Comment

Are lipid-lowering guidelines evidence-based?

There is uncertainty regarding the impact of statins on the risk of atherosclerotic cardiovascular disease (ASCVD) and its major complication, acute heart failure (AHF).

The aim of this study was to investigate whether previous statin therapy translates into lower AHF events and improved survival from AHF among patients presenting with an acute coronary syndrome (ACS) as a first manifestation of ASCVD.

Data were drawn from the International Survey of Acute Coronary Syndromes Archives. The study participants consisted of 14,542 Caucasian patients presenting with ACS without previous ASCVD events. Statin users before the index event were compared with nonusers by using inverse probability weighting models. Estimates were compared by test of interaction on the log scale. Main outcome measures were the incidence of AHF according to Killip class and the rate of 30-day all-cause mortality in patients presenting with AHF.

Previous statin therapy was associated with a significantly decreased rate of AHF on admission (4.3% absolute risk reduction; risk ratio [RR]: 0.72; 95% CI: 0.62-0.83) regardless of younger (40-75 years) or older age (interaction P = 0.27) and sex (interaction P = 0.22). Moreover, previous statin therapy predicted a lower risk of 30-day mortality in the subset of patients presenting with AHF on admission (5.2 % absolute risk reduction; RR: 0.71; 95% CI: 0.50-0.99).

Among adults presenting with ACS as a first manifestation of ASCVD, previous statin therapy is associated with a reduced risk of AHF and improved survival from AHF. (International Survey of Acute Coronary Syndromes [ISACS] Archives; NCT04008173)

Drawing on economic theory and institutional analysis, this paper reframes Akerlof's theory of how a market for lemons operates and argues that each of the many markets for lemons must be studied empirically to document how different stakeholders cope with the problems of information asymmetry, secrecy, and power. Such markets are a new field for sociological analysis. To illustrate, the paper characterizes pharmaceuticals as a multi-tier market of information asymmetry in which actors in each tier have substantial control over how much they disclose about hidden risks of harm. Such a market rewards the production and sale of “lemons.” Current incentives and institutional practices reward developing a large number of barely therapeutically innovative drugs and ignoring their often hidden or understated harmful side effects. They reward designing and executing substandard, biased trials that mislead the FDA and regulators abroad to approve new drugs without clear evidence of their degree of harm. Approved drugs are likely to be “lemons” but promoted as “safe and effective.” The result is substantial hospitalizations and deaths from adverse drug reactions. A “risk proliferation syndrome” of institutional practices maximizes sales, profits, and exposure to toxic side effects. An “inverse benefit law” of marketing operates as companies try to maximize sales. The probability of benefits decreases but the chances of lemons adverse events do not. The details presented here deepen understanding of how markets for lemons thrive on information asymmetry, secrecy, and power. Lessons can be applied to other markets.

Guideline recommended medical therapy (GRMT) plays a pivotal role in improving long-term outcomes and healthcare burden of acute myocardial infarction (AMI) patients. We evaluated patients’ adherence to GRMT following AMI and the association with long-term (up-to 10 years) mortality, healthcare resource utilization and costs.

AMI patients hospitalized in a tertiary medical center in Israel that survived at least a year following post-discharge and enrolled in the two largest health plans were analyzed. Data were obtained from computerized medical records. Patients were defined as adherent when ≥80 % of the GRMT prescriptions were issue during the first post-discharge year. Hospitalizations, emergency department (ED) visits, primary care utilization and outpatient consulting clinic and other ambulatory services expenditure were calculated annually.

Overall 8287 patients qualified for the study (mean age 65.0 ± 13.6 years, 69.7 % males). Adherent patients (n = 1767, 21.3 %) were more likely to be younger, women and increased prevalence of most traditional cardiovascular risk factors. Throughout the follow-up, 2620 patients (31.6 %) died, 22.0 % versus 34.2 %, in the adherent vs. the non-adherent group (adjHR = 0.816, 95 % CI:0.730−0.913, p < 0.001). Reduced hospitalizations (adjOR = 0.783, p < 0.001), ED visits (adjOR = 0.895, p = 0.033), and costs (adjOR = 0.744, p < 0.001), yet increased primary clinics (adjOR = 2.173, p < 0.001) ambulatory (adjOR = 1.072, p = 0.018) and consultant (adjOR = 1.162, p < 0.001) visits, were observed.

Adherence to GRMT following AMI is associated with decreased mortality, hospitalizations and costs.

This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy—ie, adverse effects of the statin—are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50–100 new cases of diabetes, and 5–10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50–100 patients (ie, 0·5–1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.

Cardiovascular disease (CVD) remains the leading cause of death globally. A class of medications, known as statins, lowers low-density lipoprotein cholesterol levels, which are associated with CVD. The newest 2013 U.S. cholesterol guideline contains an assessment of risk that greatly expands the number of individuals without CVD for whom statins are recommended. Other countries are also moving in this direction. This article examines the controversy surrounding these guidelines using the 2013 cholesterol guidelines as a case study of broader trends in clinical guidelines to use a narrow evidence base, expand the boundaries of disease and overemphasize pharmaceutical treatment.

We find that the recommendation in the 2013 cholesterol guidelines to initiate statins in individuals with a lower risk of CVD is controversial and there is much disagreement on whether there is evidence for the guideline change. We note that, in general, clinical guidelines may use evidence that has a number of biases, are subject to conflicts of interest at multiple levels, and often do not include unpublished research. Further, guidelines may contribute to the “medicalization” or “pharmaceuticalization” of healthcare.

Specific policy recommendations to improve clinical guidelines are indicated: these include improving the evidence base, establishing a public registry of all results, including unpublished ones, and freeing the research process from pharmaceutical sector control.

Cardiovascular risk in men rises around the fourth decade of life, whereas women appear to be protected by sex hormones until menopause. This, in turn, tends to negatively affect the lipid profile. Since the 1980s, the incidence of cardiovascular diseases has been reported to progressively decline in men, but it has persisted almost unchanged in women. Major clinical trials on statins have been mostly conducted in men and have fostered the introduction of these agents into clinical practice worldwide. However, only few reports have examined a possible differential activity of statins in the 2 genders, providing in some cases opposite findings.

To evaluate gender-related differences in statin responses.

Variations of lipid profile after 1-year of treatment with different statins in 337 dyslipidemic patients (171 men and 166 women).

In this series of patients, a significantly attenuated reduction of total cholesterol and low-density lipoprotein cholesterol in women vs men on drug treatment was noted after adjustment for dose and statin power (low-density lipoprotein cholesterol: −28.5 ± 11.8% in men vs −22.7 ± 11.8% in women; P < .001).

The present study indicates that statin treatment has a reduced effectiveness in improving the plasma lipid profile in dyslipidemic women vs men. Whether such gender-related differences may have an impact on clinical outcomes remains to be elucidated.