{"id":8949,"date":"2022-05-02T11:30:22","date_gmt":"2022-05-02T10:30:22","guid":{"rendered":"https:\/\/www.zoeharcombe.com\/?p=8949"},"modified":"2022-05-04T09:12:22","modified_gmt":"2022-05-04T08:12:22","slug":"a-new-look-at-statins-ldl-cholesterol-cvd","status":"publish","type":"post","link":"https:\/\/www.zoeharcombe.com\/2022\/05\/a-new-look-at-statins-ldl-cholesterol-cvd\/","title":{"rendered":"A new look at statins, LDL-Cholesterol & CVD"},"content":{"rendered":"
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Executive summary<\/strong>\n<\/p>\n * Most papers presenting the benefits of statins have been done by the Oxford Cholesterol Treatment Trialists (CTT) team. They tend to present benefits of statins in relative risk terms \u2013 with claims of benefits of approximately 20% being typical.\n<\/p>\n * This week’s paper set out to evaluate the absolute risk reduction for relationships between statins, LDL-cholesterol and deaths\/disease.\n <\/p>\n * The authors used the same trials that the CTT use and found potential for bias in a number of areas, not least that all of the included trials were funded, in part or wholly, by the pharmaceutical industry.\n <\/p>\n * The study examined all-cause mortality, heart attacks and strokes for all trials together and then separately examined trials that included people who had previously had a heart event or not. The relative risk reductions ranged between 9% and 38%, which seems large. The absolute risk reductions ranged between 0.3% and 2.2%, which doesn’t seem large. \n <\/p>\n * The authors conducted a number of tests that led to concerns about the reliability of pooling these trials given their differences and inconsistent definitions of key terms.\n <\/p>\n * The authors also tried to establish what role reductions in LDL-Cholesterol played in any benefits from statins. They found no consistent impact of reducing LDL-cholesterol. \n <\/p>\n * Patients are presented with the information that taking a statin (for 4.4 years on average) would reduce their risk of having a heart attack by 29% (relative risk). The same information could be presented as 77 people would need to take statins for approximately 4.4 years on average to prevent 1 heart attack (absolute risk). \n <\/p>\n * This paper was simple and powerful and should change patient-doctor consultations, but I suspect that it won’t.\n <\/p>\n <\/p>\n Introduction<\/strong>\n <\/p>\n I need to declare an interest for this week’s note. I know the second author, Dr Maryanne Demasi. We have met at a couple of conferences, and we email each other with research queries from time to time. I don’t know the lead author, Dr Paula Byrne, or any of the other authors, but I’m impressed by whoever thought of this study. It’s one of those where you wonder why it hadn’t been done sooner. The paper was called “Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment. A Systematic Review and Meta-analysis<\/em>” (Ref 1).\n <\/p>\n The aim of the study was brilliant in its simplicity \u2013 to evaluate the absolute risk reduction for relationships between statins, LDL-cholesterol and deaths\/disease. The benefits of statins and LDL-cholesterol reduction are habitually presented in relative risk terms. For example, this paper called “Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials<\/em>” reported in the abstract “Overall, statin therapy or a more intensive statin regimen produced a 21% proportional reduction in major vascular events per 1\u00b70 mmol\/L reduction in LDL cholesterol” <\/em>(Ref 2).\n <\/p>\n Later in the same paper, a side effect of statins was reported as follows: “Statins have been estimated to increase the risk of myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase) typically by one case per 10,000 patients treated with statins per year<\/em>.” The benefits of statins were thus presented in relative risk terms (21%). One side effect was reported in absolute risk terms (1 in 10,000 in a year). That’s clearly disingenuous. The side effect was also carefully worded to be an extreme one (myopathy) rather than a common one (muscle pain). The patient information leaflet reported “joint pain, muscle pain and back pain<\/em>” as a common side effect, which was defined as “may affect up to 1 in 10 people<\/em>” \u00a0(Ref 3). The patient leaflet reports absolute risk.\n <\/p>\n <\/p>\n The study<\/strong>\n <\/p>\n Byrne et al<\/em> searched academic databases for large randomised clinical trials that examined the effectiveness of statins in reducing total mortality and cardiovascular outcomes. Inclusion criteria included: a planned study duration of two or more years (long enough); more than 1,000 participants (large enough); and the study needed to report absolute changes in LDL-Cholesterol levels. The trial interventions were statins vs placebo or usual care. Participants were men and women older than 18 years. \n <\/p>\n Maryanne has worked at the Nordic Cochrane Collaboration \u2013 the one centre that produced unbiased research until that too got corrupted. The research team clearly had Cochrane level discipline, as research protocols were thoroughly followed and documented throughout the study and paper. The protocol had originally intended to extract data on major vascular events and major coronary events. However, the researchers found that these outcomes were not consistently defined across trials, leading them to conclude that producing a meta-analysis of differently defined terms would be inappropriate. They found similar difficulties with the definitions of cardiovascular death and cardiovascular events and thus focused their analyses on all-cause mortality, spontaneous myocardial infarction (heart attack) and spontaneous stroke. The word spontaneous excluded procedure related events. E.g., someone can have a stroke following an operation to prevent a stroke (this is more common than people might realise \u2013 it happened to a close relative of mine). Excluding these focuses analysis on objective events, independently of procedures.\n <\/p>\n The database search returned 21 trials to be included in the analysis. The trials were listed in the supplemental online content (Table e1 in the supplemental is an excellent summary of the large enough and long enough statin trials and the headline details on each). For those of you who know your statin trials, the 21 were: 4S 1994; WOSCOPS 1995; CARE 1996; LIPID 1998; AFCAPS\/TexCAPS 1998; LIPS 2002; HPS 2002; PROSPER 2002; ALLHAT-LLT 2002; ASCOT-LLA 2003; ALERT 2003; CARDS 2004; 4D 2005; ASPEN 2006; MEGA 2006; SPARCL 2006; CORONA 2007; JUPITER 2008; GISSI-HF 2008; AURORA 2009; and HOPE-3 2016. The Oxford Cholesterol Treatment Trialists (CTT) are the main producers of meta-analyses of statin trials. These are the same trials that they commonly use in their papers to make relative risk claims. \n <\/p>\n The 21 trials included similar numbers of primary prevention trials (7), secondary prevention trials (6), and trials that included participants from primary and secondary prevention populations (8). Primary prevention refers to participants who have not had a cardiovascular event and the trial is trying to prevent the first (primary) event. Secondary prevention refers to participants who have had a cardiovascular event and the trial is trying to prevent the second (secondary) event. \n <\/p>\n The 21 trials achieved LDL-Cholesterol differences between the statin and placebo groups ranging from 17mg\/dL (0.44 mmol\/L) to 68 mg\/dL (1.75 mmol\/L) for each individual trial. The CTT papers usually make their relative risk reduction claims on the basis of each 1 mmol\/L reduction in LDL-C. Of the 21 trials, 12 achieved a reduction of 1 mmol\/L or greater, so this level of reduction is not achieved in all trials. The average trial follow-up period was 4.4 years, ranging from 1.9 to 6.1 years. The number of trial participants ranged from 1,255 (trial 4D 2005) to 20,536 (trial HPS 2002). \n <\/p>\n A key part of the process for meta-analysis is to examine possible bias in the trials being pooled. It’s a way of reviewing how robust the pooled findings are. If the original trials are of poor quality, then pooling them together amplifies that poor quality. The bias assessment in the Byrne et al<\/em> paper reported some concerns related to the 21 trials. In the 4D trial, it was unclear from the protocol how the authors planned to measure or analyse fatal stroke. In the ASPEN trial, there were changes to the inclusion criteria for participants after two years. (However, it was unclear if this would have introduced bias.) Four trials (JUPITER, CARDS, AFCAPS\/TexCAPS, and ASCOT-LLA20-23) were terminated early, and this may have been a source of bias. The researchers also noted that all of the included trials were funded, in part or wholly, by the pharmaceutical industry.\n <\/p>\n<\/p>\n