Trials Of Statins For Prevention Research Articles

Statin Exposure and Risk of Heart Failure After Anthracycline- or Trastuzumab-Based Chemotherapy for Early Breast Cancer: A Propensity Score‒Matched Cohort Study.

BackgroundStatins are hypothesized to reduce the risk of cardiotoxicity associated with anthracyclines and trastuzumab. Our aim was to study the association of statin exposure with hospitalization or emergency department visits (hospital presentations) for heart failure (HF) after anthracycline‐ and/or trastuzumab‐containing chemotherapy for early breast cancer.Methods and ResultsUsing linked administrative databases, we conducted a retrospective cohort study of women aged ≥66 years without prior HF who received anthracyclines or trastuzumab for newly diagnosed early breast cancer in Ontario between 2007 to 2017. Statin‐exposed and unexposed women were matched 1:1 using propensity scores. Trastuzumab‐treated women were also matched on anthracycline exposure. We matched 666 statin‐discordant pairs of anthracycline‐treated women and 390 pairs of trastuzumab‐treated women (median age, 69 and 71 years, respectively). The 5‐year cumulative incidence of HF hospital presentations after anthracyclines was 1.2% (95% CI, 0.5%–2.6%) in statin‐exposed women and 2.9% (95% CI, 1.7%–4.6%) in unexposed women (P value, 0.01). The cause‐specific hazard ratio associated with statins in the anthracycline cohort was 0.45 (95% CI, 0.24–0.85; P value, 0.01). After trastuzumab, the 5‐year cumulative incidence of HF hospital presentations was 2.7% (95% CI, 1.2%–5.2%) in statin‐exposed women and 3.7% (95% CI, 2.0%–6.2%) in unexposed women (P value 0.09). The cause‐specific hazard ratio associated with statins in the trastuzumab cohort was 0.46 (95% CI, 0.20–1.07; P value, 0.07).ConclusionsStatin‐exposed women had a lower risk of HF hospital presentations after early breast cancer chemotherapy involving anthracyclines, with non‐significant trends towards lower risk following trastuzumab. These findings support the development of randomized controlled trials of statins for prevention of cardiotoxicity.

Effectiveness of Lipid-Lowering Statin Therapy in Patients With and Without Psoriasis.

Psoriasis is associated with dyslipidemia and metabolic syndrome, and has been linked to an increased cardiovascular risk. The aim of this study was to compare baseline characteristics and effects of statin therapy on lipid levels and cardiovascular outcomes in patients with and without psoriasis. This post-hoc analysis assessed patients from one primary cardiovascular prevention statin trial (Collaborative AtoRvastatin Diabetes Study [CARDS]) and two secondary cardiovascular prevention statin trials (Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL]). Baseline characteristics, lipid changes from baseline, and cardiovascular event rates were analyzed. TNT and IDEAL data were pooled. Baseline characteristics and lipid profiles differed minimally in patients with and without psoriasis. In CARDS and TNT/IDEAL, similar apolipoprotein B, total cholesterol, and low-density lipoprotein cholesterol reductions occurred with statin therapy in patients with or without psoriasis. High-dose atorvastatin significantly reduced cardiovascular events vs. standard/low-dose statins in patients without psoriasis in TNT/IDEAL; similar numeric differences in event rates were observed in patients with psoriasis. In this post-hoc analysis, statins improved lipid levels and cardiovascular outcomes in patients with and without psoriasis, supporting statin use in patients with psoriasis. Trial registration (ClinicalTrials.gov) NCT00327418, registered 16 May, 2006; NCT00327691, registered 16 May, 2006; NCT00159835, registered 8 September, 2005.

PRM65 - An Evaluation Of Competing Models For Predicting Cv Event Rates From Ldl-C Levels In Secondary Prevention

This study aims to evaluate four alternative models that each describe the relationship between LDL-C and CV event rates in secondary prevention. A secondary aim of this analysis is to promote an approach to develop more reliable disease simulation models in cardiovascular disease. Data describing LDL-C and nfMI+CV Death outcomes were abstracted from several landmark secondary prevention statin trials in clinically stable patient populations (4S, CARE, LIPID, HPS, TNT, IDEAL, GREACE, AVERT, and LIPS). Linear (L), quadratic (Q), one-knot linear spline (S1L) and two-knot quadratic spline (S2Q) models were fit. RMSE, leave-one-out cross validated (LOOCV) and Monte Carlo cross validated (MCCV) RMSE (90% training, 1,000 replicates) were used to evaluate predictive performance. Predicted event rates based on LDL-C = 50mg/dL were estimated to illustrate the clinical implications of each model. To encourage full reproducibility and transparency, all raw data and code (R) will be made freely available for download online via authors Git repository. A total of eight models were fit and evaluated, including four distinct functional forms (L, Q, S1L, and S2Q) across two sets of data (all data (A) and data censured for high leverage studies(C)). Of all the models evaluated, S2Q-C exhibited the lowest RMSE (0.317) while L-C produced both the lowest LOOCVRMSE (0.463) and MCCVRMSE (0.389). Model selection had an impact on predicted percentage of events/yr at 50mg/dL (range= 0.769 to 2.09). This analysis suggests that a linear model may be among the most appropriate when describing the relationship between LDL and nfMI+CV Death in secondary prevention; however, other models (linear spline and quadratic) warrant further investigation. These findings along with additional research will help inform more reliable and accurate models of long-term outcomes and economic benefit of LDL-C lowering treatment modalities.

Accumulating Evidence for Statins in Primary Prevention

Many voices in the public and themedical community argue strongly against thewidespreaduse of statins for the primary prevention of atherosclerotic cardiovascular disease. Critics give several reasons to avoid statin therapy, including concerns about adverse effects, lack of a total mortality benefit, cost, and a philosophical aversion to drug therapy. However, the passage of time has allowed sufficient evidence to accumulate to refute each of these concerns. Meta-analyses now provide extensive evidence that statins reduce cardiovascular events and totalmortality in individuals at lower risk of cardiovascular events than has previously been appreciated, and do sowith an excellentmargin of safety.1-3 In this issue of JAMA, Taylorandcolleagues4 provide a summary of the 2013Cochrane2meta-analysis (anupdatedversionof the2011Cochranemeta-analysison this topic3) of 18 primary prevention statin trials including 56 934 participants. The authors report that statins significantly reduce all-causemortality (−14%), fatal andnonfatal cardiovascular disease (−22%), coronary heart disease (−27%), stroke (−22%), and coronary revascularization (−38%). These risk reduction benefits occurred in the absence of an increased risk of cancer, myalgia, rhabdomyolysis, liver enzyme elevation, renal dysfunction, or arthritis. Importantly,participants treatedwithstatinswerenomore likely to discontinue treatment than the placebo group (12%). This means that the adverse event rates were similar in both statin and placebo/control groups, and not just an artifact of thosewith adverse effectswho stopped the statin. Only newonset diabetes was observed to occur frequently in the statin group, consistentwith anothermeta-analysis of statin trials.5 The 2013 Cochrane meta-analysis was reviewed as part of theevidence-base for the recently released2013AmericanCollegeofCardiologyandAmericanHeartAssociationguidelineon thetreatmentofbloodcholesterol topreventatheroscleroticcardiovascular disease in adults.6 The 2013 cholesterol guideline was the result of a rigorous systematic review of higherquality randomized trials, and systematic reviews and metaanalysesof randomized trialsofdrug therapy to reduceatherosclerotic cardiovascular disease events. The 2010 and 2012 Cholesterol Treatment Trialists (CTT) individual-level metaanalyses of statin trials and the individual primary prevention trialswerealso included in theguidelineevidence review.7The guideline recommends moderateor high-intensity statin therapy for the primary prevention of atherosclerotic cardiovasculardisease in individualswith7.5%orgreater 10-yearatherosclerotic cardiovascular disease risk based on strong evidence that the reduction in atherosclerotic cardiovascular disease events outweighs the potential for adverse effects (includingnew-onsetdiabetes).6Moderate-intensitystatintherapy canbeconsidered in individualswith5%to lower than7.5%10yearatheroscleroticcardiovasculardiseaserisk.Thesecutpoints are indeed lower than were recommended in the Adult Treatment Panel III update8 and are consistent with the findings in the 2013 Cochranemeta-analysis. Notably, the2013cholesterolguidelinecutpointswerederived fromtheplacebo rates formyocardial infarction, stroke, and cardiovascular disease death observed in the 3 exclusively primary prevention statin trials, Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, and the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).9-11 Subsequent to the initial development of the 2013 cholesterol guidelineprimarypreventionrecommendations, the2012CTT individual-levelmeta-analysisconfirmedthereduction incardiovascular disease events, as well as in total mortality, from statin therapy used in low-risk individuals.1 Indeed, the 2012 CTTmeta-analysis foundagreater reduction intherelativerisk ofmajor cardiovascular disease events (including revascularizations) inthosewithalowerthan10%5-yearriskthaninthose with 10% or higher 5-year risk. To guide the decision to initiate a statin for primary prevention, the 2013 cholesterol guideline used estimated 10year atherosclerotic cardiovasculardisease risk (definedas the first of “hard” events of nonfatalmyocardial infarction, coronaryheart diseasedeath, and fatal andnonfatal stroke, not including revascularization).6 Rates of revascularization are roughly equivalent to the rates of myocardial infarction and stroke,7 so theguideline cutpoints of 7.5%and5%10-year atherosclerotic cardiovascular disease risk roughly correspond to 15% and 10% 10-year combined event rates (including revascularizations), respectively, in the 2013 Cochrane evidence synopsis.4 In contrast to the 2013 Cochrane trial-level meta-analysis of 18 primaryprevention trials, theCTT individual-levelmetaanalysisof28primaryandsecondarypreventionstatin trialsdid findavery slightly increased riskof seriousmyopathy, rhabdomyolysis, andhemorrhagicstroke instatin-treated individuals.1 These findings do not alter the atherosclerotic cardiovascular diseasebenefit-adverseeffect considerationsused for the2013 cholesterol guideline primary prevention recommendations.5 The guideline further notesmuscle complaints are common in patientswhoaretreated,aswellas thosewhoareuntreated,and it is difficult to determine whether those symptoms are related to statin treatment without a rechallenge. Thus, a manRelated article page 2451 Opinion

The Role of Atherosclerosis Imaging in Redefining Normal and Abnormal Cholesterol Values, and Risk Reduction in Primary Prevention Statin Trials

The emergence of atherosclerosis imaging, using coronary calcium scanning (CAC) and carotid intima media thickness (CIMT) and plaque as stronger predictors of cardiovascular events than risk factors of atherosclerosis, has created a paradigm shift in the primary prevention of cardiovascular disease. Rather than population-derived indices to define normal or abnormal low-density lipoprotein (or other lipid values) in the untreated individual patient, it is more appropriate to define "normal" as "cholesterol values at which level there is no subclinical atherosclerosis" and "abnormal" as "cholesterol values at which level there is subclinical atherosclerosis," with the severity of "abnormal" depending on the degree of subclinical atherosclerosis. Similarly, the low-density lipoprotein treatment goal is the level at which atherosclerosis progression is halted. Extension of the subclinical atherosclerosis risk-based paradigms to primary prevention trials dramatically changes the manner in which trials should be conducted in the future, as well as the results of trials already performed. For example, asymptomatic patients with a CAC score of 0 have an extraordinarily low event rate but have been included in primary prevention statin trials even though their risk without treatment is very small. Reanalysis of the statin primary prevention trials after excluding the percentage (40%) of patients who would be expected to have a CAC score of 0 yields an absolute risk increase of 60% in both the placebo group (from 5.4% to 8.5%), and the statin group (from 3.0% to 4.8%). Absolute risk reduction increased by 58% (from 2.4% to 3.8%). Relative risk reduction of 44% was unchanged. In conclusion, 1) the presence or absence of atherosclerosis as measured by CAC redefines normal or abnormal lipid levels in an individual patient; 2) statin absolute risk reduction is significantly greater than previously appreciated; and 3) patients with a CAC score of 0 should be excluded from primary prevention randomized controlled trials.

Statins for the Primary Prevention of Cardiovascular Events in Women With Elevated High-Sensitivity C-Reactive Protein or Dyslipidemia

Background— Statin therapy in women without cardiovascular disease (CVD) is controversial, given the insufficient evidence of benefit. We analyzed sex-specific outcomes in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and synthesized the results with prior trials. Methods and Results— JUPITER participants included 6801 women ≥60 years of age and 11 001 men ≥50 years of age with high-sensitivity C-reactive protein ≥2 mg/L and low-density lipoprotein cholesterol <130 mg/dL randomized to rosuvastatin versus placebo. Meta-analysis studies were randomized placebo-controlled statin trials with predominantly or exclusively primary prevention in women and sex-specific outcomes (20 147 women; >276 CVD events; mean age, 63 to 69 years). Absolute CVD rates (per 100 person-years) in JUPITER women for rosuvastatin and placebo (0.57 and 1.04, respectively) were lower than for men (0.88 and 1.54, respectively), with similar relative risk reduction in women (hazard ratio, 0.54; 95% confidence interval, 0.37 to 0.80; P =0.002) and men (hazard ratio, 0.58; 95% confidence interval, 0.45 to 0.73; P <0.001). In women, there was significant reduction in revascularization/unstable angina and nonsignificant reductions in other components of the primary end point. Meta-analysis of 13 154 women (240 CVD events; 216 total deaths) from exclusively primary prevention trials found a significant reduction in primary CVD events with statins by a third (relative risk, 0.63; 95% confidence interval, 0.49 to 0.82; P <0.001; P for heterogeneity=0.56) with a smaller nonsignificant effect on total mortality (relative risk, 0.78; 95% confidence interval, 0.53 to 1.15; P =0.21; P for heterogeneity=0.20). Similar results were obtained for trials that were predominantly but not exclusively primary prevention. Conclusion— JUPITER demonstrated that in primary prevention rosuvastatin reduced CVD events in women with a relative risk reduction similar to that in men, a finding supported by meta-analysis of primary prevention statin trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Questioning Conventional Wisdom

In science, what seems obvious may not be true, and what is accepted as conventional wisdom, may sometimes be based on flawed assumptions. What is more obvious than the fact that the sun revolves around the earth? Each day the sun rises in the eastern horizon, and we observe it moving across the sky until it retires in the west. And yet, it is not true that the earth is the center of the universe. Galileo de’ Galilei, the scientist born in Pisa, was persecuted for questioning such conventional wisdom and supporting the theory proposed by Nicolaus Copernicus of a heliocentric universe. Ultimately, the truth could not be suppressed. We have many examples of progress that resulted from the questioning of strongly held beliefs that once seemed so obvious. Who anticipated that a gastric ulcer could be considered an infectious disease?1 Who expected that drugs that effectively suppressed premature ventricular beats in patients with ischemic heart disease would cause harm?2 Who believed that treatment strategies associated with substantial risk reduction might be poorly adopted into practice even 10 years after the publication of the trials establishing their efficacy?3 Who could …

“Risky Business”

Nobody can go back and start a new beginning, but anyone can start today and make a new ending. — —Maria Robinson Although the Framingham Risk Score forms the bedrock of coronary heart disease (CHD) risk prediction, it has several limitations that have been well documented.1 The clinician is left to manage a significant proportion of patients who have “low to intermediate” estimated risk but accrue the majority of CHD events because they form the majority (≈65%) of the population. Article p 382 To address these deficiencies in the prediction of risk, several investigators have included other markers of risk such as biomarkers related to inflammation, genotypes, or imaging tests with traditional risk factors to improve CHD risk prediction. These analyses have resulted in the creation of novel risk-prediction schemes such as the Reynolds risk score, which added family history and high-sensitivity C-reactive protein (hs-CRP) to blood pressure, smoking, total and high-density lipoprotein cholesterol, and hemoglobin A1C to predict risk.2 However, whether algorithms have used biomarkers such as hs-CRP, imaging tests such as coronary calcium score or carotid intima-media thickness, or novel genotypes such as the single-nucleotide polymorphism on chromosome 9p21, the improvements in risk prediction have been modest. Other investigators have suggested that anybody who is not at very low risk should get an imaging test to further stratify risk.3 On the other hand, there have been efforts to identify the “lifetime risk” of CHD for individuals in various age groups. The concept of lifetime risk was highlighted in the National Cholesterol Education Program Adult Treatment Panel (ATP) III guidelines4 and is an important one, especially for individuals who are young to middle-aged. Traditional risk factors become manifest more often in the 4th and 5th decades of life when the estimated lifespan based on …

Statins for the Prevention of First or Recurrent Stroke

This review considers the evidence showing that statins can prevent first or recurrent stroke or improve its outcome in subjects at moderate or high risk for cardiovascular disease (CVD). Data are reviewed according to trial design (observational or prospective) and baseline CVD risk. Two (ASCOT, CARDS) out of five primary CVD prevention statin trials showed a considerable reduction in stroke rates. In two (MIRACL and PROVE IT) out of five acute coronary syndrome trials, the prevention of first stroke was significant. Most secondary prevention trials (4S, CARE, LIPID, HPS, GREACE and TNT) showed a beneficial effect of statins in stroke prevention. Finally, SPARCL, the only secondary stroke prevention trial in subjects without overt coronary heart disease (CHD), showed a significant reduction in total and ischaemic (fatal and nonfatal) stroke rate, although a small but significant increase in nonfatal haemorrhagic stroke was noted. There was also a significant reduction in CHD-related events. The possible mechanisms responsible for statin-associated stroke prevention are discussed. The evidence suggests the need to consider early and long-term statin treatment (with substantial low-density lipoprotein cholesterol reduction) in all patients at high risk of any type of major vascular event, without discriminating CHD from stroke. Thus, statins may be beneficial to both the heart and the brain.

Panel discussion

Presented is a report of a panel discussion held as part of the ISA 2006 Sankyo Forum titled "A Trilogy of Primary Prevention Statin Trials--The Impact of These Landmark Studies on Clinical Practice," Rome, Italy, June 2006. The themes of the panel discussion were the design features of three trials, WOSCOPS, AFCAPS/TexCAPS, and Japan's MEGA Study; comparison of their primary endpoints; and the implications of their results. Among the topics discussed by the panel of experts from Japan, USA, and UK were observations on the benefits associated with pravastatin at low dose as demonstrated in the MEGA Study as well as that study's implications for women, who represented the majority of subjects. Several suggestions were put forth to explain how the low dose used in MEGA elicited similar LDL-C reductions to those observed in WOSCOPS and AFCAPS/TexCAPS at higher doses including the body size hypothesis, genetic variation, and statin-diet interaction. It was felt that in Japan, the current guidelines are adequate; there seemed no merit in radically reducing LDL-C levels since in the Japanese population the risk is generally low. Japanese physicians tend to use small doses of statin and believe that these are effective in lowering cholesterol sufficiently with few side effects and encourage good compliance.

Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis

Atherosclerosis and sepsis share several pathophysiological similarities, including immune dysregulation, increased thrombogenesis, and systemic inflammation. The relation between statins and risk of sepsis in patients with atherosclerosis is unknown. We did a population-based cohort analysis through linked administrative databases in Ontario, Canada, with accrual from 1997 to 2002. We identified 141,487 patients older than 65 years who had been hospitalised for an acute coronary syndrome, ischaemic stroke, or revascularisation, who survived for at least 3 months after discharge. 46,662 (33%) were prescribed a statin within 90 days of discharge, 94,825 (67%) were not. Propensity-based matching, which accounted for each individual's likelihood of receiving a statin, yielded a cohort of 69,168 patients, of whom half (34,584) received a statin and half (34,584) did not. Incidence of sepsis was lower in patients receiving statins than in controls (71.2 vs 88.0 events per 10,000 person-years; hazard ratio [HR] 0.81; 95% CI 0.72-0.91). Adjustment for demographic characteristics, sepsis risk factors, comorbidities, and health-care use gave similar results (HR 0.81; 95% CI 0.72-0.90). The protective association between statins and sepsis persisted in high-risk subgroups, including patients with diabetes mellitus, chronic renal failure, or a history of infections. Significant reductions in severe sepsis (HR 0.83; 95% CI 0.70-0.97) and fatal sepsis (0.75; 0.61-0.93) were also observed. No benefit was noted with non-statin lipid-lowering agents (0.95; 0.75-1.22). Use of statins in patients with atherosclerosis is associated with a reduced risk of subsequent sepsis. Randomised trials of statins for prevention of sepsis are warranted.

Cardiovascular outcomes among participants with diabetes in the recent large statin trials.

Despite their increased cardiovascular risk and its continuous relationship with cholesterol, until recently only diabetic patients with marked dyslipidaemia were routinely offered lipid-lowering therapy. The secondary prevention statin trials led to more widespread cholesterol lowering in patients with coronary disease and diabetes. Here we review the results of recent randomized trials, which included substantial numbers of patients with diabetes and no vascular disease. The MRC/BHF Heart Protection Study included 5963 participants with diabetes, of whom 2912 had no history of vascular disease at baseline. Patients were randomized to 40 mg simvastatin daily or matching placebo for 5 years, which, on average, reduced LDL by 1.0 mmol/l compared with placebo. Highly significant reductions of about one-quarter in major vascular events were seen both overall and in different types of patient with diabetes, including those with average and below average lipid levels. Recent data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and the Anglo-Scandinavian Cardiac Outcomes Trial support these findings and are consistent with these effects. Good quality, randomized trials including substantial numbers of patients with diabetes show that such patients obtain the same proportional benefit as other groups studied. Given their increased cardiovascular risk, these findings argue for a simple strategy of considering routine statin therapy for patients with type 2 diabetes and adult patients with type 1 diabetes, irrespective of lipid levels. As generic statins become available this could have a greater impact on the burden of cardiovascular disease in diabetes than restricted and targeted therapy.