Commentary: Applying wisdom from Pearl Jam to LDL, IMPROVE-IT

ByRoger S. Blumenthal, MD

BySeth S. Martin, MD, MHS, FACC, FAHA, FASPC

by Seth S. Martin, MD; and Roger S. Blumenthal, MD

Editor’s note: This is the second part of a two-part commentary. Click here to read part one, in which Martin and Blumenthal share their thoughts on the main results of the IMPROVE-IT trial.

A remaining question is whether IMPROVE-IT is relevant to clinical practice a decade later. We think the answer is definitely yes.

Some may be quick to make the appropriate point that the background statin intensity in IMPROVE-IT was of moderate intensity and not high-intensity therapy, which had been shown beneficial in ACS patients in the PROVE-IT trial. Even so, high-risk patients who are semi–statin-intolerant and can only tolerate moderate-intensity statin therapy or who do not have on-treatment LDL levels of about 50 mg/dL could be candidates for the addition of ezetimibe.

Seth S. Martin

Roger S. Blumenthal

Varied expert reactions

The first reaction of some colleagues seemed to be that while the trial result is statistically significant, it may not be clinically significant. We can see such a perspective; relative and absolute risk reductions of approximately 6% and 2% do seem small. However, when framed another way, on top of modern comprehensive secondary prevention therapies, the overall trial 6-year NNT was 50 in the intention-to-treat analysis and 38 in the on-treatment analysis. These numbers are on par with current standards of care. Additionally, in the very–high-risk diabetic subgroup, the NNT was an impressive 18 in the intention-to-treat analysis. And with even long-term follow-up, we would expect the NNT to go down.

First reactions from others were concerns about cost effectiveness. Can we justify the added cost of ezetimibe when the full spectrum of statin intensities are now generically available? This is a complex question, and we suppose it depends on whom you ask: the clinician, the patient or payers. We think most would agree that selected, but not routine, addition of ezetimibe is reasonable. If our outlook is long term, it is important to note that long-term statin therapy has been shown to be not only cost effective, but cost saving. Generic availability of ezetimibe from 2016 on will certainly bode well for any cost-effectiveness analyses.

Long-term data from WOSCOPS

Supporting data regarding a drop in NNT and cost savings with long-term follow-up come from the WOSCOPS study. Twenty-year follow-up data were reported by Chris J. Packard, CBE, PhD, FRCPath, DSc, FRCP(Gla), FRSE, at the AHA Scientific Sessions immediately following the on-treatment IMPROVE-IT presentation. The data covered the period of life from age 55 to 75 years. This seems a more clinically relevant time window for atherosclerosis and CV risk than the substantially shorter time window captured in most randomized controlled trials.

Atherosclerosis is a slowly developing process, and the rate of plaque rupture and CVD events over a given time period is, of course, highly dependent on age. Therefore, to see the full difference in effects between intervention and control groups may take longer than even the time span of IMPROVE-IT. Lipid-lowering treatment may alter lipids and plaque biology in the short term, and modify the disease trajectory, but between-group differences in disease trajectories probably cannot be expected to be fully realized without decades of follow-up.

Using the 20-year data, the WOSCOPS investigators modeled CVD prevention benefits by degree of LDL reduction. The NNT was 6 to prevent one CVD admission during the 20-year follow-up, with a similar 20% LDL reduction as in IMPROVE-IT but a much higher starting baseline LDL (approximately 190 mg/dL). When the investigators set the baseline LDL to 70 mg/dL, a 20% LDL reduction produced a 14-mg/dL lowering and 7.5% relative risk reduction in CVD (similar to IMPROVE-IT), with a NNT to treat of 17. Therefore, the long-term NNT for the overall IMPROVE-IT population may be less than 20, and less than 10 in the diabetic subgroup.

These statistics reflect the outcome differences attributable to the randomized trial treatment allocation, the so-called “legacy effect.” In other words, in WOSCOPS, after the 5-year randomized period of the initial trial, both the intervention arm and control arms were treated similarly with statins. So the continued gain in benefit over 2 decades is attributable to that 5 years of treatment only. Even greater benefits would be anticipated if randomization was maintained; but that is unethical. We think those who had the earlier 5 years of treatment had a resetting of the biologic clock, lowering the vascular age of the patient.

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Synthesizing trial data with pathophysiology is essential. Putting aside clinical relevance and magnitude of the treatment effect for a moment, we see IMPROVE-IT first and foremost as a proof-of-principle study. As the trial investigators told the audience at the AHA Scientific Sessions, the rigorous trial reaffirms the LDL hypothesis. Relatedly, Virgil Brown, MD, said in a debate on LDL goals at the Scientific Sessions, “The fundamental issue is LDL, not statin deficiency.”

Mendelian randomization studies

Still, it matters how you lower LDL cholesterol. We now know that lowering LDL by blocking cholesterol absorption in the gut via NPC1L1 protein is a safe and efficacious method. It is encouraging to see the drug trials match up well with the Mendelian randomization genetic studies where causality was shown for LDL, but not for HDL raising.

With specific regard to genetically determined lower LDL via NPC1L1, two well-timed studies just linked NPC1L1 polymorphisms to lower LDL and CVD risk. They offer a good pathophysiologic explanation for the success of ezetimibe in the IMPROVE-IT trial. One study was presented by Ference and colleagues at the AHA Scientific Sessions, and the other was published in The New England Journal of Medicine.

The latter study involved 100,000 patients who had mean LDL levels 12 mg/dL lower in NPC1L1 mutation carriers vs. noncarriers. The relative risk reduction was 53% — far exceeding that produced by drug therapy when introduced later in life for a shorter window. It has been proposed that these genetic findings show what could be expected from a lifetime of exposure to ezetimibe. So it remains possible that benefits of ezetimibe would be greater if given earlier and longer.

We need to determine, as a community, how far we are willing to extrapolate the IMPROVE-IT data. We know that randomized controlled trial drug treatment data will always leave gaps when it comes to lifetime LDL exposure and management. Rene Descartes said, “If we cannot determine the truth, we have to follow what is the most probable.” We think the spirit of this quote is aligned with the spirit of evidence-based medicine to synthesize and best apply current best evidence for the care of individual patients.

Especially given the results of IMPROVE-IT, together with recent high-quality genetic data that reinforce the central role of LDL in CVD, we remain optimistic that similar drugs in the pipeline will lower CVD events, namely PCSK9 inhibitors. While awaiting long-term clinical outcomes data from ongoing trials, IMPROVE-IT weakens arguments against using LDL in regulatory approval. Genetic studies also have shown dramatic CVD risk reductions for lower LDL due to polymorphisms in PCSK9. Hopefully, we will not see any non-CV adverse efforts that outweigh the favorable reduction in CVD events. So far, safety signals for PCSK9 inhibitors have looked excellent. This is a very exciting time indeed.

Views of Eugene Braunwald (and Pearl Jam)

Eugene Braunwald

In conclusion, IMPROVE-IT is the first trial to show incremental benefit of adding a nonstatin agent to a background of statin monotherapy for the overall trial population. The trial showed that even lower is even better (LDL, 53 mg/dL vs. 70 mg/dL). This finding fits well with JUPITER data in high-risk primary prevention showing that patients with LDL <50 mg/dL did the best. The safety of ezetimibe is confirmed and options for proven lipid-lowering therapy are expanded.

IMPROVE-IT serves as a reaffirmation of the well-established central role of lowering LDL in CV prevention. For those who may have forgotten this fundamental aspect of medicine during the course of the past decade, Pearl Jam, one of the greatest rock bands of all time, has some wise words: “He who forgets will be destined to remember.” But we leave the final word to someone who knows more about cardiology than Pearl Jam, one of our idols, Eugene Braunwald, MD, who told The New York Times that the controversy over the central role of cholesterol lowering is settled: “People can stop yapping.”

For more information:

Cannon CP. LBCT.02: Anti-Lipid Therapy and Prevention of CAD. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.

Seth S. Martin, MD, is a clinical fellow at The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease and a member of the Cardiology Today Fellows Advisory Board. Roger S. Blumenthal, MD, is director of the Ciccarone Center for the Prevention of Heart Disease and is the CHD and Prevention Section Editor of Cardiology Today.

Disclosure: The authors report no relevant financial disclosures.