime time horizon. In contrast none of the 12 secondary modelling studies provided transparent results. They assumed lifelong treatment, leading to life table estimations of 2.4 and 2.0 (undiscounted) years saved for 40 and 60 year olds, with peak savings at around the mean age of death: 75–80 years. With 5% discounting, these effects reduced to 0.4 and 0.8 years respectively.

Conclusion

Reporting of essential data and assumptions on statin treatment was poor for secondary modelling analyses and satisfactory for primary modelling studies. Secondary modeling studies made assumptions on long term effectiveness that were hard to justify with the available evidence, and that led to the majority of life years saved at high ages. Further standardisation in economic analyses is important to guarantee transparency and reproducibility of results.

OBJECTIVES--To provide a commentary on the economic evaluations of the Oxcheck and British family heart studies: direct comparison of their relative effectiveness and cost effectiveness; comparisons with other interventions; and consideration of problems encountered. DESIGN--Modelling from cost and effectiveness data to estimate of cost per life year gained. SUBJECTS--Middle aged men and women. INTERVENTIONS--Screening for cardiovascular risk factors followed by appropriate lifestyle advice and drug intervention in general practice, and other primary coronary risk management strategies. MAIN OUTCOME MEASURES--Life years gained; cost per life year gained. RESULTS--Depending on the assumed duration of risk reduction, the programme cost per discounted life year gained ranged from 34,800 pounds for a 1 year duration to 1500 pounds for 20 years for the British family heart study and from 29,300 pounds to 900 pounds for Oxcheck. These figures exclude broader net clinical and cost effects and longer term clinical and cost effects other than coronary mortality. CONCLUSIONS--Despite differences in underlying methods, the estimates in the two economic analyses of the studies can be directly compared. Neither study was large enough to provide precise estimates of the overall net cost. Modelling to cost per life year gained provides more readily interpretable measures. These estimates emphasise the importance of the relatively weak evidence on duration effect. Only if the effect lasts at least five years is the Oxcheck programme likely to be cost effective. The effect must last for about 10 years to justify the extra cost associated with the British family heart study.

Cardiovascular disease and renal disease have a close relationship that forms a vicious cycle as a cardiorenal syndrome (CRS). Oxidative stress, endothelial dysfunction, and vascular inflammation could be therapeutic targets when the renin-angiotensin-aldosterone system is activated by accumulation of conventional cardiovascular risk factors; however, a strategy for management of CRS has not been established yet. Statins, HMG-CoA reductase inhibitors, have not only cholesterol-lowering effects but also pleiotropic effects on cardiovascular systems, including anti-inflammatory and antioxidant effects and improvement of nitric oxide bioavailability. Since recent studies have indicated that statins have beneficial effects on chronic kidney disease and heart failure as well as coronary artery disease in cholesterol-lowering-dependent/independent manners, treatment with statins might be a successful strategy for preventing deterioration of CRS.

Background

Pharmacogenetic research has shown that genetic variation may influence statin responsiveness. Statins exert a variety of beneficial effects beyond lipid lowering, including antithrombotic effects, which contribute to the risk reduction of cardiovascular disease. Statins have been shown to influence the expression of coagulation factors II, V, VII, XII and XIII.

AimData from a large randomized clinical trial of pravastatin, designed to show efficacy relative to usual care, were used to investigate whether a pharmacogenetic effect of polymorphisms in genes coding for coagulation factors II, V, VII, XII and XIII is associated with reduced fatal coronary heart disease (CHD) and nonfatal myocardial infarction, combined CHD and all-cause mortality.

Methods

The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. The genotyped population in the lipid-lowering trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality, CHD plus nonfatal myocardial infarction and combined CHD, was compared among genotype strata by examining an interaction term in a proportional hazards modelAQ2.

Results

None of the polymorphisms were associated with the clinical outcomes. For the F7 (−323) del/ins polymorphism there was no interaction with pravastatin for either outcome. For both the F5 Arg506Gln G>A (rs6025) polymorphism and F7 Arg353Gln G>A (rs6046) polymorphism there were no interactions with pravastatin in relation to all-cause mortality, but there were significant interactions with combined CHD [interaction hazard ratioλ=λ1.33, 95% confidence interval (1.01−1.76) and interaction hazard ratioλ=λ1.92, 95% confidence interval (1.00−3.65), respectively]AQ3. There were no interactions between the polymorphisms in the other coagulation genes and pravastatin in relation to any outcome.

Conclusion

Polymorphisms in anticoagulation genes (F5 and F7) seem to modify the efficacy of pravastatin in reducing risk of cardiovascular events.