Reduction In Major Vascular Events Research Articles

Effect of Statin Therapy on Cardiovascular Outcome in Stroke Patients with Low Baseline Low-Density Lipoprotein Cholesterol.

To investigate whether post-stroke statin therapy reduces subsequent major vascular events in statin-naïve patients with pretreatment low-density lipoprotein cholesterol (LDL-C) below the recommended target (≤70 mg/dL for atherosclerotic stroke and ≤100 mg/dL for non-atherosclerotic stroke) at stroke onset. Patients from an ongoing stroke registry who had an ischemic stroke between 2011 and 2020 were screened. Statin naïve patients with baseline LDL-C below the target were assessed. The effect of post-stroke statin therapy on major vascular events (composite of recurrent stroke, myocardial infarction, and death) was investigated using weighted Cox regression analyses using stabilized inverse probability treatment weighting. The baseline LDL-C level of the 1,858 patients (mean age 67.9 ± 15.3 years, 61.4% men, 13.2% atherosclerotic stroke) included in the study was 75.7 ± 17.0 mg/dL. Statins were prescribed to 1,256 (67.7%) patients (low-to-moderate intensity, 23.5%; high intensity, 44.1%). Post-stroke statin therapy was associated with a lower risk of major vascular events during 1-year follow-up (weighted hazard ratio 0.55, 95% confidence interval 0.42-0.71). In a subgroup of patients who were at very high risk of atherosclerotic cardiovascular disease with LDL-C <55 mg/dL or patients who were not at very high risk of atherosclerotic cardiovascular disease with LDL-C <70 mg/dL, post-stroke statin therapy was also associated with a reduction in major vascular events (weighted hazard ratio 0.45, 95% confidence interval 0.29-0.70). The intensity of the most beneficial statin varied by subtype of stroke. Statin therapy may improve vascular outcomes after ischemic stroke, even in cases of LDL-C below the target without pre-stroke lipid-lowering therapy. ANN NEUROL 2024;95:876-885.

THU584 Comparison Of The Cardiovascular Benefits Of Bempedoic Acid With Statins- Analysis By The Cholesterol Treatment Trialists’ Methodology

Abstract Disclosure: A. Lincoff: Advisory Board Member; Self; Novo Nordisk, Eli Lilly &amp; Company. Consulting Fee; Self; GlaxoSmithKline, Medtronic, Ardelyx, Akebia, Endologix, Provention Bio. Grant Recipient; Self; Abbvie, Novartis Pharmaceuticals, Esperion, AstraZeneca, CSL Behring. Stock Owner; Self; Cadrenal. K. Ray: Consulting Fee; Self; Amgen Inc, Sanofi, Regeneron, Pfizer, Inc., Viatris, Abbott Laboratories, AstraZeneca, Eli Lilly &amp; Company, Kowa, Novo Nordisk, Boehringer Ingelheim, Esperion, Cargene, Resverlogix, Novartis Pharmaceuticals, Silence Therapeutics, New Amsterdam, SCRIBE, CRISPR, VAXXINITY, CSL Behring, Bayer, Inc., Biologixpharma, Amarin. Grant Recipient; Self; Amgen Inc, Sanofi, Regeron, Merck, Pfizer, Inc. W. Sasiela: Consulting Fee; Self; Esperion. Employee; Self; Esperion. Stock Owner; Self; Esperion. T. Haddad: None. S. Nicholls: Consulting Fee; Self; Amgen Inc, Akcea Therapeutics, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly &amp; Company, Esperion, Kowa, Merck, Takeda, Pfizer, Inc., Sanofi-Regeneron, Novo Nordisk. Grant Recipient; Self; AstraZeneca, Amgen Inc, Anthera, CSL Behring, Cerenis, Eli Lilly &amp; Company, Esperion, Resverlogix, Novartis Pharmaceuticals, InfraReDx, Sanofi-Regeneron. N. Li: Employee; Self; Esperion. L. Cho: Consulting Fee; Self; Merck, AstraZeneca. Grant Recipient; Self; AstraZeneca, Novartis Pharmaceuticals. D. Mason: None. P. Libby: Advisory Board Member; Self; Amgen Inc, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharamceuticals, Olatec Therapeutics, Medimmune, Novartis Pharmaceuticals, PlaqueTec, TenSixteen Bio, Soley Therapeutics, XBiotech, Inc. Grant Recipient; Self; Novartis Pharmaceuticals, Novo Nordisk, Genentech, Inc. S. Nissen: Grant Recipient; Self; Abbvie, AstraZeneca, Amgen Inc, Bristol-Myers Squibb, Eli Lilly &amp; Company, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis Pharmaceuticals, Pfizer, Inc., Silence Therapeutics. Background: Statins are the foundation of treatment for atherosclerotic cardiovascular (CV) disease. The Cholesterol Treatment Trialists’ (CTT) Collaboration calculated in their meta-analyses of statin trials that every 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a 22% reduction in major vascular events (MVE), a benefit which increased with cumulative duration of therapy. In the CLEAR Outcomes trial, treatment of statin-intolerant pts with the ATP citrate lyase inhibitor bempedoic acid (BA) was associated with a 21% decrease in LDL-C compared with placebo and a 13% relative reduction in the risk of major adverse CV events (MACE) [hazard ratio (HR) 0.87, 95% CI 0.79-0.96. p=0.004]. It is unknown whether the relationship between LDL-C reduction and magnitude of CV benefits achieved with non-statin therapies such as BA differs from statins. Methods: The CLEAR Outcomes trial enrolled 13,970 pts with or at high risk for CV disease, 46% of whom had diabetes and 42% pre-diabetes, and with a baseline mean LDL-C of 3.60 mmol/L. We applied the CTT methodology and endpoint definitions to CLEAR Outcomes to derive normalized HRs associated with BA treatment for the composite MVE endpoint (fatal coronary heart disease, non-fatal MI, stroke, or revascularization) and individual CV outcomes per 1 mmol/L LDL-C reduction at 1 year. We assessed treatment effect of BA on CV events relative to LDL-C reduction in the Intention to Treat (ITT) population (all randomized pts) and in an on-treatment Per Protocol Set (PPS) population (censoring events occurring &amp;gt;30 days after early study drug discontinuation, which occurred in 29% and 32% of pts allocated to BA and placebo, respectively). Cumulative HRs were calculated per year of treatment duration. Results: In the ITT analysis, placebo-corrected absolute LDL-C reduction by BA at month 12 was 0.58 mmol/L with a HR (95% CI) for MVE of 0.85 (0.77, 0.94). In the PPS analysis, LDL-C reduction was 0.71 mmol/L with a HR for MVE of 0.80 (0.71, 0.89). When normalized to 1.0 mmol/L LDL-C reduction, HRs for ITT and PPS were 0.75 (0.63, 0.90) and 0.73 (0.62, 0.85), respectively and were comparable to normalized risk reduction with statins observed in the CTT meta-analyses [risk ratio (RR) 0.78, 95% CI 0.76, 0.80]. The cumulative normalized HR for MVE improved from 0.77 at year 1 to 0.72 by year 4 of BA treatment. Normalized HRs for individual endpoints of major coronary events, non-fatal MI, revascularization, and stroke for BA vs placebo in CLEAR Outcomes were comparable to the RRs for those endpoints with statins in the CTT meta-analyses. Conclusions: CV benefits achieved with BA are comparable to those obtained with statins, being proportional to the magnitude of absolute reductions in LDL-C, and increase over time. Use of and adherence to BA can provide substantial reductions in CV risk, in particular for those pts at high CV risk due to statin intolerance and high baseline LDL-C. Presentation: Thursday, June 15, 2023

Abstract TMP104: Effect Of Statin Therapy In Stroke Patients With Low Baseline Low-density Lipoprotein Cholesterol

Introduction: Post-stroke statin therapy is known to reduce subsequent major vascular events in patients with ischemic stroke. However, the efficacy of statin therapy in acute ischemic stroke patients with low low-density lipoprotein cholesterol (LDL-C) at baseline is not well defined. This study aimed to determine whether statin therapy would be beneficial in stroke patients with low or well-controlled LDL-C at baseline. Methods: We assessed ischemic stroke patients with baseline LDL-C &lt;100mg/dL without prior statin therapy or &lt;70mg/dL with prior statin therapy who were hospitalized between 2011 and 2020. The effect of post-stroke statin therapy on major vascular events, defined as a composite of recurrent stroke, myocardial infarction, and all-cause death within 1 year after stroke was assessed using multivariable Cox regression analyses. Results: A total of 3,350 patients (mean age 68.6 ± 13.9 years; 62.9% male; 21.5% with previous statin therapy; 37.0% with atherosclerotic stroke) were included. The mean baseline LDL-C of the patients was 73.6 ± 17.6mg/dL, which did not differ between patients with or without post-stroke statin therapy (74.0 ± 17.7mg/dL in statin users; 73.4 ± 17.6mg/dL in statin non-users). Statins were prescribed in 2,638 (78.8%) after stroke and LDL-C was significantly reduced in patients who received statin therapy (65.9 ± 21.7mg/dL in statin users; 80.2 ± 26.7mg/dL in statin non-users). Statin therapy was significantly associated with a lower risk of major vascular events (adjusted hazard ratios (aHR) 0.37 [95% confidence interval (CI) 0.31 - 0.46]). However, post-stroke LDL-C reduction (aHR 1.00 [95% CI 0.995 - 1.01]), percent LDL-C reduction (aHR 0.999 [95% CI 0.996 - 1.003]) and achieved LDL-C &lt;55mg/dL after stroke (aHR 0.96 [95% CI 0.67 - 1.37]) were not associated with the occurrence of major vascular events within 1 year after stroke. Conclusions: Post-stroke statin therapy was associated with a reduction in major vascular events after acute ischemic stroke, even in patients with low or well-controlled LDL-C. However, achieved LDL-C levels were not associated with post-stroke major vascular events in this population.

Is It About the Destination or About the Journey?

HomeStrokeVol. 53, No. 11Is It About the Destination or About the Journey? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIs It About the Destination or About the Journey? Dylan Blacquiere, Holly Sim and Dar Dowlatshahi Dylan BlacquiereDylan Blacquiere https://orcid.org/0000-0002-8421-2646 Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Canada (D.B., D.D.). Search for more papers by this author , Holly SimHolly Sim https://orcid.org/0000-0002-7721-0191 Department of Medicine, University of Ottawa, Canada (H.S.). Search for more papers by this author and Dar DowlatshahiDar Dowlatshahi Correspondence to: Dar Dowlatshahi, MD, PhD, The Ottawa Hospital Civic Campus, Division of Neurology, 1053 Carling Ave, Room C2182b, Ottawa ON, K1Y 4E9, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0003-1379-3612 Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Canada (D.B., D.D.). Search for more papers by this author Originally published26 Sep 2022https://doi.org/10.1161/STROKEAHA.122.040567Stroke. 2022;53:3268–3269This article is a commentary on the followingYield of Dual Therapy With Statin and Ezetimibe in the Treat Stroke to Target Trialis related toNovember 2022 Stroke HighlightsOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 26, 2022: Ahead of Print See related article, p 3260In a post hoc analysis of the TST trial (Treat Stroke to Target),1 Amarenco et al2 provide data showing patients treated with ezetimibe in addition to statin therapy with a target LDL (low-density lipoprotein) of <70 mg/dL had a reduction in major vascular events as compared with patients with a target of LDL<100 mg/dL; this effect was not seen with statin monotherapy, despite reaching comparable LDL targets. This finding likely reflects a higher baseline LDL in those patients prescribed dual therapy, which resulted in a higher magnitude of LDL reduction.The role of cholesterol reduction in the prevention of vascular disease has long been established. The SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol) in 2006 was pivotal in showing that that atorvastatin therapy was associated with reduced stroke risk.3 Thereafter, recurrent stroke risk reduction was thought to be related to a statin-specific mechanism of action; patients were prescribed statins irrespective of lipid profile. Subsequent trials showed that the more aggressive the target, the better.1,4 The TST trial, in particular, demonstrated that therapy toward a lower LDL target of 70 mg/dL was associated with reduced risk of stroke when compared with a more lenient 100 mg/dL. Clinical practice guidelines were adapted to reflect this more aggressive target,5 but the choice of agents for LDL reduction was left to the discretion of treating clinicians. In the cardiology literature, studies such as the IMPROVE-IT trial (Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes) have shown that nonstatin agents may offer additional benefit when added to statins, both in achieving more aggressive LDL targets, and in reducing recurrent coronary syndromes.6 In contrast, stroke clinicians have generally continued to use statins as the mainstay of therapy, with agents like ezetimibe as adjuncts where targets are not achieved.Despite the usual caveats associated with post hoc analyses, including the limited ability to assess for subgroup effects (sex, age), this study by Amarenco and colleagues makes intuitive sense and supports a personalized approach to secondary prevention. Moreover, the results are generalizable as the patients are relatively representative of those seen in stroke prevention clinics across many jurisdictions, with a high proportion of statin-naive patients. Finally, the study supports the notion that the magnitude of LDL reduction may be equally, if not more, important than the LDL target itself. It may not just be the LDL target that provides the benefit, but rather how we reach that target, and the place where we started from.Article InformationDisclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.This manuscript was sent to Hanne Christensen, Senior Guest Editor, for review by expert referees, editorial decision, and final disposition.For Disclosures, see page 3268.Correspondence to: Dar Dowlatshahi, MD, PhD, The Ottawa Hospital Civic Campus, Division of Neurology, 1053 Carling Ave, Room C2182b, Ottawa ON, K1Y 4E9, Canada. Email [email protected]ca

Compounding Benefits of Cholesterol-Lowering Therapy for the Reduction of Major Cardiovascular Events: Systematic Review and Meta-Analysis.

Mendelian randomization studies use genetic variants as natural experiments to provide evidence about causal relations between modifiable risk factors and disease. Recent Mendelian randomization studies suggest each mmol/L reduction in low-density lipoprotein cholesterol (LDL-C) sustained over a lifetime can reduce the risk of cardiovascular disease by more than half. However, these findings have not been replicated in randomized clinical trials, and the effect of treatment duration on the magnitude of risk reduction remains uncertain. The aim of this article was to evaluate the relationship between lipid-lowering drug exposure time and relative risk reduction of major cardiovascular events in randomized clinical trials. We conducted a systematic review and meta-analysis of randomized clinical trials of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors that report LDL-C levels and effect sizes for each year of follow-up. The primary end point was major vascular events, defined as the composite of cardiovascular death, myocardial infarction, stroke, and coronary revascularization. Hazard ratios during each year of follow-up were meta-analyzed using random-effects models. A total of 21 trials with 184 012 patients and an average mean follow-up of 4.4 years were included. Meta-regression showed there was greater relative risk reduction in major vascular events with increasing duration of treatment (P<0.001). For example, each mmol/L LDL-C lowered was associated with a relative risk reduction in major vascular events of 12% (95% CI, 8%-16%) for year 1, 20% (95% CI, 16%-24%) for year 3, 23% (95% CI, 18%-27%) for year 5, and 29% (95% CI, 14%-42%) for year 7. The benefits of LDL-C lowering do not seem to be fixed but increase steadily with longer durations of treatment. The results from short-term randomized trials are compatible with the very strong associations between LDL-C and cardiovascular events seen in Mendelian randomization studies.

STATIN INTOLERANCE: CURRENT STATUS AND MANAGEMENT

Statins (HMG-CoA reductase inhibitors), since their introduction in 1987 are considered the first-line pharmacotherapy for cholesterol reduction. Because of their proven therapeutic ability to prevent cardiovascular disease and to extend life, statins are among one of the most widely prescribed medications. Various randomized clinical trials have consistently shown that statins have a beneficial role in both primary and secondary prevention strategies, with a significant reduction in major vascular events, including death, myocardial infarction, stroke, and coronary revascularization[1].

Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials.

Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events. We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters. A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76-0.82; P<0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; P<0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; P=0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; P<0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81-1.006; P=0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; P<0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]). In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.

Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

SummaryBackgroundStatin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages.MethodsIn this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups.Findings14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence.InterpretationStatin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials.FundingAustralian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation.

More Intensive LDL-C Lowering Reduces Major Vascular Events Beyond Current Recommendations: Systematic Review and Meta-Analysis

Aims: To determine the relationship between more intensive low-density lipoprotein (LDL-C) lowering therapy and relative risk of major vascular events (MVEs) across different LDL-C levels. Methods: Randomised trials of statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that reported rates of MVEs were included. Random-effects and network meta-analyses evaluated associations between baseline LDL-C, achieved LDL-C, degree of LDL-C lowering and 10-year risk of cardiovascular (CVD) death with the relative risk (RR) of MVEs. Results: Fifty studies, totalling 316,605 patients with mean follow-up 3.6 ± 1.6 years were included. Although more intensive LDL-C lowering was associated with greater reductions in MVEs in patients with higher baseline LDL-C (p < 0.001), there was benefit in further lowering LDL-C amongst subgroups of patients with all baseline LDL-C <2.07 mmol/l (RR, 0.89; 95% CI, 0.82–0.96). In a network meta-analysis, patients with achieved LDL-C <1.50 mmol/l were most likely free from MVEs (surface under the cumulative ranking curve, 0.98), followed by 1.50–1.79, 1.80–2.59, 2.60–3.39, 3.40–4.09 and ≥4.10 mmol/l respectively. In meta-regression of primary prevention trials, LDL-C lowering therapy provided greater RR reductions in MVEs in populations with lower 10-year risk of CVD death (p = 0.030). Patients aged >75 years who received intensive LDL-C lowering therapy had significantly less MVEs. There was significantly more adverse drug reactions in the intensive LDL-C lowering arm (RR, 1.18; 95% CI, 1.10–1.27), but no significant difference in serious adverse effects. Conclusions: This meta-analysis provides new evidence that further lowering LDL-C is associated with greater reductions in MVEs beyond current recommendations.

Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: Analysis From FOURIER.

The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab. The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared. A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had ≥2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval [CI],1.22-1.53), 1.78 (95% CI, 1.59-1.99), and 1.39 (95% CI, 1.24-1.56; all P<0.001). The relative risk reductions with evolocumab for the primary end point tended to be greater in the high-risk subgroups and were 20% (HR, 0.80; 95% CI, 0.71-0.91), 18% (HR, 0.82; 95% CI, 0.72-0.93), and 21% (HR, 0.79; 95% CI, 0.69-0.91) for those with more recent MI, multiple prior MIs, and residual multivessel coronary artery disease, whereas they were 5% (HR, 0.95; 95% CI, 0.85-1.05), 8% (HR, 0.92; 95% CI, 0.84-1.02), and 7% (HR, 0.93; 95% CI, 0.85-1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) versus ≈1% in the low-risk groups (0.8%, 1.3%, and 1.2%). Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

Efficacy and Safety of Further Lowering of Low-Density Lipoprotein Cholesterol in Patients Starting With Very Low Levels

In the Cholesterol Treatment Trialists Collaboration (CTTC), in patients starting with low-density lipoprotein cholesterol (LDL-C) levels of approximately 3.4 mmol/L (131.5 mg/dL), there was a 22% reduction in major vascular events per 1-mmol/L (38.7-mg/dL) lowering of LDL-C. The magnitude of clinical benefit of further LDL-C lowering in patients already with very low LDL-C levels remains debated. To evaluate efficacy and safety of further lowering LDL-C levels in patient populations presenting with median LDL-C levels of 1.8 mmol/L (70 mg/dL) or less. The CTTC was used for statin data. For nonstatin therapy, Medline database was searched (2015-April 2018). Key inclusion criteria were a randomized, double-blind, controlled cardiovascular outcome trial of LDL-C lowering with data in populations starting with LDL-C levels averaging 1.8 mmol/L (70 mg/dL) or less. Two authors independently extracted data into standardized data sheets, and data were analyzed using meta-analysis. The risk ratio (RR) of major vascular events (a composite of coronary heart death, myocardial infarction, ischemic stroke, or coronary revascularization) per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level. In the subgroup of patients from the CTTC meta-analysis of statins with a mean LDL-C in the control arm of 1.7 mmol/L (65.7 mg/dL), 1922 major vascular events occurred and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 0.78 (95% CI, 0.65-0.94). For 3 trials of nonstatin LDL-C-lowering therapies added to statins, there were 50 627 patients, the median LDL-C in the control arms ranged from 1.6 mmol/L to 1.8 mmol/L (63 mg/dL to 70 mg/dL), and 9570 major vascular events occurred. Nonstatin therapy lowered LDL-C by 0.3 to 1.2 mmol/L (11 mg/dL to 45 mg/dL), and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 0.79 (95% CI, 0.70-0.88). For statins and nonstatins combined, the RR was 0.79 (95% CI, 0.71-0.87; P < .001). Low-density lipoprotein cholesterol lowering was not associated with an increased risk of serious adverse events, myalgias and/or myositis, elevation in the level of aminotransferases, new-onset diabetes, hemorrhagic stroke, or cancer. There is a consistent relative risk reduction in major vascular events per change in LDL-C in patient populations starting as low as a median of 1.6 mmol/L (63 mg/dL) and achieving levels as low as a median of 0.5 mmol/L (21 mg/dL), with no observed offsetting adverse effects. These data suggest further lowering of LDL-C beyond the lowest current targets would further reduce cardiovascular risk.

Statins for primary prevention in people with a 10% 10-year cardiovascular risk: too much medicine too soon?

The National Institute for Health and Care Excellence (NICE) guidelines on lipid modification advise offering statins for primary prevention to patients with over 10% 10-year modelled risk of a cardiovascular event, a change from 20%. This has generated controversy among clinicians, researchers, and journal editors. Patients already taking statins were more likely to stop taking them after the intense media coverage between March and October 2014, though there was no associated change in initiation.1 Clinicians’ worries were crystallised in a letter of concern from leading UK medical figures to NICE concerning the frequency of adverse events and the magnitude of the effectiveness of statins.2 Two sources of evidence were cited regarding risk levels, the meta-analyses by the Cholesterol Collaboration Trialists (CTT) Collaboration and Cochrane.3,4 The CTT Collaboration meta-analysis used individual patient data from 22 randomised controlled trials (RCTs) of statin versus control ( n = 134 537);3 authors were able to stratify individuals into risk categories. The CTT Collaboration is the only group to have been granted access to individual patient data by pharmaceutical companies funding RCTs, but they were not allowed to share data with third parties and were not granted access to individual patient adverse event data.5 For primary prevention, among those at high risk (10–20% risk over 5 years), statins led to a significant relative risk reduction in major vascular events and a non-significant relative risk reduction in vascular mortality. Among intermediate-risk patients (5–10% risk over 5 years), statins were associated with a significant relative risk reduction in major vascular events and major coronary events, but to non-significant reductions in coronary heart disease (CHD) mortality and all-cause mortality. Among those receiving statins for 5 …

Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials

Statin therapy is effective for the prevention of coronary heart disease and stroke in patients with mild-to-moderate chronic kidney disease, but its effects in individuals with more advanced disease, particularly those undergoing dialysis, are uncertain. We did a meta-analysis of individual participant data from 28 trials (n=183 419), examining effects of statin-based therapy on major vascular events (major coronary event [non-fatal myocardial infarction or coronary death], stroke, or coronary revascularisation) and cause-specific mortality. Participants were subdivided into categories of estimated glomerular filtration rate (eGFR) at baseline. Treatment effects were estimated with rate ratio (RR) per mmol/L reduction in LDL cholesterol. Overall, statin-based therapy reduced the risk of a first major vascular event by 21% (RR 0·79, 95% CI 0·77-0·81; p<0·0001) per mmol/L reduction in LDL cholesterol. Smaller relative effects on major vascular events were observed as eGFR declined (p=0·008 for trend; RR 0·78, 99% CI 0·75-0·82 for eGFR ≥60 mL/min per 1·73 m(2); 0·76, 0·70-0·81 for eGFR 45 to <60 mL/min per 1·73 m(2); 0·85, 0·75-0·96 for eGFR 30 to <45 mL/min per 1·73 m(2); 0·85, 0·71-1·02 for eGFR <30 mL/min per 1·73 m(2) and not on dialysis; and 0·94, 0·79-1·11 for patients on dialysis). Analogous trends by baseline renal function were seen for major coronary events (p=0·01 for trend) and vascular mortality (p=0·03 for trend), but there was no significant trend for coronary revascularisation (p=0·90). Reducing LDL cholesterol with statin-based therapy had no effect on non-vascular mortality, irrespective of eGFR. Even after allowing for the smaller reductions in LDL cholesterol achieved by patients with more advanced chronic kidney disease, and for differences in outcome definitions between dialysis trials, the relative reductions in major vascular events observed with statin-based treatment became smaller as eGFR declined, with little evidence of benefit in patients on dialysis. In patients with chronic kidney disease, statin-based regimens should be chosen to maximise the absolute reduction in LDL cholesterol to achieve the largest treatment benefits. UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Community Biomed Programme, Australian National Health and Medical Research Council, Australian National Heart Foundation.

Abstract 18904: VARSITY Study (VA Retrospective study of Statin IntensiTY): Utilizing a Large VA Cohort to Determine the Actual Clinical Response of LDL Reduction After Initiating Statin Therapy in Newly Diagnosed ASCVD

Background: According to the 2013 ACC/AHA Blood Cholesterol Guideline (BCGL), high-intensity statin therapy (HIST) is recommended in individuals with newly diagnosed atherosclerotic cardiovascular disease (ASCVD) and this therapy is expected to lower LDL by &gt;50%. These recommendations come from multiple studies which demonstrated that the reduction in major vascular events was proportional to the absolute LDL reduction. This retrospective study utilized a large VA cohort to report the LDL reduction with the initiation of statin therapy after an initial diagnosis of ASCVD. Methods: A national cohort of VA patients with a new diagnosis of ASCVD and subsequent initiation of statin therapy was constructed. The most proximate LDL measured within 12 weeks before (PreLDL) and 4-12 weeks after (PostLDL) initiation of statin therapy were recorded. Patients with a prior diagnosis of ASCVD, a prior prescription for any lipid lowering drug, or a prior prescription for immunosuppressant agents were excluded. The statin doses were categorized as high-, moderate- or low-intensity as defined in the 2013 BCGL. Results: This cohort consisted of 92,755 VA patients with an initial ASCVD diagnosis from 5/1992 to 7/2014. The cohort was 97% male, 19% ethnic minority, and the average age was 66.7 (± 10.9) years. The average PreLDL was 129.8 (±35.1), the average PostLDL was 94.2 (±31.7) mg/dl, and only 2.5% were prescribed HIST. The results are summarized in Table 1. Conclusion: This cohort study examined statin intensity and LDL reduction after the initial diagnosis of ASCVD. HIST was rarely prescribed as initial therapy and in a majority of these patients the expected &gt;50% LDL reduction was not achieved. This study suggests the need for additional research to explore the factors contributing to a &gt;50% reduction in LDL following the initiation of statin therapy in patients with ASCVD, and that the monitoring of response to HIST may be clinically important.

Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice pesearch datalink.

BackgroundThere is strong evidence of reductions in major vascular events from statins across all cardiovascular risk categories. However, trials of statin therapy have provided conflicting results regarding statin use and type 2 diabetes (T2DM). We aimed to assess the effect of statins on T2DM development.MethodWe carried out a population-based cohort study using the Clinical Practice Research Datalink (CPRD), a database of computerized clinical records. Every patient aged 30–85 years old starting a statin between 1989 and 2009 was matched with up to five non-statin users. The observation period in CPRD ended in 31 December 2011. Cox proportional hazard regression was used to compare rates of T2DM between statin users and non-users, using propensity score method to adjust for systematic differences between groups.ResultsThe study basis comprised 2,016,094 individuals, including 430,890 people who received a statin, matched to 1,585,204 people not prescribed a statin. Mean follow-up time was 5.43 years for statin users and 3.89 years for nonusers. During follow-up 130,395 individuals developed T2DM. Statin use was associated with an increased risk of T2DM (HR 1.57; 95% CI 1.54-1.59), which increases with longer duration of use. The increased risk was smaller among people with hypertension or cardiovascular disease and was only apparent after 5 or more years treatment with statins in these groups. Conversely, age-specific risk ratios decreased in older people.ConclusionsStatin use is associated with an increased risk of T2DM. Our results suggest that the relative risk is higher among people without diagnosed hypertension or cardiovascular disease. These findings should be considered in the context of the observational nature of the data which is prone to bias and unmeasured confounding.

A current approach to statin intolerance.

Statins are the first-line pharmacotherapy for cholesterol reduction. Use of these drugs in large randomized clinical trials has consistently shown significant reductions in major vascular events, including death, myocardial infarction, stroke, and coronary revascularization. The updated guidelines for the treatment of high blood cholesterol from the American College of Cardiology/American Heart Association (ACC/AHA), will lead to an increase in the number of patients taking statins. Hence, the number of cases of statin intolerance may subsequently increase, emphasizing the need to understand and treat this important problem.

Statins for primary prevention of cardiovascular disease

Statins significantly reduce cardiovascular morbidity and mortality in patients with and without coronary heart disease. Recently, much debate has focused on use of statins for primary prevention following a class-wide safety label change by the US Food and Drug Administration amidst concerns of worsened hyperglycemia. Here, we review the evidence for statins in primary prevention and offer guidance for their appropriate use. Two meta-analyses published since 2012 unequivocally support statins for primary prevention. Data from the Cholesterol Treatment Trialists' Collaborators demonstrated a 9% [relative risk (RR) 0.91, 95% confidence interval (CI) 0.85-0.97] reduction in all-cause mortality and a 25% (RR 0.75, 95% CI 0.70-0.80) reduction in major vascular events per 1.0 mmol/l reduction in low-density lipoprotein cholesterol, even among low-risk patients. A 2013 Cochrane review corroborated these findings including a 14% (OR 0.86, 95% CI 0.79-0.94) reduction in all-cause mortality and a 25% (RR 0.75, 95% CI 0.70-0.81) reduction in cardiovascular disease events with statin therapy despite an 18% (RR 1.18, 95% CI 1.01-1.39) increase in incident diabetes. Statins effectively lower atherogenic lipoproteins and result in clinically significant reductions in cardiovascular morbidity and mortality. When well tolerated, the cardiovascular benefits of statins for primary prevention generally far outweigh the reported harms.

The case for more intensive use of statins.

The case for more intensive use of statins.

Balancing the cardiometabolic benefits and risks of statins

Although the cardiovascular benefits of statins are unquestionable, concern has been raised about the potential diabetogenic effect of these drugs. 1 Rajpathak SN Kumbhani DJ Crandall J Barzilai N Alderman M Ridker PM Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009; 32: 1924-1929 Crossref PubMed Scopus (346) Google Scholar , 2 Preiss D Seshasai SR Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011; 305: 2556-2564 Crossref PubMed Scopus (1078) Google Scholar This risk is most pertinent to the prescription of statins for people at low risk of cardiovascular disease—so-called primary prevention. In this setting, the absolute cardiovascular benefits of statins are less than in individuals at higher risk of cardiovascular disease and might be offset by drug side-effects, particularly new-onset diabetes. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trialIn the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including in participants at high risk of developing diabetes. Full-Text PDF The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trialsIn individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. Full-Text PDF Open Access

The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials

SummaryBackgroundStatins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain.MethodsThis meta-analysis included individual participant data from 22 trials of statin versus control (n=134 537; mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin (n=39 612; difference 0·51 mmol/L; 5·1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1·0 mmol/L LDL cholesterol reduction was estimated.FindingsReduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, 95% CI 0·77–0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1·0 mmol/L reduction from lowest to highest risk: 0·62 [99% CI 0·47–0·81], 0·69 [99% CI 0·60–0·79], 0·79 [99% CI 0·74–0·85], 0·81 [99% CI 0·77–0·86], and 0·79 [99% CI 0·74–0·84]; trend p=0·04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0·57, 99% CI 0·36–0·89, p=0·0012, and 0·61, 99% CI 0·50–0·74, p<0·0001) and in coronary revascularisations (RR 0·52, 99% CI 0·35–0·75, and 0·63, 99% CI 0·51–0·79; both p<0·0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1·0 mmol/L LDL cholesterol reduction 0·76, 99% CI 0·61–0·95, p=0·0012) was also similar to that seen in higher risk categories (trend p=0·3). In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1·0 mmol/L LDL cholesterol reduction 0·85, 95% CI 0·77–0·95) and all-cause mortality (RR 0·91, 95% CI 0·85–0·97), and the proportional reductions were similar by baseline risk. There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1·0 mmol/L LDL cholesterol reduction 1·00, 95% CI 0·96–1·04), cancer mortality (RR 0·99, 95% CI 0·93–1·06), or other non-vascular mortality.InterpretationIn individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.FundingBritish Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.