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IMPROVE-IT becomes the first trial to prove the LDL Hypothesis with a non-statin drug

09 December 2014 Margaret Labban

Merck's Vytorin can IMPROVE-IT
Merck & Co (US) presented positive results from the long-awaited outcomes trial (IMROVE-IT) last week at the 2014 meeting of the American Heart Association (AHA) in Chicago, demonstrating a significant reduction in the risk of cardiovascular events with Vytorin (ezetimibe + simvastatin) compared with simvastatin alone in patients that have already had a heart attack or acute coronary condition requiring hospitalisation. The primary endpoint cardiovascular events in the trial included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, re-hospitalisation for unstable angina, or coronary revascularisation occurring at least 30 days after randomisation. Vytorin is a low-density lipoprotein cholesterol (LDL-C) lowering drug composed of Merck's Zetia (ezetimibe) and a commonly prescribed off-patent statin. The positive results are great news for Merck, but they also have far-reaching and favourable implications on the industry, particularly for drug manufacturers of non-statin LDL-C lowering drugs.

IMPROVE-IT, which was initiated in 2005, enrolled 18,144 high-risk patients and successfully demonstrated that Vytorin treatment led to significantly less primary endpoint cardiovascular events (32.7%) including death and non-fatal heart attacks or strokes, than simvastatin alone (34.7%). While to some the risk reduction is modest, the statistically significant improvement in outcomes likely resulting from the reduction in LDL-C levels from around 70mg/dL (average on statin alone) to 53 mg/dL (average with Vytorin) has the potential to markedly impact prescribing practices.

Merck has definitely recovered Vytorin's reputation after another outcomes trial ENHANCE cast a shadow on the drug back in 2008. Although a reduction in LDL-C was believed to decrease the risk of coronary heart disease, ENHANCE raised some doubts regarding whether reduced cholesterol levels in fact can translate into improved outcomes. Data from that trial found that Merck's Vytorin was no more effective in reducing plaque in the carotid artery than statin alone and did not answer the question of whether the addition of ezetimibe cuts the rate of heart attacks further. IMPROVE-IT has definitely answered that question, and although the benefits are relatively modest, there is a clear and significant improvement in heart health if LDL-C levels are reduced well below 70mg/dL.

Far-reaching implications of IMPROVE-IT
More importantly, IMPROVE-IT marks a significant milestone for the industry as the first long-term cardiovascular outcomes trial to lend notable support to non-statin cholesterol-lowering medicines. Manufacturers of LDL-C-lowering medications can breathe a sigh of relief as initial fears have likely been quelled in light of the successful trial - there was concern that negative results might push the FDA towards imposing a requirement for long-term cardiovascular outcomes trials before granting approval to non-statin cholesterol-lowering therapies that have long relied on LDL-C levels as a valid surrogate endpoint.

Existing products such as Vytorin and potential new market entrants, such as the promising class of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, including US firm Amgen's evolocumab, and French company Sanofi and US firm Regeneron's alirocumab, currently have a particularly favourable outlook as prescribers realise the benefit of reducing LDL-C below previously recommended levels.

Prescription of statins may also be boosted to further lower LDL-C levels moving forward. The new AHA/American American College of Cardiology (ACC) guidelines for identification of atherosclerotic risk and blood cholesterol treatment issued in November last year notably lowered the threshold of eligibility for statin therapy. The guidelines, however, do not establish an optimal LDL-C level to be achieved during treatment, but merely suggest that based on clinical evidence, "high-intensity" statin therapy, such as a 40-80 mg daily dose of atorvastatin that can achieve greater than 50% reduction in LDL-C levels, is associated with greater cardiovascular risk reduction.

IMPROVE-IT definitely supports increased prescription of cholesterol-lowering drugs, and may alter the recommended LDL-C levels for heart disease patients moving forward - with early implementation of sizeable reductions in LDL-C, the risk of cardiovascular events is likely to drop accordingly.

The IMPROVE-IT results are one small victory against the world's number ONE killer and could go a long way towards changing the standard of care for heart disease.

Margaret Labban is a life sciences analyst for IHS
Posted December 9, 2014

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