November 9th, 2010

Intensive Statin Therapy Examined in Meta-Analysis and SEARCH Trial

A new meta-analysis and a large clinical trial shed new light on the additive effects of intensive statin therapy over standard therapy. The meta-analysis from the Cholesterol Treatment Trialists’ Collaboration and the results from SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) are published online in the Lancet.

The meta-analysis examined individual patient data from nearly 40,000 patients enrolled in five  trials comparing intensive versus standard statin therapy and nearly 130,000 patients enrolled in 21 trials of statin therapy versus controls. Major vascular events were reduced by 15% in the intensive versus standard therapy arm. When all trials were combined, the authors observed a 20% reduction in deaths due to coronary heart disease associated with each 1.0 mmol/L reduction in LDL. The authors report that they found no significant evidence “that further lowering of LDL cholesterol … produced any adverse effects”, thereby “suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%.”

The SEARCH trial, which was originally presented in 2008 at the AHA, compared the effects of 80 mg versus 20 mg simvastatin in 12,000 patients with a history of MI. The SEARCH Collaborative Group reported a nonsignificant 6% reduction in major vascular events from 25.7% in the 20-mg arm to 24.5% in the 80-mg arm. Myopathy occurred in 0.03% in the 20-mg group compared with 0.9% in the 80-mg group. The authors conclude that “for patients deemed to be at sufficient risk of major vascular events, a more appropriate strategy (by contrast with current guidance) could be to consider regimens involving newer, more potent, statins… or the combination of standard doses of generic statins… with other agents that can lower LDL cholesterol substantially without producing such increases in the risk of myopathy.”

In an accompanying editorial, Bernard Cheung and Karen Lam write: “People with substantial cardiovascular risk should have intensive lipid-lowering therapy. A low baseline LDL concentration is not a reason to withhold statin therapy if the patient is at a definite risk of cardiovascular events (eg, secondary prevention or diabetes). In this setting, the absolute risk reduction, number needed to treat, and risk–benefit and cost–benefit ratios are favourable. These numbers will be less persuasive for people at low cardiovascular risk, such as young people with no risk factors.”

12 Responses to “Intensive Statin Therapy Examined in Meta-Analysis and SEARCH Trial”

  1. There is absolutely no question that the risk/benefit of intensive therapy is high, and that this is the way to go. This meta-analysis and editorial are yet another reflection of this view.

  2. Saurav Chatterjee, MD says:

    Is the mortality benefit of intensive statins more from greater lipid lowering potency or is it from additive pleiotropic effect?

    Competing interests pertaining specifically to this post, comment, or both:

  3. I was really puzzled that this study of statins generalized to lipid lowering – and then promoted the idea of using non-statin drugs – as if they know that the same effect would be achieved. I do not know why this sophisticated group made did that – if you are not paying attention it would be easy to miss it. The trials were not studies of targets – but trials of the effect of drugs. It should not be suggested that any intervention that lowers LDL would achieve the same effect. We know that is not true.

  4. Rohan Parikh, M.B.B.S. says:

    Fantastic!! Dr.Harlan M. Krumholz. Everytime your teaching gives some extraordinary edge.

  5. Please educate me. How do we know that any intervention that lowers LDL would not achieve the same effect as when a statin lowers the LDL?

  6. The most obvious example that comes to mind is the ILLUMINATE trial where torcetrapib lowered LDL by almost 25% (and increased HDL over 70%) but did not result in an improved outcome.

    Competing interests pertaining specifically to this post, comment, or both:

  7. The other example that comes to mind is ezitimibe. Despite LDL lowering, arterial endpoints were not improved in ENHANCE (c/w placebo control) or ARBITER-6 HALT (c/w niacin). We eagerly await the results of IMPROVE-IT trial which will address outcome data with ezitimibe.

    The “lower is better” hypothesis can only be validated in trials where patients are randomized to treatment strategy targeted to high vs. low LDL levels. To my knowledge, such a trial has not been done.

    Extrapolating from trials where patients are randomized to FIXED doses of different statins, and drawing inferences based on LDL levels achieved is not, in my opinion, consistent with the scientific process. Hypotheses should be proved, not assumed.

  8. Saurav Chatterjee, MD says:

    but treating to target LDLs-especially to really low levels in a definite period of time might also unmask the side effects of statins like rhabdomyolysis……in which case the study would probably have to be terminated early.Kindly enlighten….

  9. I think an important thing to keep in mind is that statins have effects beyond lowering LDL cholesterol, and that these effects may, at least in part, account for any reductions in cardiovascular risk. In particular, work in recent years has shown the association between inflammatory processes and risk. Studies have also shown that the inflammatory biomarker, hsCRP, can be reduced by at least some statins. Thus, it may not be LDL reduction alone that is responsible for any observed reduction in risk.

    Competing interests pertaining specifically to this post, comment, or both:
    No competing interests.

  10. I think Dr. Krumholz illuminates 2 critical points here.

    1) We have seen drugs in the past which lower LDL and even raise HDL (such as hormone replacement therapy, torcetrabib) that are associated with a higher risk of cardiovascular events. We also have drugs (such as ezetimide) which we know lowers LDL but have no data to support their use to improve patient outcomes.

    2) There is also a tendency to interpret the statin RCTs as titration to target trials. While those on intensive statin therapy were more likely to achieve lower LDLs, they were also more likely to achieve lower hsCRP levels. Moreover, these trials were not treat-to-target trials. The only thing we can soundly infer from the RCTs is that more intensive statin treatment was associated with lower cardiovascular morbidity and/or mortality. Initiation of intensive statin therapy in the intervention arm in these trials was done regardless of baseline LDL. To date, we do not have convincing treat-to-target (for LDL or hsCRP) RCTs. The experience with the ACCORD trial for intensive management of BP and HbA1C should give us pause that what makes intuitive sense may not ultimately pan out.

    Competing interests pertaining specifically to this post, comment, or both:

  11. Saurav Chatterjee, MD says:

    my point exactly………

  12. Torcetrabib rendered HDL useless and resulted in increased deaths, not a surprise but hardly an issue of lower LDL not being effective.

    With both Enhance and Arbiter-6 HALTS, they looked at serial CIMT results which based on a recent met-analysis do not seem to correlate with vascular outcomes in statin treated subjects. Further more in the Arbiter study, adding niacin reduced LDL similar to zetia and raised HDL substantially better than zetia.

    Estrogens do indeed retard the progression of plaque, however due to the increased thrombosis seen with oral estrogens, they increase the short term event rates in subjects with existing atherosclerosis.

    As Dr. Krumholtz made the statement regarding statin lowered LDL, I assume he has studies to support same.

    I am looking for any evidence that LDL lowering with a statin is superior to LDL lowering with a bile salt sequestrate, diet, or any other intervention with respect to hard outcomes.