Introduction

Ischaemic heart disease and stroke were the leading causes of death in 2010, with a relative increase in rates compared with 1990 of 35% and 26%, respectively, and they are still ranked the first and second causes of death worldwide; this represents approximately one in four deaths worldwide for the two diseases combined .

When focusing on western countries, such as the USA, an opposite trend is observed, with declining rates of death attributable to cardiovascular diseases (CVDs) in the past decade , although they still account for one in every three deaths in the USA. In Europe, the same trends are noted, with deaths due to cardiovascular disease and coronary heart disease (CHD), accounting for 46% and 20% of deaths, respectively, although there are substantial inequalities between countries . In parallel, we have observed a decline in the prevalence of some modifiable risk factors, such as cigarette smoking rate, uncontrolled high blood pressure (HBP) and average low-density lipoprotein cholesterol (LDL-C) concentration in the population, concurrent with improvements in lifestyle and pharmacological interventions. For instance, regarding HBP control, when comparing data from the 1988–1994 National Health and Nutrition Examination Survey in the USA and the 2007–2008 period, awareness improved from 69.1% to 80.7%, the use of anti-hypertensive drugs increased from 54.0% to 73.5% and the ratio of controlled/treated HBP rates improved from 50.6% to 72.3% . In addition, nowadays, most higher risk patients with HBP and co-morbidities receive anti-hypertensive agents (88.3% use in HBP with chronic kidney disease [CKD], 93.4% use in concomitant diabetes and 94.0% use in patients with CVD in 2010); these rates are higher than for HBP without co-morbidities (67.8%) . Regarding the LDL-C rate, interesting recent data from the French MONICA registry show that treatment with statins in primary prevention is able to change the initial presentation of acute coronary syndrome (ACS), with more non-ST-segment elevation myocardial infarction and unstable angina and less ST-segment elevation myocardial infarction in comparison with patients not treated with statins before the first manifestation of acute CHD. The objectives of this review are to summarize the clinical research data supporting primary prevention with statins and to analyse gaps in actual practice.

Why focus on primary prevention with statins in high-risk groups?

In contrast to the marked improvement in HBP awareness and treatment rates in high-risk patients, the adoption of lipid-lowering drugs seems to lag behind in a substantial proportion of patients with hypercholesterolaemia and co-morbidities. In the USA, in patients with diabetes, approximately 60% do not receive a lipid-lowering agent , and in patients with CKD, fewer than one third receive lipid-lowering drugs and only 40% are at LDL-C goal .

In Europe, we observed encouraging trends towards a decrease in mean LDL-C concentrations , but we also noticed that LDL-C management was worryingly suboptimal in high-risk groups. For instance, in the French MONA LISA study , only 42% of patients at high- or very high-risk, according to the latest European guidelines , received lipid-lowering therapy. Although a slight majority of patients at very high-risk (58%) actually benefit from a lipid-lowering agent, the vast majority (72%) of those eligible for primary prevention (high-risk group with multiple co-morbidities but no CVD) are excluded from the recommended therapy .

We also observed in a large European Union/Canadian registry that the low-density lipoprotein (LDL) control rate was not correlated to the actual risk level. The control rate averaged approximately 50% in all patients, varying slightly from 44% in patients with low European Society of Cardiology scores to 58% in very high-risk CVD patients ( Table 1 ) .

In France, results from a study conducted in a more specific population of patients aged > 45 years who had been treated with statins for > 3 months, the control rate was worse in the higher risk group (52% not at goal) compared with in the overall population of statin users (38% not at goal) .

Overall, the key findings of these observational studies suggest that the management of high LDL-C is particularly limited in highest risk groups eligible for primary prevention compared with in those treated for secondary prevention and lower-risk groups.

What is the indirect evidence in favour of earlier initiation and prolonged LDL-lowering interventions?

In a recently published meta-analysis of 312,321 subjects, the researchers used a Mendelian randomization approach to estimate the clinical benefit of lowering LDL early in life. The authors used, as a proxy for a treatment that would decrease LDL-C beginning at birth, the inherited allocation to protective genotypes (for nine single nucleotide polymorphisms associated with lower LDL-C). Results showed that a low LDL-C concentration following this random natural allocation decreases the risk of CHD by 54.5% for each mmol/L decrease in LDL-C. Comparatively, for the same level of LDL-C decrease, statin therapy started later in life would “only” reduce the risk of CHD by 24.0% ( Fig. 1 ) . The authors concluded that long-term exposure to a protective lower LDL-C beginning early in life was associated with a greater reduction in the risk of CHD than the current practice of starting to lower LDL-C later in life.

Comparative coronary heart disease risk reduction of earlier and later low-density lipoprotein cholesterol (LDL-C) lowering. CI: confidence interval; OR: odds ratio.

Reproduced with permission from .

Mirroring these results, the deleterious effect of early and long-term exposure to dyslipidaemia was studied in the Coronary Artery Risk Development in Young Adults (CARDIA) study . The effect of time-averaged cumulative exposure to dyslipidaemia starting in young adulthood (healthy subjects at enrolment, aged 18–30 years) was assessed over a 20-year period and related to coronary calcium levels measured later in life (estimation based on computed tomography scan by analysts blinded to participant characteristics). Among the 3258 participants, 65% of patients were exposed to LDL-C concentrations > 100 mg/dL. The result showed that exposure to high LDL-C concentrations was strongly associated with coronary calcium later in life. Compared with in subjects with optimal LDL-C concentrations < 70 mg/dL, the risk of coronary calcium in subjects exposed to slightly suboptimal LDL-C (between 70–99 mg/dL) was 1.5 times higher, although not significantly different (95% confidence interval [CI] 0.7–3.3). Nevertheless, subjects with concentrations even marginally higher (100–129 mg/dL) had an amazing 2.4 times higher risk of coronary calcium (odds ratio [OR] 2.4, 95% CI 1.1–5.3) and those with concentrations ≥ 160 mg/dL had a 5.6 times higher risk (OR 5.6, 95% CI 2.0–16).

This indirect evidence supports the paradigm of earlier and longer duration of high LDL-C management and suggests a need for earlier screening and improved identification of patients who would be eligible for pharmacological intervention. Regarding the pharmacological management of patients with high LDL-C, the recently published “American Heart Association/American College of Cardiology guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults” are very specific. Adults aged ≥ 21 years with primary LDL-C ≥ 190 mg/dL should be treated with statin therapy using a high dosage unless contraindicated .

What is the direct evidence for benefit and risk of primary prevention with statins?

The Cochrane Collaboration is a non-profit organization founded in 1993, consisting of an international group of close to 30,000 researchers from more than 100 countries that aims to independently review and analyse medical information in the interests of evidence-based medicine and public health. Since 2011, the collaboration has developed, as a non-governmental organization, an official partnership with the World Health Organization, with a seat on the World Health Assembly to provide input into World Health Organization resolutions .

In the most recently published Cochrane systematic review and meta-analysis of randomized clinical trials (RCTs), Taylor et al. concluded that the evidence showed that primary prevention with statins was likely to be cost-effective and may also improve patient quality of life . Two years earlier, the same authors had argued the opposite position, contending that the evidence did not advocate routine implementation of primary prevention with regard to cost-effectiveness, although a reduction in all-cause mortality and composite cardiovascular events was already observed in this 2011 meta-analysis; they expressed concerns about the interpretation of the results due to possible under-reports of outcomes and adverse events and the inclusion of some patients with a history of CVD . What changed between the two publications was the arrival of new evidence from RCTs, enlarging the clinical data set from 34,000 patients/14 RCTs in the 2011 meta-analysis to 57,000 patients/18 RCTs in the 2013 review.

What has this new clinical evidence taught us? The most important finding is that primary prevention with statins significantly reduces all-cause mortality by 14% (OR 0.86, 95% CI 0.79–0.94); it also decreases the risk of fatal and non-fatal CVD by approximately 20–25% (relative risk [RR] 0.75, 95% CI 0.70–0.81), the risk of combined fatal and non-fatal CHD events (RR 0.73, 95% CI 0.67–0.80) and the risk of combined fatal and non-fatal strokes (RR 0.78, 95% CI 0.68–0.89). More importantly, in terms of cost-effectiveness, the corresponding number needed to treat (NNT) for 5 years to prevent one event would be fairly low: an NNT of 96 to avoid one death from all causes; an NNT of 56 to prevent one CHD event (fatal or not); an NNT of 35 to avoid one cardiovascular event (fatal or not); and an NNT of only 20 to prevent one stroke (fatal or not).

The work conducted by the Cholesterol Treatment Trialists’ (CTT) Collaborators showed results consistent with and complementary to the analysis performed by the Cochrane collaboration. This very large individual patient data meta-analysis included 27 trials with approximately 175,000 patients with high LDL-C concentrations, which compared statins versus control (22 RCTs) or high-dose versus low-dose statins (5 RCTs). The primary finding in the overall population was that for each 1.0 mmol/L reduction of LDL-C by statin therapy, the risk of major vascular events decreased by 21% (RR 0.79, 95% CI 0.77–0.81, per 1.0 mmol/L). The RR reduction (RRR) for major vascular events was 25% (RR 0.75, 95% CI 0.70–0.80) when statins were used in patients without a previous history of vascular disease, which was similar to the RRR of 20% (RR 0.80, 95% CI 0.77–0.82) achieved for secondary prevention ( Fig. 2 ) . Significant reductions in vascular death by 15% and 12% per 1.0 mmol/L LDL-C decrease were observed in the primary and secondary prevention settings, respectively. This mortality reduction remained significant even after exclusion of patients with diabetes or CKD at baseline. Interestingly, the reduction in major vascular events was also statistically significant in the subset of patients with low estimated cardiovascular risk at baseline (risk < 10% at 5 years).

Global effects on major vascular events (MVE) per 1.0 mmol/L reduction in low-density lipoprotein (LDL) cholesterol at different levels of risk, by history of vascular disease. CI: confidence interval; RR: relative risk.

Reproduced with permission from .

We therefore have strong evidence coming from large well-conducted meta-analyses that primary prevention with statins is beneficial in reducing MACE, cardiovascular death and all-cause mortality and, owing to the low NNTs observed, that this therapeutic strategy is cost-effective .

One should, however, consider the balance between benefit and risk related to statin therapy. In the latest Cochrane meta-analysis, there was no overall difference in the occurrence of all adverse events between the statin and control groups (RR 1.00, 95% CI 0.97–1.03) and no evidence for any serious harm induced by primary prevention with statins, particularly regarding the risk of cancer, haemorrhagic stroke and rhabdomyolysis. However, a significantly higher rate of diabetes was observed in the active treatment arm versus control (RR 1.18, 95% CI 1.01–1.39); this corresponded to an absolute risk increase of 0.4% (2.8% for statins compared with 2.4% in the control and placebo arms, respectively), which would correspond to a number needed to harm (NNH) of 250 patients treated with statins over 5 years to induce one case of diabetes. Similar findings were observed in an earlier meta-analysis performed among more than 90,000 patients, focusing on incidental diabetes in statin trials . The authors used a conservative pre-specified criterion for defining the incidental diabetes cases: two glucose concentrations ≥ 7.0 mmol/L in trials that measured fasting glucose every 6 months and only one value ≥ 7.0 mmol/L in trials that measured fasting glucose less frequently than 6 months. The risk of incident diabetes was 1.09 times higher with statins (OR 1.09, 95% CI 1.02–1.17), corresponding to an NNH of 255 patients treated for 4 years to induce one extra case of “diabetes” as defined above. We cannot therefore rule out the possibility that statin-treated patients may have an increased likelihood of diabetes, but when translating these results in a clinically meaningful way, we should stress that incidental diabetes as defined in RCTs is only a biological surrogate for possible diabetic long-term complications. In other words, for 250 patients treated over 5 years, one case of hyperglycaemia/diabetes might be due to the statin use, but in parallel, you would avoid at least two deaths and prevent four CHD events and 12 strokes.

Moreover, in patients with documented diabetes at baseline, irrespective of whether the patient has a prior history of vascular disease, statins significantly reduce the risk of myocardial infarction or coronary death, coronary revascularization and the risk of stroke .

Regarding other biological abnormalities possibly induced by the use of statins, the Cochrane review suggested that primary prevention with statins might induce a non-significant trend toward more cases of liver enzyme elevation (RR 1.16, 95% CI 0.87–1.54) but without any increase in the risk of clinically relevant liver dysfunction. However, in a larger meta-analysis (close to 250,000 patients), including trials in primary and secondary prevention, the increased risk of transaminase elevation associated with statins was statistically significant (OR 1.51, 95% CI 1.24–1.84). These results probably reflect the dose-dependent relationship of statins with some specific adverse effects .

The dose-dependent relationship is also questioned for statin-induced myotoxicity, ranging from the asymptomatic rise in creatine kinase concentration, myalgia and myositis to the rare but severe rhabdomyolysis. Whereas there was no increase in myalgia in the Cochrane primary prevention meta-analysis (RR 1.03, 95% CI 0.97–1.09), other systematic reviews have suggested that statin type and/or high statin dose (secondary prevention) would increase the risk in creatine kinase elevation and myalgia by up to four times versus control and the risk of rhabdomyolysis by three times .

This statin-induced myotoxicity not found in primary prevention trials and meta-analyses may, however, have a broader implication for clinical practice than increasing asymptomatic glycaemia elevation. In the non-selected patients in our real-life practice, the incidence of skeletal muscle-related adverse effects is more important than in RCTs and could affect patient adherence to statin therapy, thus, leading to a deleterious effect on the risk of MACE. The observed difference between RCTs and real-life uncontrolled studies is likely to be related to the lower representation in RCTs of patients with factors associated with an increased risk of myopathy (e.g. polypharmacy, concomitant use of fibrates, use of statins above recommended dose, young sporty subjects, etc.) . For instance, one trigger of symptomatic myopathy commonly seen in our clinical practice is abrupt intensive physical activity . Statins were also shown recently to increase exercise-related muscle injury in marathon runners .

As for severe chronic muscle toxicity, literature is scarce and review is made even more complex due to the various definitions of “myotoxicity” used by different Health Authorities or academic entities . For example, the US Food and Drug Administration defines myotoxicity as the presence of symptoms of myalgia and creatine kinase > 10 times the upper limit of normal, whereas the American College of Cardiology considers symptoms of myalgia to be sufficient. In addition, the most important barrier that clearly influences the importance of statin-induced severe myotoxicity is the rarity of occurrence. Large cohort studies suggest that the incidence of rhabdomyolysis ranges from 0.44 to 5.4 per 10,000 person-years with statin monotherapy, corresponding to an NNH of 23,000 to induce one case . Another issue is the difficulty in diagnosing and definitely attributing the serious adverse event to the lipid-lowering therapy. For instance, immune myositis (a newly identified entity among chronic statin-induced myopathy) is a rare adverse event with a prevalence not clearly established, and its diagnosis relies on a complex set of clinical, biological and imaging criteria. An immune myositis diagnosis can be suspected in case of muscle weakness/atrophy persisting for weeks or months after statin discontinuation, biopsy showing a predominantly necrotizing myopathy with minimal lymphocytic infiltrates and positive anti-HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) antibodies .

Until now, studies have failed to identify genetic variations with large effects on statin efficacy or toxicity. Mangravite et al. recently identified six expression quantitative trait loci that interact with simvastatin exposure and, especially, one locus associated with incidence of statin-induced myotoxicity .