Cochrane Review Stirs Controversy Over Statins in Primary Prevention

From Heartwire CME

News Author: Sue Hughes
CME Author: Hien T. Nghiem, MD

January 25, 2011 — A new Cochrane review has provoked controversy by concluding that there is not enough evidence to recommend the widespread use of statins in the primary prevention of heart disease.

The authors of the new Cochrane meta-analysis, led by Dr Fiona Taylor (London School of Hygiene and Tropical Medicine, UK), issued a press release questioning the benefit of statins in primary prevention and suggesting that the previous data showing benefit may have been biased by industry-funded studies.
This has led to headlines in many UK newspapers saying that the drugs are being overused and that millions of people are needlessly exposing themselves to potential side effects.

This has angered researchers who have conducted other large statin meta-analyses, who say the drugs are beneficial, even in the lowest-risk individuals, and their risk of side effects is negligible.
They maintain that the Cochrane reviewers have misrepresented the data, which they say could have serious negative consequences for many patients currently taking these agents.

The Cochrane authors reviewed data from 14 trials involving 34 272 patients. Outcomes in patients given statins were compared with outcomes in patients given placebos or usual care. Although results suggested that deaths were reduced on statins, the researchers say the effect is not large enough to justify the cost/effort and risk of adverse effects.

Senior author Dr Shah Ebrahim (South Asia Network for Chronic Disease, New Delhi, India) told heartwire that their review differed from others done in primary prevention in that it looked at just those at low risk, limiting the studies included to just those with populations where <10% had a previous history of cardiovascular disease (CVD). It is probably a real effect but it means a lot of people have to be treated to gain this small benefit. Ebrahim commented to heartwire : "If you look at the hard end points of all deaths and coronary deaths, the effects are consistent with both benefit and with the play of chance. But importantly, the absolute benefits are really rather small--1000 people have to be treated for one year to prevent one death. It is probably a real effect, but it means a lot of people have to be treated to gain this small benefit. As we don't know the harms, it seems wrong-minded to me to treat everyone with a statin. In these circumstances, lifestyle changes and stopping smoking would be far preferable." I object to the conclusions they have drawn from their review. But Dr Colin Baigent (Clinical Trials Service Unit, Oxford, UK) commented to heartwire : "I object to the conclusions they have drawn from their review. They say there is not good evidence of benefit, but their own data show significant reductions in deaths and cardiac events." And Baigent further objects to the Cochrane authors' suggestion that harms are not known with statins. "They didn't show any increase in adverse events in their review, but they then say the benefit is not worth the risk. That doesn't make sense." Cochrane Results The Cochrane review showed that in the eight trials that reported on total mortality, none of the individual trials showed strong evidence of a reduction in total mortality, but when the data were pooled, a relative risk reduction of 17% was observed with statin treatment. On combined fatal and nonfatal coronary heart disease (CHD) events, nine trials reported on this end point, with four trials showing evidence of a reduction in this combined outcome, which was maintained in the pooled analysis, with a 28% relative reduction. Seven trials reported on fatal and nonfatal stroke, and on pooled analysis, statin treatment was associated with a 22% relative reduction. Cochrane Review: Risk Ratio of Major Events With Statins in Lower-Risk Primary-Prevention Patients No excess in combined adverse events, cancers, or specific biochemical markers were found. The authors conclude: "This current systematic review highlights the shortcomings in the published trials of statins for primary prevention. Selective reporting and inclusion of people with cardiovascular disease in many of the trials . . . in previous reviews of [statins'] role in primary prevention make the evidence impossible to disentangle without individual patient data." They say that in people at high risk of cardiovascular events (>20% 10-year risk), "it is likely that the benefits of statins are greater than potential short-term harms, although long-term effects (over decades) remain unknown." They conclude: "Any decision to use statins for primary prevention should be made cautiously and in the light of an assessment of the patient's overall cardiovascular risk profile. Widespread use of statins in people at low risk of cardiovascular events--below a 1% annual all-cause mortality risk or an annual CVD event rate of below 2% observed in the control groups in the trials considered here--is not supported by the existing evidence."

Latest Oxford Meta-Analysis Not Included

The Cochrane review did not include the recent meta-analysis from the Oxford group, published late last year, which showed a clear reduction in events with statin therapy in primary-prevention patients.
Baigent noted that this meta-analysis was more reliable than the Cochrane review, as the Oxford researchers used individual patient data from all the trials. "Our 2010 meta-analysis in primary prevention is substantially more complete than the Cochrane review and provides direct and overwhelmingly statistically convincing evidence of a clear reduction in events in all patient groups, right down to those at the lowest risk."

On the possible hazards of taking these drugs, Baigent says: "Statin therapy is very safe. The most serious hazard, rhabdomyolysis, is very rare, and most often seen at high doses. There is a possibility that reducing low-density lipoprotein cholesterol might increase the risk of hemorrhagic stroke, but even in primary prevention these hazards would be much smaller than the benefits, and there is no reliable evidence for other hazards mentioned by the Cochrane authors, such as depression and cognitive impairment."

It All Comes Down to Economics

Baigent says the only argument against using statins in low-risk people is economic. "The absolute benefits of statin therapy become very small when used among people at low absolute risk, so it is important that the costs of such treatment are considered when weighing how widely statins should be used. That is a government decision."

In the UK, the National Institute for Clinical Excellence [NICE] currently recommends that statins not be used for people with a CHD risk below 20% over 10 years. Ebrahim says the Cochrane conclusions are in line with this.

But Baigent argues that the benefits of statins are clear at levels far below this threshold. "Whether or not it is economic to use them in the lowest-risk individuals is not for me to say, but generic statins are now very cheap, and there is clear evidence of benefit and safety based on substantial numbers of individuals studied in large-scale trials. So, when all the relevant randomized evidence is considered, there does not seem to me to be any justification at all for the Cochrane authors' claim that the evidence is unclear on this issue."

Educational Programs Also of Little Benefit

In a separate Cochrane review [2], the same group looked at the use of "healthy heart programs" that use counseling and educational methods to encourage people to reduce their risks for developing heart disease. These risk factors include high cholesterol, excessive salt intake, high blood pressure, excess weight, a high-fat diet, smoking, diabetes, and a sedentary lifestyle. They reviewed 55 trials that aimed to reduce more than one risk factor in people without evidence of cardiovascular disease. Results showed that after a median duration of 12 months of follow-up, multiple risk-factor intervention was associated with small reductions in risk factors, including blood pressure, cholesterol, and smoking, but had little or no impact on the risk of coronary heart disease mortality or morbidity. They conclude: "The methods of attempting behavior change in the general population are limited and do not appear to be effective. Different approaches to behavior change are needed and should be tested empirically before being widely promoted, particularly in developing countries where cardiovascular disease rates are rising."

In an accompanying editorial [3], Dr Carl Heneghan (University of Oxford, UK) suggests an alternative approach for policy is to focus on populationwide prevention. He reports that "legislating for smoke-free public spaces, redesigning public spaces to improve exercise, or reducing daily dietary salt intake prove generally effective and can be cost-saving interventions. Given the scale of the worldwide CVD problem, large-scale commissioned studies of multiple risk-factor interventions are urgently required."

References

1. Taylor F, Ward K, Moore THM, et al. Statins for the primary prevention of cardiovascular disease - Available here.Cochrane Database Syst Rev 2011; 1 (CD004816).
2. Ebrahim S, Taylor F, Ward K et al. Multiple risk factor interventions for primary prevention of coronary heart disease - Available here. Cochrane Database Syst Rev 2011; 1 (CD001561).
3. Heneghan C. Considerable uncertainty remains in the evidence for primary prevention of cardiovascular disease [editorial].Cochrane Libr2011 (January 19, 2011). Available here.

Clinical Context

CVD is mutifactorial in its causation, and lifestyle changes are the basis of any treatment strategy. Treatment usually includes eating a healthy diet, ceasing tobacco use, and increasing physical activity. Reducing high blood cholesterol, a risk factor for CVD events in people with and without a history of CHD, is an important goal of pharmacotherapy. Typically, statins are the first-line agents. Studies have demonstrated the effects of statins and its benefits in people with coronary artery disease; however, the case for primary prevention is less clear.

The aim of this study was to assess the effects, both harms and benefits, of statins in people with no history of CVD.
Study Highlights

* The investigators conducted a search within the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (2001 to March 2007), and EMBASE (2003 to March 2007) for trials comparing statins vs usual care or placebo. There were no language restrictions.
* Randomized controlled trials of statins with minimum duration of 1 year and follow-up of 6 months, trials of adults with no restrictions on their total low-density lipoprotein or high-density lipoprotein cholesterol levels, and trials in which 10% or less of participants had a history of CVD were included.
* Drug treatments and other interventions were accepted, provided they were given to both groups of the intervention groups.
* 2 authors independently selected studies for inclusion and extracted data.
* Outcomes included all-cause mortality, fatal and nonfatal CHD, CVD, stroke events, combined endpoints (fatal and nonfatal CHD, CVD, and stroke events), change in blood total cholesterol concentration, revascularization, adverse events, quality of life, and costs.
* Relative risk was calculated for dichotomous data, and for continuous data, pooled weighted mean differences (with 95% confidence intervals) were calculated.
* 14 randomized control trials (16 trial groups; 34,272 participants) were included.
* 11 trials recruited patients with specific conditions (increased lipid levels, diabetes, hypertension, and microalbuminuria).
* All tested the effectiveness of a statin vs placebo, 9 studies tested pravastatin (10 - 40 mg/day) and atorvastatin (10 mg/day), 2 studies tested fluvastatin (40 - 80 mg/day) and lovastatin (20 - 40 mg/day), and the remaining studies tested simvastatin (40 mg/day).
* 2 trials — the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) 1998 and the Collaborative AtoRvastatin Diabetes Study (CARDS) 2004 — were stopped prematurely because of significant reductions in primary composite outcomes between the intervention and placebo groups.
* Results demonstrated that all-cause mortality risk was reduced by statins (relative risk, 0.83; 95% CI, 0.73 - 0.95), as were combined fatal and nonfatal CVD endpoints (relative risk, 0.70; 95% CI, 0.61 - 0.79).
* No significant risk reduction was observed in fatal CHD events and fatal and nonfatal stroke events.
* Benefits were also seen in the reduction of revascularization rates (relative risk, 0.66; 95% CI, 0.53 - 0.83).
* Total cholesterol and low-density lipoprotein cholesterol levels were reduced in all trials; however, there was evidence of heterogeneity of effects, possibly because of differences in the statin and dosage used as well as reporting biases.
* There was no clear evidence of any significant harm caused by statin prescription or of effects on patient quality of life.
* No statistical differences in outcomes were observed in age and sex.
* There was limited evidence to suggest that the use of statins for primary prevention may be cost effective and improve patient-perceived quality of life.

Clinical Implications

* According to the World Health Organization in 2008, the major causes of CVD are unhealthy diet, tobacco use, and physical inactivity.
* Although reductions in all-cause mortality risk, composite endpoints, and revascularizations were found with no excess of adverse events, there was evidence of selective reporting of outcomes, failure to report adverse events, and inclusion of people with cardiovascular disease. Therefore, caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.