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Cholesterol paradox: A correlate does not a surrogate make
Abstract
The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world. Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect. The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol in high-risk patients with coronary disease. This clinical trial adds to a growing volume of knowledge that challenges the validity of the cholesterol hypothesis and the utility of cholesterol as a surrogate end point. Inadvertently, the cholesterol hypothesis may have even contributed to this pandemic. This perspective critically reviews this evidence and our reluctance to acknowledge contradictory information.
... 21 Other meta-analyses 16,17,18 found similar lowering of MVEs without significant mortality reduction. Of note, at least 44 cholesterol-lowering RCTs reported no survival benefit (26 of them are statin trials), seven non-statin trials with significant reductions in LDL-C reported substantial clinical harms, including the cholesterol ester transfer protein-CETP inhibitor trials 22,23 Women, young adults and the elderly are typically under-represented in RCTs: a meta-analysis of over 65,000 subjects including 35% women was published without gender specific results. 16 Among individual studies, JUPITER showed no mortality reduction in females <65 years. ...
... 14,25 However, the total events and effects (AE) were higher in women, who were more likely to develop muscle pains, hepatic dysfunction and diabetes. 8,14,18,22,24,25,26 The increased mortality reported in elderly individuals with lower cholesterol levels needs further evaluation. ...
... 27,30 PROSPER was designed to evaluate individuals aged 70-82 years given pravastatin for 3 years and reported lower CVD but similar all-cause mortality owing to higher cancer deaths. 32 Finally, most trials enrolled men > 40 years of age and women > 50-60 years age, hence the recommendation to initiate statins in adults > 20 years of age also appears to be without adequate evidence, except in FH. [1][2][3][4][5][6][7][8][12][13][14][15][16][17][18]22,24,25 In sum, the data for primary prevention is consistent for reduction of events, not total mortality, and that too only in middle-aged males. ...
... We performed a historical prospective analysis of the electronic medical documentation of all non-selected, consecutive patients admitted to a university hospital during the course of 2 years, i.e. between July 1, 2014 and June 30,2016. During this period, 70 076 hospitalizations were carried out, of which 64 856 (92.55%) concerned patients older than 18 years, and 53 375 (76.17%) lasted more than one day. ...
... Our univariate analysis identified a worse prognosis for hospitalized patients with the lowest TC, LDL-C and TG, which, although contrary to findings in outpatient studies and in the general literature [1][2][3], corroborated results of recent, experimental, randomized and controlled trials. Recently, a few studies have failed to show a cardiovascular benefit of the aggressive lowering of LDL-C and raising of HDL-C blood concentration using cholesteryl ester transfer protein (CETP) inhibitors, evacetrapib [30], anacetrapib and dalcetrapib [31]. Torcetrapib even showed an increase in CVD events, despite an increase in HDL-C level [31]. ...
... It is also possible that such aggressive therapy may lead to non-cardiovascular mortality, secondary to still undiagnosed adverse effects [7,19], e.g. similar to statins, which cause a dose-dependent increase in the risk of diabetes mellitus [30,32,33]. ...
Introduction:
There is evidence of positive relationships between cholesterol concentration and risk of cardiovascular diseases. However, higher mortality in patients with a low cholesterol level has been reported (the "cholesterol paradox").
Material and methods:
Medical records of 34 191 inpatients between 2014 and 2016 were reviewed and the relationships between total (TC), low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) cholesterol and triglyceride blood concentrations and all-cause in-hospital death and readmission within 14 and 30 days and 1 year were determined in univariate and multivariate analyses.
Results:
Patients with TC in the lower quartile and LDL-C < 70 mg/dl had greater risk of the outcomes measured than individuals with a TC level in the remaining quartiles and LDL-C ≥ 70 mg/dl. Moreover, patients with TC in the highest quartile, OR (95% CI): 0.36 (0.13-0.99), p < 0.05, and LDL-C ≥ 115 mg/dl, OR (95% CI): 0.53 (0.37-0.77), p < 0.05, had the lowest all-cause in-hospital mortality. However, multivariate analysis using logistic regression and a Cox proportional hazard model showed no significant influence of blood lipid levels on the occurrence of the outcomes measured.
Conclusions:
A significant effect of a "cholesterol paradox" linking better prognosis with higher blood lipid concentration was found only in univariate analysis but, after adjustment for clinical characteristics in multivariate analysis, the plasma lipid level had a neutral influence on the occurrence of the measured outcomes. This suggests that a low cholesterol level should be interpreted as a biomarker of illness severity.
... Regretfully, previously released RCT and 'academic' meta-analyses (68) report exceptionally composite outcomes with all-cause mortality, but not a coronary/cardiovascular mortality alone (notwithstanding, actually, ten trials reported on cardiovascular mortality; pooled analysis found an RR of 0.69 (95% CI: 0.54-0.88; P value was not provided) after 2 to 6 years, although statistical heterogeneity was present and there was some inconsistency in the individual trials (65,66) that doesn't allow judgement on gains of statins for mortality rates (66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82). Certainly, there is a graded association between intensity of statin therapy and all-cause mortality. ...
... A number of the manuscripts that criticize statins are swiftly surging due to some mess in statistical luggage especially with side effects and a dull impact on mortality rates in younger and older populations as well as by the fact of the existence of the 'aggressive' industry-funded scientific lobby. For instance, an independent analysis of the largest and most comprehensive meta-analysis carried out by the CTT Collaboration in 27 trials revealed no mortality benefit in individuals with a <20 % risk of developing CVD in the next 10 years (69)(70)(71)82). At least three another Cochrane meta-analyses (70,82) with 18 trials failed to report mortality benefits of statins either. ...
... At least three another Cochrane meta-analyses (70,82) with 18 trials failed to report mortality benefits of statins either. In case of no significant mortality benefit in both RCT and observational studies, the question logically moves to non-mortality gains, and potential harms (82). Further research with focused RCT would be needed to more definitively establish the relationship between statin use, cardiovascular mortality and any associated side effects. ...
The atheroprotective potential of the lipid-lowering and invasive strategies remain disputable. The aim of the study was to estimate racial disparities in these studies. This hypothesis-generating pooled analysis comparatively evaluates baseline characteristics of the coronary anatomy and patterns of the regression of atherosclerosis in Caucasian and East Asian populations (EAP) of the different Y-DNA haplogroups in 38 intravascular ultrasound (IVUS) imaging studies (N = 9,146). The analysis has revealed 7 so called Classic (51.1% of the total analyzed population) studies (conducted by the group of Nicholls/ Nissen) with mostly Caucasian population (R1b, Q3, C4 and K4 Y-DNA dominant haplogroups), 18 clinical studies (31.7%) with White/ Caucasian population (mostly Europeans of R1 haplogroup), and 13 trials (17.2%) with East Asian populations (EAP) (11 Japanese studies, 2 – South Korean, and 1 – Chinese with O and D Y-DNA dominant haplogroups). The classic trials perform superior with lower mean risk of bias (10.96%) if compare with the rest of Caucasian (21.62%) or EAP (28.88%) studies. The regression of atherosclerosis was documented in 18 of 38 studies. A -1.67±5.99% mean absolute reduction of PB reported in all 38 studies with a -18.46±20.35% decrease of LDL cholesterol. The Glagovian threshold of a 40% plaque burden (PB) with a baseline PAV above 40% was achieved in one study, a NANOM-FIM trial. The rule “the higher baseline PB the less atheroprotective effect” has been trending with a baseline plaque burden (PB) <40.30% (p=0.14) and >65.50% (p=0.39). A pooled linear regression analysis revealed moderate association between LDL-C and PB (r=0.3314, p=0.008) with a LDL-C threshold of 106 mg/dl. The EAP studies substantially differ from Caucasian trials by the smaller size of both lesions and vessels. A baseline total atheroma volume (TAV) in EAP achieved 114.25±80.44 mm3 with a mean total vessel volume (TVV) of 216.31±150.15 mm3 if compare with a 185.64±21.75 mm3 (p=0.007) TAV, and a 489.40±48.76 mm3 (p<0.0001) TVV in classic Caucasian trials. Unlike the modest 0.14±0.94% (p = 0.89) progression of atherosclerosis in classic studies (p = 0.11) LDL-C reduction), the EAP demonstrate a -1.99±3.57% (p = 0.19) atheroregression amid a mean -31.29±15.66% (p < 0.0001) decrease of LDL-C. So, the relatively tiny size of coronary arteries and high baseline plaque burden in East Asian studies drive the gains in these populations. Regretfully, unlike the invasive strategy, lipid-lowering therapy was not successful enough for regression of atherosclerosis despite substantial reduction of LDL-C. A race with a genetic haplogroup and a level of the per cent atheroma volume must be reckoned for the stages of study preparation and then analysis of the results.
... Furthermore, the baseline risk was not pre-specified in the individual trials. 5,13,22 The group with ASCVD risk <10%, had 0.3% ARR for MVEs (0.2% in females) after 5 years of statin use. Notably, the total mortality in the lowest-risk group was similar with statins or placebo (195 vs. 193) due to higher non-vascular mortality with statins (116 vs. 101). ...
... 21 Other meta-analyses 16e18 found similar lowering of MVEs without significant mortality reduction. Of note, at least 44 cholesterol-lowering RCTs reported no survival benefit (26 of them are statin trials), seven non-statin trials with significant reductions in LDL-C reported substantial clinical harms, including the cholesterol ester transfer protein-CETP inhibitor trials 22,23 Women, young adults and the elderly are typically underrepresented in RCTs: a meta-analysis of over 65,000 subjects including 35% women was published without gender specific results. 16 Among individual studies, JUPITER showed no mortality reduction in females <65 years. ...
... 27,30 PROSPER was designed to evaluate individuals aged 70e82 years given pravastatin for 3 years and reported lower CVD but similar all-cause mortality owing to higher cancer deaths. 32 Finally, most trials enrolled men > 40 years of age and women > 50e60 years age, hence the recommendation to initiate statins in adults > 20 years of age also appears to be without adequate evidence, except in FH. 1e8,12e18, 22,24,25 In sum, the data for primary prevention is consistent for reduction of events, not total mortality, and that too only in middle-aged males. ...
Tricuspid valve involvement is not uncommon in patients with rheumatic heart disease and is frequently missed on routine clinical examination. We prospectively studied the echocardiographic profile of tricuspid valve disease in 788 consecutive patients with rheumatic heart disease. Out of these patients 9% (70) had tricuspid valve disease and 55.7% (39) of these were of < or = 20 years of age. Of these 60% were females and 40% were males. Their ages ranged from 9 to 64 years (mean 24.2+/-13.6 years). Of these patients, 50% had tricuspid stenosis with or without tricuspid regurgitation whereas 50% had isolated tricuspid regurgitation. Isolated tricuspid stenosis was present in 7.4% of these cases. All patients had associated mitral stenosis. Severe mitral stenosis was present more commonly in patients with juvenile tricuspid stenosis compared to older patients (94.1% vs. 55.6%, P<0.005). Mitral regurgitation was present more commonly in juvenile age group patients compared to older patients (53.8% vs. 25.8%, P<0.01). A combination of mitral, aortic and tricuspid stenosis was present in five cases and four of these were in the juvenile age group. Left ventricular enlargement and dysfunction were present in 28.6 and 14.3% patients, respectively, and the majority of these patients were in the juvenile age group (P<0.05). We conclude that rheumatic tricuspid valve disease occurs early in the course of the disease and progresses faster in India and is always associated with mitral stenosis. Juvenile tricuspid stenosis is more commonly associated with severe mitral stenosis, mitral regurgitation, left ventricular enlargement and dysfunction as compared with older patients.
... Finally, and most significantly, DuBroff reported that 44 prospective, randomized controlled studies of cholesterol-lowering therapy, three of which involved diet, showed no mortality benefit despite reductions in LDL-cholesterol levels of up to 50%. Additionally, 30 of these studies showed no reduction in cardiovascular events [10]. ...
... Thus, someone under the impression that discordant finds are rare may dismiss them as statistical outliers and not shortcomings of the theory. The work of DuBroff et al. [10] shows that discordant data are too common to be dismissed and must be considered a shortcoming in lipid theory. ...
Deaths due to atherothrombosis are increasing throughout the world except in the lowest socio-demographic stratum. This is despite 60 years of study and expenditure of billions of dollars on lipid theory. Nevertheless, mainstream atherothrombosis theory persists even though it has failed numerous tests. Contrary data are ignored, consistent with the practice of science as envisioned by Thomas Kuhn. This paper examines defects in mainstream atherogenesis theory and the flawed logic which allows its persistence in the face of what should be obvious shortcomings.
... Similarly, selected RCTs of statins in other high-risk populations-diabetes mellitus, chronic kidney disease, ischemic heart failure, post-MI and post-CABG-have also reported no clinical benefit. 4 In another study, only 25% of relatively young patients with myocardial infarctions would have qualified for statin therapy based upon their risk scores. These and other limitations of the risk-guided model were not addressed in these guidelines. ...
... Furthermore, recent reviews affirming the benefits of cholesterol reduction have largely ignored nearly four dozen RCTs of cholesterol lowering that have failed to reduce mortality or CV events. 4 To ensure balance and fairness medical experts must incorporate the entire empirical record, not simply the evidence that substantiates their own viewpoint. We must also acknowledge that financial relationships between the pharmaceutical industry and some medical experts can engender both conflicts of interest and bias that can jeopardize the credibility of their opinions. ...
... Though numerous RCTs have shown statins to reduce cardiovascular risk, it is equally important to note the findings of several RCTs that have found no significant link between lower cholesterol levels and increased cardiovascular risk [10][11][12] . Approximately 40 randomised controlled trials (RCTs) using cholesterol-lowering drugs such as statins, clofibrate, ezetimibe, and evacetrapib have found no reduction in mortality or cardiovascular events 13 . Furthermore, only a few RCTs 14 have found a significant risk with cholesterol-lowering drugs. ...
A decrease in cardiovascular event risk with a decrease in total and LDL – cholesterol level is termed as “cholesterol paradox” or “risk factor reversal”. Cardiovascular risk does not have a linear relationship between LDL – cholesterol levels, and other substantial risk factors of cardiovascular events are being disregarded.The aim of this study is, to identify modifiable risk factors of cardiovascular events other than those well proved to cause dyslipidemia. A cross-sectional study was conducted with 652 participants in a tertiary care hospital. Patients were grouped into two, based on the history of cardiovascular events. Demographics and patient responses captured using pre-validated questionnaires were analyzed. 5mL blood samples were collected by venipuncture and lipid profile was estimated. Association between cardiovascular events and explanatory variables. was determined using Chi square test and Odds ratio at 95% confidence intervals. Higher risk of CV events was found among smokers 0.232 [0.144 – 0.373]. Consumption of white sugar, refined oil, processed cold beverages and fast food products increased CV risk respectively. Moreover, total cholesterol, LDL-C and triglycerides were found to decrease after one year of counselling the patients. The classical hypothesis of dyslipidemia induced atherosclerosis may not be the predominant cause of CV events. Herein, we report no association between high fat diet and CV risk while we observed higher risk in consumers of refined and ultra processed food products. However, significant control of cholesterol was observed in patients who shifted to Unrefined food products.
... This paradoxical situation exists and has been discussed in the statistical and medical literature. 13,17 As recently discussed by Buyse et al, 13 to serve as a surrogate, an end point should ideally be on the causal pathway between treatment and final end point. 18 This would-in a perfect situation-imply that the treatment effect on the final end point is indirect and entirely mediated by the effect on the surrogate. ...
Trial-level surrogacy is critical before early response endpoints are used to approve new therapies.
... Though numerous RCTs have shown statins to reduce cardiovascular risk, it is equally important to note the findings of several RCTs that have found no significant link between lower cholesterol levels and increased cardiovascular risk [10][11][12] . Approximately 40 randomised controlled trials (RCTs) using cholesterollowering drugs such as statins, clofibrate, ezetimibe, and evacetrapib have found no reduction in mortality or cardiovascular events 13 . Furthermore, only a few RCTs 14 have found a significant risk with cholesterol-lowering drugs. ...
A decrease in cardiovascular event risk with a decrease in total and LDL – cholesterol level is termed as “cholesterol paradox” or “risk factor reversal”. Cardiovascular risk does not have a linear relationship between LDL – cholesterol levels, and other substantial risk factors of cardiovascular events are being disregarded. The aim of this study is, to identify modifiable risk factors of cardiovascular events other than those well proved to cause dyslipidemia. A cross-sectional study was conducted with 652 participants in a tertiary care hospital. Patients were grouped into two, based on the history of cardiovascular events. Demographics and patient responses captured using pre-validated questionnaires were analyzed. 5mL blood samples were collected by venipuncture and lipid profile was estimated. Association between cardiovascular events and explanatory variables. was determined using Chi square test and Odds ratio at 95% confidence intervals. Higher risk of CV events was found among smokers 0.232 [0.144 – 0.373]. Consumption of white sugar, refined oil, processed cold beverages and fast food products increased CV risk respectively. Moreover, total cholesterol, LDL-C and triglycerides were found to decrease after one year of counselling the patients. The classical hypothesis of dyslipidemia induced atherosclerosis may not be the predominant cause of CV events. Herein, we report no association between high fat diet and CV risk while we observed higher risk in consumers of refined and ultra processed food products. However, significant control of cholesterol was observed in patients who shifted to Unrefined food products.
... Indeed evidence disputing the traditional diet-heart and lipid hypotheses, now seemingly also disproven by the WHIRCDMT, continues to accumulate. [48][49][50][51][52][53][54][55][56][57][58][59] ...
The Women's Health Initiative Randomized Controlled Dietary Modification Trial (WHIRCDMT) was designed to test whether the US Department of Agriculture's 1977 Dietary Guidelines for Americans protects against coronary heart disease (CHD) and other chronic diseases. The only significant finding in the original 2006 WHIRCDMT publication was that postmenopausal women with CHD randomised to a low-fat 'heart-healthy' diet in 1993 were at 26% greater risk of developing additional CHD events compared with women with CHD eating the control diet. A 2017 WHIRCDMT publication includes data for an additional 5 years of follow-up. It finds that CHD risk in this subgroup of postmenopausal women had increased further to 47%-61%. The authors present three post-hoc rationalisations to explain why this finding is 'inadmissible': (1) only women in this subgroup were less likely to adhere to the prescribed dietary intervention; (2) their failure to follow the intervention diet increased their CHD risk; and (3) only these women were more likely to not have received cholesterol-lowering drugs. These rationalisations appear spurious. Rather these findings are better explained as a direct consequence of postmenopausal women with features of insulin resistance (IR) eating a low-fat high-carbohydrate diet for 13 years. All the worst clinical features of IR, including type 2 diabetes mellitus (T2DM) in some, can be 'reversed' by the prescription of a high-fat low-carbohydrate diet. The Women's Health Study has recently reported that T2DM (10.71-fold increased risk) and other markers of IR including metabolic syndrome (6.09-fold increased risk) were the most powerful predictors of future CHD development in women; blood low-density lipoprotein-cholesterol concentration was a poor predictor (1.38-fold increased risk). These studies challenge the prescription of the low-fat high-carbohydrate heart-healthy diet, at least in postmenopausal women with IR, especially T2DM. According to the medical principle of 'first do no harm', this practice is now shown to be not evidence-based, making it scientifically unjustifiable, perhaps unethical.
... If, for example, category III represented herbivores defined as all animals for which plant material represents ≥90% of the natural diet, and category II, omnivores as those animals for which plant material is less than 90% (but more than 10%), there would obviously be no space between these categories, and hence, allowing an intermediate category ( A comparison is instructive with a field where diagnoses based on proxies against a "background pattern" are vital: human medicine. A classic statement in human medicine is that "a correlate does not a surrogate make" (DuBroff, 2017;Fleming & DeMets, 1996), meaning that even though there may be statistical correlations between categories (such as the patterns depicted in Figure 1a and c), this does not automatically mean that the measurements also represent powerful diagnostic proxies. This has been shown repeatedly in biological datasets. ...
In paleontology and biology, measures that correlate with specific traits are often used as proxies for these traits without a clear concept of how their discriminatory power is assessed. This note warns about this practice.
... 26 These observational findings are further supported by RCTs with statin or anti-PCSK9 interventions, in which risk reduction was primarily achieved for non-fatal endpoints. [27][28][29] Furthermore, our findings are supported by several other studies, some performed already before wide use of cholesterol lowering medications, that have shown that cardiovascular risk prediction by LDL-C or TC for CHD tend to decrease with increasing age. [30][31][32][33] Especially, the young adulthood may be the most important time to find individuals with potential life-long exposure to high LDL-cholesterol levels and to start preventive measures. ...
Aims
Low-density lipoprotein cholesterol (LDL-C) is an established causal driver of atherosclerotic cardiovascular disease (ASCVD), but its performance and age-dependency as a biomarker for incident events and mortality arising from ASCVD is less clear. The aim was to determine the value of LDL-C as a susceptibility/risk biomarker for incident coronary heart disease (CHD), ASCVD, and stroke events and deaths, for the age groups <50 and ≥50 years.
Methods and results
The performance of LDL-C was evaluated in three cohorts, FINRISK 2002 (n = 7709), HUSK (n = 5431), and ESTHER (n = 4559), by Cox proportional hazards models, C-statistics, and net reclassification index calculations. Additionally, the hazard ratios (HRs) for the three cohorts were pooled by meta-analysis. The most consistent association was observed for CHD [95% confidence interval (CI) for HRs per standard deviation ranging from 0.99 to 1.37], whereas the results were more modest for ASCVD (0.96–1.18) due to lack of association with stroke (0.77–1.24). The association and discriminatory value of LDL-C with all endpoints in FINRISK 2002 and HUSK were attenuated in subjects 50 years and older [HRs (95% CI) obtained from meta-analysis 1.11 (1.04–1.18) for CHD, 1.15 (1.02–1.29) for CHD death, 1.02 (0.98–1.06) for ASCVD, 1.12 (1.02–1.23) for ASCVD death, and 0.97 (0.89–1.05) for stroke].
Conclusion
In middle-aged and older adults, associations between LDL-C and all the studied cardiovascular endpoints were relatively weak, while LDL-C showed stronger association with rare events of pre-mature CHD or ASCVD death among middle-aged adults. The predictive performance of LDL-C also depends on the studied cardiovascular endpoint.
... 26,27 Concerning the possibly misleading evidence about LDL role in CVD, few years ago 44 randomized controlled trials (RCTs) of drugs or dietary interventions to lower LDL have been revised, without eliciting any benefit on all-cause mortality. 28 Little beneficial, most neutral or detrimental effects on CVD events were demonstrated in these examined studies. Moreover, the ACCELERATE Trial showed no relevant reduction in CVD events or overall mortality, despite a 130% increase in HDL and a 37% decrease in LDL. ...
Literature concerning the causative factors of atherosclerotic cardiovascular disease shows complex and sometimes contrasting evidence. Most guidelines suggest a strategy aimed at lowering circulating low density lipoproteins (LDL) and ApoB lipoprotein levels. The use of statins and of cholesteryl ester transfer protein inhibitors has led to a number of controversial outcomes, generating a certain degree of concern about the real efficacy and especially safety of these drugs. Literature data show that the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors results in a dramatic reduction of various markers of lipid metabolism (namely LDL); however, several critical scientific papers have questioned the value, the need and especially the safety of these innovative drugs. LDL are a protective factor against lipopolysaccharides and other microbial derivatives. Similarly, these Gram negative bacteria-derived compounds have been identified as probable culprits of cardiovascular atherogenesis; moreover, lipopolysaccharides increase hepatic synthesis of PCSK9, as defense mechanism. This enzyme modulates LDL receptors level in the liver, as well as in other organs, such as adrenal gland and reproductive organs. Hence, PCSK9 inhibition may influence glucocorticoid secretion and fertility. Lastly, the consequent reduction of circulating LDL may relevantly hindrance immune system and favor lipopolysaccharides diffusion.
... С нашей точки зрения, такой подход требует широкого врачебного обсуждения и согласования, поскольку совершенно точно это повлечет за собой: а) дальнейший рост показателей заболеваемости ишемической болезнью сердца (болезнью коронарных артерий) за счет установления диагноза всем обратившимся за медицинской помощью при наличии факторов риска развития сердечно-сосудистых осложнений; б) назначение необоснованной терапии. Вопросы медикаментозного, эндоваскулярного и хирургического лечения (с учетом данных, не отраженных в рекомендациях ESC [17][18][19][20][21][22][23]), также требуют согласования. ...
In 2019, the European Society for Cardiology (ESC) published guidelines with a new term, “chronic coronary syndromes” (CCS). These guidelines presented 6 clinical scenarios, which are most common in outpatient practice. The diagnostic approach described in these guidelines shifts from the standardization to the rationality of individualized solutions on using various diagnostic methods. The diagnostic approach suggested in the ESC guidelines requires extensive medical discussion and consensus because this will definitely entail a) further increase in indexes that reflect the morbidity of ischemic heart disease (IHD) due to unconfirmed diagnoses and b) administration of unreasoned therapy. This article presents statements of the guidelines, which cannot be automatically transmitted to the existing medical practice and should be discussed and adjusted by experts of the Russian Society of Cardiology.
... An iconoclast argument: cholesterol does not cause coronary heart disease. 3 The reluctance to accept the cholesterol hypothesis is nothing new. The amazing discoveries of legendary Russian scientist Nikolai N. Anichkov, who in 1913, via elegant experiments showed the role of cholesterol in the genesis of atherosclerosis, 4 has been rampantly negated or belittled even to these days, partly for ignorance but also for racists and political prejudices. ...
This manuscript is an addendum to the positioning around the diagnosis and treatment of dyslipidemias of ANCAM and the joint group of associated medical societies, already published. It is the fi rst part of a wider refl ection aimed on refute several of the theses and arguments of a group of clinicians and researchers who question the validity of the "cholesterol hypothesis", the usefulness and safety of statins and the most modern inhibitors of proprotein convertase of subtilisin/kexin type 9 (iPCSK9,) and the role of saturated fatty acids consumed in the usual diet in the atherosclerotic risk. This iconoclastic point of view is dangerous insofar as it undermines the scaff olding that supports the primary and secondary prevention of atherosclerosis. In this section of the manuscript, only the cholesterol hypothesis is discussed. The data of comparative zoology are reviewed, and several experimental animal models are analyzed, both supporting the link between cholesterol and the appearance and evolution of atherosclerotic lesions. The methodology and the results of the Study of the 7 Countries are defended and are exposed the numerous epidemiological, pathological, clinical and interventional evidences, which in our opinion give a solid sustenance to the cholesterol hypothesis. Based on this knowledge it is criticized the LDL cholesterol values currently considered adequate. Furthermore, the so-called residual risk is considered, as well as the confl icting evidence about the usefulness of statins in elderly patients. © 2018 Asociacion Nacional de Cardiologos de Mexico. All Rights Reserved.
... DuBroff cataloged 44 randomized controlled trials of cholesterol-lowering therapy which showed no benefit in cardiovascular mortality. Thirty of these trials showed no decrease in nonfatal cardiovascular events [50]. In addition to spurring the development of more effective therapies, insight into the true cause of atherothrombosis will inform nutritional recommendations. ...
The authors hypothesize that thrombosis causes both the complications of atherosclerosis as well as the underlying lesion, the atherosclerotic plaque, which develops from the organization of mural thrombi. These form in areas of slow blood flow, which develop because of flow separation created by changing vascular geometry and elevated blood viscosity. Many phenomena typically ascribed to inflammation or “chronic oxidative stress”, such as the development of fatty streaks, “endothelial dysfunction,” “vulnerable plaques,” and the association of mild elevations of C-reactive protein and cytokines with atherothrombosis are better explained by hemorheologic and hemodynamic abnormalities, particularly elevated blood viscosity. Elevated blood viscosity decreases the perfusion of skeletal muscle, leading to myocyte expression of the myokine IL-6, decreased glucose uptake, insulin resistance, hyperglycemia, and metabolic syndrome. The hyperfibrinogenemia and hypergammaglobulinemia present in true inflammatory diseases foster atherothrombosis by increasing blood viscosity.
... Multiple lines of evidence have established that cholesterol-rich LDL and other apolipoprotein B (apoB)-containing lipoproteins, including very low-density lipoproteins (VLDL) and their remnants, intermediate density lipoproteins (IDL), and lipoprotein(a) [Lp(a)], are directly implicated in the development of ASCVD. 2 Despite this extensive body of evidence, however, some still express scepticism of the causal nature of the relationship between LDL and the development of ASCVD. 3 With the availability of new, highly efficacious LDL-lowering agents and the development of additional novel lipid-lowering agents with prolonged duration of action, there is a need for a consensus as to whether LDL causes ASCVD in order to inform treatment guidelines and help shape regulatory agency guidance for the approval of new medicines. ...
Aims:
To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).
Methods and results:
We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects.
Conclusion:
Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
Aim : to examine the opinions of healthcare professionals on using codes from the ICD-10 group chronic ischemic heart disease (CIHD) (I25.0, I25.1, I25.8, I25.9) as the primary cause of death and discuss the results in the context of comparing with regional variability of standardized mortality ratio (SMR) from different forms of CIHD. Materials and methods . A one-stage study was conducted. This article describes the results of a survey of 366 medical workers (cardiologists, internists/general practitioners/family doctors, pathologists, public health and healthcare specialists, paramedics) from 47 subjects of the Russian Federation who fill out a medical death certificate (MDS) more often than 2–3 times a month. In addition, SMR from coronary heart disease were determined based on a brief nomenclature of causes of death of Rosstat in 82 regions of the Russian Federation for 2022. Results . 80.1 % of respondents expressed the opinion that I25.0, I25.1, I25.8, I25.9 are necessary for coding causes of death, but half of those surveyed do not see any differences in them. At the same time, respondents admit the possibility of using these CIHD codes as the primary cause of death without ante-mortem and pathological verification. The relatively small coefficient of variation of SMR overall from CIHD (34.19 per 100,000 population) is associated with high values from its individual forms: the coefficient of variation of average regional SMRs ranged from 62 % for code I25.1 to 174 % for code I25.0. Conclusions . The results of this study indicate a variable attitude of specialists filling out MSD towards choosing ICD-10 codes from the CIHD group, leading to significant interregional differences in CIHD mortality rates. It is necessary to develop unified recommendations describing situations in which codes from the CIHD group can be considered the primary (main) cause of death.
Developing engaging activities that build skills for understanding and appreciating research is important for undergraduate and postgraduate science students. Comparing and contrasting opposing research studies does this, and more: it also appropriately for these cohorts challenges higher-level cognitive processing. Here, we present and discuss one such scenario, that of calcineurin in the heart and its response to exercise training. This scenario is further accentuated by the existence of only 2 studies. The background is that regular aerobic endurance exercise training stimulates the heart to physiologically adapt to chronically increase its ability to produce a greater cardiac output to meet the increased demand for oxygenated blood in working muscles, and this happens by 2 main mechanisms: 1) increased cardiac contractile function and 2) physiologic hypertrophy. The major underlying mechanisms have been delineated over the last decades, but one aspect has not been resolved: the potential role of calcineurin in modulating physiologic hypertrophy. This is partly because the existing research has provided opposing and contrasting findings, one line showing that exercise training does activate cardiac calcineurin in conjunction with myocardial hypertrophy, but another line showing that exercise training does not activate cardiac calcineurin even if myocardial hypertrophy is blatantly occurring. Here, we review and present the current evidence in the field and discuss reasons for this controversy. We present real-life examples from physiology research and discuss how this may enhance student engagement and participation, widen the scope of learning, and thereby also further facilitate higher-level cognitive processing.
Résumé
Le terme d’hypercholestérolémie désigne les dyslipidémies avec augmentation du taux de cholestérol circulant. Il s’agit de la dyslipidémie la plus fréquente et qui est associée à une augmentation du risque de survenue d’une maladie cardio-vasculaire athéromateuse. Un des enjeux majeur en prévention primaire est de définir le seuil d’intervention thérapeutique permettant à la fois d’obtenir un bénéfice clinique significatif sans exposer inutilement le patient aux potentiels effets secondaires des traitements hypolipémiants. Il s’agit également de ne pas méconnaître une hypercholestérolémie familiale hétérozygote, une maladie génétique du métabolisme lipidique fréquente, responsable de complications coronaires particulièrement graves et précoces. Dans cet article, seront abordées les questions du dépistage de l’hypercholestérolémie, de la définition des objectifs thérapeutiques et bénéfices attendus ainsi que des modalités de prise en charge thérapeutique en abordant la problématique de l’intolérance aux statines.
Drug treatment to reduce cholesterol to new target levels is now recommended in four moderate- to high-risk patient populations: patients who have already sustained a cardiovascular event, adult diabetic patients, individuals with low density lipoprotein cholesterol levels ≥190 mg/dL and individuals with an estimated 10-year cardiovascular risk ≥7.5%. Achieving these cholesterol target levels did not confer any additional benefit in a systematic review of 35 randomised controlled trials. Recommending cholesterol lowering treatment based on estimated cardiovascular risk fails to identify many high-risk patients and may lead to unnecessary treatment of low-risk individuals. The negative results of numerous cholesterol lowering randomised controlled trials call into question the validity of using low density lipoprotein cholesterol as a surrogate target for the prevention of cardiovascular disease.
Evidence-based recommendations for increasing subjective happiness and wellbeing or decreasing depression and anxiety in non-clinical populations: systematic review of meta-analyses of observational studies, interventional trials and meta-analyses of interventional trials.
Statins are the most widely prescribed, cholesterol-lowering drugs in the world. Despite the expiration of their patents, revenue for statins is expected to rise, with total sales on track to reach an estimated US$1 trillion by 2020. A bitter dispute has erupted among doctors over suggestions that statins should be prescribed to millions of healthy people at low risk of heart disease. There are concerns that the benefits have been exaggerated and the risks have been underplayed. Also, the raw data on the efficacy and safety of statins are being kept secret and have not been subjected to scrutiny by other scientists. This lack of transparency has led to an erosion of public confidence. Doctors and patients are being misled about the true benefits and harms of statins, and it is now a matter of urgency that the raw data from the clinical trials are released.
Early warning signals of the coronary heart disease (CHD) risk of sugar (sucrose) emerged in the 1950s. We examined Sugar Research Foundation (SRF) internal documents, historical reports, and statements relevant to early debates about the dietary causes of CHD and assembled findings chronologically into a narrative case study. The SRF sponsored its first CHD research project in 1965, a literature review published in the New England Journal of Medicine, which singled out fat and cholesterol as the dietary causes of CHD and downplayed evidence that sucrose consumption was also a risk factor. The SRF set the review’s objective, contributed articles for inclusion, and received drafts. The SRF’s funding and role was not disclosed. Together with other recent analyses of sugar industry documents, our findings suggest the industry sponsored a research program in the 1960s and 1970s that successfully cast doubt about the hazards of sucrose while promoting fat as the dietary culprit in CHD. Policymaking committees should consider giving less weight to food industry–funded studies and include mechanistic and animal studies as well as studies appraising the effect of added sugars on multiple CHD biomarkers and disease development.
Objective To estimate the average postponement of death in statin trials.
Setting A systematic literature review of all statin trials that presented all-cause survival curves for treated and untreated.
Intervention Statin treatment compared to placebo.
Primary outcome measures The average postponement of death as represented by the area between the survival curves.
Results 6 studies for primary prevention and 5 for secondary prevention with a follow-up between 2.0 and 6.1 years were identified. Death was postponed between −5 and 19 days in primary prevention trials and between −10 and 27 days in secondary prevention trials. The median postponement of death for primary and secondary prevention trials were 3.2 and 4.1 days, respectively.
Conclusions Statin treatment results in a surprisingly small average gain in overall survival within the trials’ running time. For patients whose life expectancy is limited or who have adverse effects of treatment, withholding statin therapy should be considered.
Importance
Both dietary modification and use of statins can lower blood cholesterol. The increase in caloric intake among the general population is reported to have plateaued in the last decade, but no study has examined the relationship between the time trends of caloric intake and statin use.Objective
To examine the difference in the temporal trends of caloric and fat intake between statin users and nonusers among US adults.Design, Setting, and Participants
A repeated cross-sectional study in a nationally representative sample of 27 886 US adults, 20 years or older, from the National Health and Nutrition Examination Survey, 1999 through 2010.Exposures
Statin use.Main Outcomes and Measures
Caloric and fat intake measured through 24-hour dietary recall. Generalized linear models with interaction term between survey cycle and statin use were constructed to investigate the time trends of dietary intake for statin users and nonusers after adjustment for possible confounders. We calculated model-adjusted caloric and fat intake using these models and examined if the time trends differed by statin use. Body mass index (BMI) changes were also compared between statin users and nonusers.Results
In the 1999-2000 period, the caloric intake was significantly less for statin users compared with nonusers (2000 vs 2179 kcal/d; P = .007). The difference between the groups became smaller as time went by, and there was no statistical difference after the 2005-2006 period. Among statin users, caloric intake in the 2009-2010 period was 9.6% higher (95% CI, 1.8-18.1; P = .02) than that in the 1999-2000 period. In contrast, no significant change was observed among nonusers during the same study period. Statin users also consumed significantly less fat in the 1999-2000 period (71.7 vs 81.2 g/d; P = .003). Fat intake increased 14.4% among statin users (95% CI, 3.8-26.1; P = .007) while not changing significantly among nonusers. Also, BMI increased more among statin users (+1.3) than among nonusers (+0.4) in the adjusted model (P = .02).Conclusions and Relevance
Caloric and fat intake have increased among statin users over time, which was not true for nonusers. The increase in BMI was faster for statin users than for nonusers. Efforts aimed at dietary control among statin users may be becoming less intensive. The importance of dietary composition may need to be reemphasized for statin users.
Randomised controlled trials are objective, free of bias, and produce robust conclusions about the benefits and risks of treatment, and clinicians should be trained to rely on them; so says the gospel of evidence based practice. In this article we argue, using the United Kingdom prospective diabetes study (UKPDS) as an example, that there is one stage in the conduct of a randomised controlled trial—the interpretation and dissemination ofresults—that is open to several biases that can seriously distort the conclusions. By bias, we mean the epidemiological definition: anything that systematically distorts the comparisons between groups. We will argue that certain biases arise when different stakeholders assign their individual values to the interpretation of the final results of randomised controlled trials.
Summary points
Randomised trials are subject to interpretation bias as shown by the example of the UK prospective diabetes study
The UK prospective diabetes study shows no benefit on macrovascular end points in patients with type 2 diabetes treated with sulphonylureas or insulin over 10 years
The study shows a clinically important benefit on macrovascular end points from metformin in patients with type 2 diabetes that seems somewhat independent of the drug's ability to lower blood glucose concentrations
Nevertheless, many authors, journal editors, and the wider scientific community interpreted the study as providing evidence of the benefit of intensive glucose control
Journal editors should be aware of this important potential bias and encourage authors to present their results initially with a minimum of discussion so as to invite a range of comments and perspectives from readers
Marketing the UK prospective diabetes study results
Until 1998, type 2 diabetes had been treated for over 25 years with drugs such as the sulphonylureas, insulin, and metformin. Only one well designed, prospective clinical trial had evaluated the effect of these drugs on the development of microvascular and macrovascular disease. This was the …
Statins have been shown to reduce the risk of all-cause mortality among individuals with clinical history of coronary heart disease. However, it remains uncertain whether statins have similar mortality benefit in a high-risk primary prevention setting. Notably, all systematic reviews to date included trials that in part incorporated participants with prior cardiovascular disease (CVD) at baseline. Our objective was to reliably determine if statin therapy reduces all-cause mortality among intermediate to high-risk individuals without a history of CVD.
Trials were identified through computerized literature searches of MEDLINE and Cochrane databases (January 1970-May 2009) using terms related to statins, clinical trials, and cardiovascular end points and through bibliographies of retrieved studies.
Prospective, randomized controlled trials of statin therapy performed in individuals free from CVD at baseline and that reported details, or could supply data, on all-cause mortality.
Relevant data including the number of patients randomized, mean duration of follow-up, and the number of incident deaths were obtained from the principal publication or by correspondence with the investigators.
Data were combined from 11 studies and effect estimates were pooled using a random-effects model meta-analysis, with heterogeneity assessed with the I(2) statistic. Data were available on 65,229 participants followed for approximately 244,000 person-years, during which 2793 deaths occurred. The use of statins in this high-risk primary prevention setting was not associated with a statistically significant reduction (risk ratio, 0.91; 95% confidence interval, 0.83-1.01) in the risk of all-cause mortality. There was no statistical evidence of heterogeneity among studies (I(2) = 23%; 95% confidence interval, 0%-61% [P = .23]).
This literature-based meta-analysis did not find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up.
Type 2 diabetes is an epidemic that is affecting an ever-increasing proportion of the US population. Although consumption of refined carbohydrates has increased and is thought to be related to the increased risk of type 2 diabetes, the ecologic effect of changes in the quality of carbohydrates in the food supply on the risk of type 2 diabetes remains to be quantified.
The objective was to examine the correlation between consumption of refined carbohydrates and the prevalence of type 2 diabetes in the United States.
In this ecologic correlation study, the per capita nutrient consumption in the United States between 1909 and 1997 obtained from the US Department of Agriculture was compared with the prevalence of type 2 diabetes obtained from the Centers for Disease Control and Prevention.
In a univariate analysis, a significant correlation with diabetes prevalence was observed for dietary fat (r = 0.84, P < 0.001), carbohydrate (r = 0.55, P < 0.001), protein (r = 0.71, P < 0.001), fiber (r = 0.16, P = 0.03), corn syrup (r = 0.83, P < 0.001), and total energy (r = 0.75, P < 0.001) intakes. In a multivariate nutrient-density model, in which total energy intake was accounted for, corn syrup was positively associated with the prevalence of type 2 diabetes (beta = 0.0132, P = 0.038). Fiber (beta = -13.86, P < 0.01) was negatively associated with the prevalence of type 2 diabetes. In contrast, protein (P = 0.084) and fat (P = 0.79) were not associated with the prevalence of type 2 diabetes when total energy was controlled for.
Increasing intakes of refined carbohydrate (corn syrup) concomitant with decreasing intakes of fiber paralleled the upward trend in the prevalence of type 2 diabetes observed in the United States during the 20th century.
The so-called LDL hypothesis is the concept that excess low-density lipoprotein (LDL) cholesterol is a causal factor in the development of atherosclerotic vascular disease. By extension, this hypothesis also assumes that reducing LDL cholesterol levels, regardless of the means, should produce a corresponding reduction in cardiovascular events. Considerable evidence supports the LDL hypothesis, including animal studies and epidemiologic studies involving humans, as well as clinical trials of both statins and nonstatin lipid-modifying agents. In a meta-analysis that included more than 90,000 participants in 14 randomized trials of statins, the Cholesterol Treatment Trialists' (CTT) collaborators found that, on average, a reduction . . .
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A review of statins for primary prevention of cardiovascular disease could alter guidance for those with a 10 year risk of less than 10%. John Abramson and colleagues argue that statins have no overall health benefit in this population and that prescribing guidelines should not be broadened
The 2013 Cochrane review of primary prevention with statins concluded that they reduce all cause mortality and cardiovascular events without increasing the risk of adverse events among people at low risk of cardiovascular disease (<10% over 10 years).1 However, just two years earlier, a Cochrane review had concluded that existing evidence did not support the use of cholesterol lowering statins for people with <20% 10 year cardiovascular risk: “Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.”2 This conclusion was consistent with the 2006-08 guidance from the National Institute for Health and Care Excellence (NICE)3 and the 2011 update of the American Heart Association’s guidelines for the prevention of cardiovascular disease in women, both of which recommended statin therapy only when the 10 year risk of disease is 20% or greater.4
If risk is estimated using the QRISK2 score,5 by the 2011 standards just 2% of women in their 50s and 16% in their 60s qualify for statin therapy (≥ 20% 10 year risk of cardiovascular disease). For men, 9% in their 50s and 48% in their 60s qualify.6 Under the proposed 2013 standards, however, no level of risk would preclude statin therapy, raising the question whether all people over the age of 50 should be treated.1 7 We argue that the evidence does not show that the benefits of …
Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain.
This 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.
Reduction 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.
In 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.
British Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.
To explore the extent to which components of composite end points in randomised controlled trials vary in importance to patients, the frequency of events in the more and less important components, and the extent of variability in the relative risk reductions across components.
Systematic review of randomised controlled trials.
Cardiovascular randomised controlled trials published in the Lancet, Annals of Internal Medicine, Circulation, European Heart Journal, JAMA, and New England Journal of Medicine, from 1 January 2002 to 30 June 2003. Component end points of composite end points were categorised according to importance to patients as fatal, critical, major, moderate, or minor.
Of 114 identified randomised controlled trials that included a composite end point of importance to patients, 68% (n=77) reported complete component data for the primary composite end point; almost all (98%; n=112) primary composite end points included a fatal end point. Of 84 composite end points for which component data were available, 54% (n=45) showed large or moderate gradients in both importance to patients and magnitude of effect across components. When analysed by categories of importance to patients, the most important components were associated with lower event rates in the control group (medians of 3.3-3.7% for fatal, critical, and major outcomes; 12.3% for moderate outcomes; and 8.0% for minor outcomes). Components of greater importance to patients were associated with smaller treatment effects than less important ones (relative risk reduction of 8% for death and 33% for components of minor importance to patients).
The use of composite end points in cardiovascular trials is frequently complicated by large gradients in importance to patients and in magnitude of the effect of treatment across component end points. Higher event rates and larger treatment effects associated with less important components may result in misleading impressions of the impact of treatment.
Background:
The early period following the onset of acute coronary syndrome (ACS) represents a critical stage of coronary heart disease, with a high risk of recurrent events and deaths. The short-term effects of early treatment with statins on patient-relevant outcomes in patients suffering from ACS are unclear. This is an update of a review previously published in 2011.
Objectives:
To assess the effects, both harms and benefits, of early administered statins in patients with ACS, in terms of mortality and cardiovascular events.
Search methods:
We updated the searches of CENTRAL (2013, Issue 3), MEDLINE (Ovid) (1946 to April Week 1 2013), EMBASE (Ovid) (1947 to 2013 Week 14), and CINAHL (EBSCO) (1938 to 2013) on 12 April 2013. We applied no language restrictions. We supplemented the search by contacting experts in the field, by reviewing the reference lists of reviews and editorials on the topic, and by searching trial registries.
Selection criteria:
Randomized controlled trials (RCTs) comparing statins with placebo or usual care, with initiation of statin therapy within 14 days following the onset of ACS, follow-up of at least 30 days, and reporting at least one clinical outcome.
Data collection and analysis:
Two authors independently assessed risk of bias and extracted data. We calculated risk ratios (RRs) for all outcomes in the treatment and control groups and pooled data using random-effects models.
Main results:
Eighteen studies (14,303 patients) compared early statin treatment versus placebo or no treatment in patients with ACS. The new search did not identify any new studies for inclusion. There were some concerns about risk of bias and imprecision of summary estimates. Based on moderate quality evidence, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction, and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) or four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up when compared to placebo or no treatment. There were no statistically significant risk reductions from statins for total death, total myocardial infarction, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month or at four months, although there were favorable trends related to statin use for each of these endpoints. Moderate quality evidence suggests that the incidence of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels more than 10 times the upper limit of normal) in statin-treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg.
Authors' conclusions:
Based on moderate quality evidence, due to concerns about risk of bias and imprecision, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS. Serious side effects were rare.
Prospective data at Framingham and elsewhere have shown conclusively that risk of coronary heart disease in persons younger than age 50 is strikingly related to the serum total cholesterol level. Within so-called normal limits risk has been found to mount over a five-fold range. The impact has been found to be augmented by other risk factors. The contribution of the serum total cholesterol to risk has also been found to be determined by its partition in the various lipoprotein fractions. A relatively large amount of cholesterol in the low-density lipoprotein fraction is atherogenic, whereas that in the high-density fraction appears protective. The independent contribution of very-low density lipoprotein and its triglyceride or cholesterol content has, on the other hand, not been established. The previous position that virtually all of the lipid information pertaining to coronary heart disease resided in the serum total cholesterol must be accordingly modified.
Phase 3 clinical trials, which evaluate the effect that new interventions have on the clinical outcomes of particular relevance to the patient (such as death, loss of vision, or other major symptomatic event), often require many participants to be followed for a long time. There has recently been great interest in using surrogate end points, such as tumor shrinkage or changes in cholesterol level, blood pressure, CD4 cell count, or other laboratory measures, to reduce the cost and duration of clinical trials. In theory, for a surrogate end point to be an effective substitute for the clinical outcome, effects of the intervention on the surrogate must reliably predict the overall effect on the clinical outcome. In practice, this requirement frequently fails. Among several explanations for this failure is the possibility that the disease process could affect the clinical outcome through several causal pathways that are not mediated through the surrogate, with the intervention's effect on these pathways differing from its effect on the surrogate. Even more likely, the intervention might also affect the clinical outcome by unintended, unanticipated, and unrecognized mechanisms of action that operate independently of the disease process. We use examples from several disease areas to illustrate how surrogate end points have been misleading about the actual effects that treatments have on the health of patients. Surrogate end points can be useful in phase 2 screening trials for identifying whether a new intervention is biologically active and for guiding decisions about whether the intervention is promising enough to justify a large definitive trial with clinically meaningful outcomes. In definitive phase 3 trials, except for rare circumstances in which the validity of the surrogate end point has already been rigorously established, the primary end point should be the true clinical outcome.
Meta-analyses are now widely used to provide evidence to support clinical strategies. However, large randomized, controlled trials are considered the gold standard in evaluating the efficacy of clinical interventions.
We compared the results of large randomized, controlled trials (involving 1000 patients or more) that were published in four journals (the New England Journal of Medicine, the Lancet, the Annals of Internal Medicine, and the Journal of the American Medical Association) with the results of meta-analyses published earlier on the same topics. Regarding the principal and secondary outcomes, we judged whether the findings of the randomized trials agreed with those of the corresponding meta-analyses, and we determined whether the study results were positive (indicating that treatment improved the outcome) or negative (indicating that the outcome with treatment was the same or worse than without it) at the conventional level of statistical significance (P<0.05).
We identified 12 large randomized, controlled trials and 19 meta-analyses addressing the same questions. For a total of 40 primary and secondary outcomes, agreement between the meta-analyses and the large clinical trials was only fair (kappa= 0.35; 95 percent confidence interval, 0.06 to 0.64). The positive predictive value of the meta-analyses was 68 percent, and the negative predictive value 67 percent. However, the difference in point estimates between the randomized trials and the meta-analyses was statistically significant for only 5 of the 40 comparisons (12 percent). Furthermore, in each case of disagreement a statistically significant effect of treatment was found by one method, whereas no statistically significant effect was found by the other.
The outcomes of the 12 large randomized, controlled trials that we studied were not predicted accurately 35 percent of the time by the meta-analyses published previously on the same topics.
A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population.
We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol.
Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).
These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.
Background:
Lipid-lowering therapy is recommended for secondary prevention in people with coronary artery disease. It may also reduce cardiovascular events and/or local disease progression in people with lower limb peripheral arterial disease (PAD).
Objectives:
To assess the effects of lipid-lowering therapy on all-cause mortality, cardiovascular events and local disease progression in patients with PAD of the lower limb.
Search strategy:
The authors searched The Cochrane Peripheral Vascular Diseases Group's Specialised Register (last searched February 2007) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 2, 2007) for publications describing randomised controlled trials of lipid-lowering therapy in peripheral arterial disease of the lower limb.
Selection criteria:
Randomised controlled trials of lipid-lowering therapy in patients with PAD of the lower limb.
Data collection and analysis:
Three authors independently assessed trial quality and extracted data.
Main results:
Eighteen trials were included, involving a total of 10,049 participants. Trials differed considerably in their inclusion criteria, outcomes measured, and type of lipid-lowering therapy used. Only one trial (PQRST) reported a detrimental effect of active treatment on blood lipid/lipoprotein levels. The pooled results from all eligible trials indicated that lipid-lowering therapy had no statistically significant effect on overall mortality (Odds Ratio (OR) 0.86; 95% Confidence Interval (CI) 0.49 to 1.50) or on total cardiovascular events (OR 0.8; 95% CI 0.59 to 1.09). However, subgroup analysis which excluded PQRST showed that lipid-lowering therapy significantly reduced the risk of total cardiovascular events (OR 0.74; CI 0.55 to 0.98). This was primarily due to a positive effect on total coronary events (OR 0.76; 95% CI 0.67 to 0.87). Greatest evidence of effectiveness came from the use of simvastatin in people with a blood cholesterol >/= 3.5 mmol/litre (HPS). Pooling of the results from several small trials on a range of different lipid-lowering agents indicated an improvement in total walking distance (Weighted Mean Difference (WMD) 152 m; 95% CI 32.11 to 271.88) and pain-free walking distance (WMD 89.76 m; 95% CI 30.05 to 149.47) but no significant impact on ankle brachial index (WMD 0.04; 95% CI -0.01 to 0.09).
Authors' conclusions:
Lipid-lowering therapy is effective in reducing cardiovascular mortality and morbidity in people with PAD. It may also improve local symptoms. Until further evidence on the relative effectiveness of different lipid-lowering agents is available, use of a statin in people with PAD and a blood cholesterol level >/=3.5 mmol/litre is most indicated.
The ACCELERATE trial: impact of the cholesteryl ester transfer protein inhibitor evacetrapib on cardiovascular outcome
- Nicholls
Late-Breaking Clinical Trials II. The ACCELERATE trial: impact of the cholesteryl ester transfer protein inhibitor evacetrapib on cardiovascular outcome. Presented at the 65th Annual Scientific Session and Expo of the American College of Cardiology
- S J Nicholls
- A Lincoff
- P Barter