Still No Good Evidence That Nonstatin Drugs Prevent Heart Attacks and Strokes

Ezetimibe (VYTORIN, ZETIA): Do Not Use

Statins have long been a mainstay of treatment for patients with high LDL (“bad” cholesterol) and cardiovascular disease. Previous studies assessing the benefits of adding nonstatin drugs to statins met with little success.[1]

This is why a study known as the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) made headlines when its initial results were made public in November 2014.[2] The study suggested that adding the drug ezetimibe (ZETIA) to a statin reduced the risk of cardiovascular events beyond that achieved with the statin alone in subjects who had a recent heart attack.[3]

However, the Food and Drug Administration (FDA) noted that it had yet to review the study in detail and therefore “it is possible that the [agency] will reach different conclusions than the trial’s investigators.”[4]

A few months after the publication of IMPROVE-IT’s full results in The New England Journal of Medicine,[5] the FDA approved two new drugs as add-ons to statins to lower LDL,[6],[7] despite the fact that neither of these high-cost drugs has yet been shown to prevent death or serious cardiovascular events in any patients.

These recent developments have major implications for the treatment of cholesterol and cardiovascular disease, and it is critical that patients with these conditions know the facts about these nonstatin treatments.

The IMPROVE-IT study

The IMPROVE-IT trial recruited more than 18,000 subjects who had a recent heart attack — or symptoms similar to a heart attack, known as unstable angina — and who had blood LDL levels of at least 50 (a relatively low level) and as much as 150.[8] All subjects took a statin (simvastatin [ZOCOR], at a dose of 40 milligrams [mg] per day), but half were randomly selected to also take 10 mg of ezetimibe per day. Subjects were followed for an average of six years. The study primarily measured whether subjects experienced a combination of one or more of the following: death from cardiovascular causes, a major coronary event (such as another heart attack) or a stroke.

The addition of ezetimibe significantly reduced LDL cholesterol levels beyond those achieved by statins alone. But adding ezetimibe reduced the risk of experiencing death from cardiovascular causes, a major coronary event or stroke by only 2 percent (from 35 to 33 percent) over simvastatin alone.

This result was barely statistically significant and was complicated by important missing data in the study. In addition, this small benefit of ezetimibe was limited to people with diabetes or those over 75, a minority of those in the study. Finally, adding ezetimibe did not reduce the risk of death compared with simvastatin alone.

Public Citizen pointed out some of these serious drawbacks to the study in testimony given at a December 2015 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. The committee discussed whether the FDA should approve ezetimibe and the combination drug ezetimibe-simvastatin (VYTORIN) for the prevention of cardiovascular events, such as heart attacks and strokes.[9] In our testimony, we strongly recommended against approval,[10] and the committee agreed with us by a vote of 10 to 5.[11]

New, unproven cholesterol drugs

Shortly after the publication of IMPROVE-IT, the FDA approved two new medications for lowering cholesterol: evolocumab (REPATHA) and alirocumab (PRALUENT).[12],[13] Public Citizen’s Health Research Group testified before FDA advisory committees against the drugs’ approvals, with the exception of approval for evolocumab to treat an extremely small number of patients with very high LDL due to a genetic condition known as homozygous familial hypercholesterolemia (HoFH).[14],[15]

We argued against approval because, while the drugs significantly reduced LDL levels, neither has been proven effective in preventing death or serious cardiovascular events in patients with cardiovascular disease.[16] Two large clinical trials are underway to assess whether the drugs are effective in this regard, but these will not be completed until 2017.[17],[18] In addition, the drugs’ side effects — and, more generally, the long-term effects of reducing LDL to levels as low as those seen in the trials — are as yet largely unknown.[19]

A further concern is that patients now using statins — which do prevent deaths and serious cardiovascular events — might inappropriately switch to the new drugs. This may occur either because of symptoms, such as muscle aches, mistakenly attributed to statins[20] or after patients and physicians are swayed by the inevitable marketing campaign for the new drugs.

What You Can Do

If you have cardiovascular disease, you should take statins to reduce your LDL level. We recommend the following four statins as first-line options because they are FDA-approved to prevent heart attacks, strokes or death from cardiovascular causes in patients with cardiovascular disease: atorvastatin (LIPITOR), lovastatin (MEVACOR), pravastatin (PRAVACHOL) and simvastatin (ZOCOR). Rosuvastatin (CRESTOR) is a Do Not Use drug.

If one of these statins fails to reduce your LDL to a healthy level (the precise value of which depends on your cardiovascular risk), your doctor should first increase the dose. If an increased dose also fails to lower LDL sufficiently or if the statin causes uncomfortable symptoms, your doctor should try switching to another statin. It is important to keep in mind that while muscle aches are a known side effect of statins and can be serious in some cases, not all such symptoms are due to statins.

We agree with the FDA’s advisory committee that the IMPROVE-IT trial failed to provide substantial evidence that adding ezetimibe to statins leads to better outcomes in cardiovascular disease. Therefore, we do not recommend the addition of ezetimibe to statins.

We recommend against using alirocumab, and you should not use evolocumab unless you have HoFH. This recommendation may change if the ongoing clinical trials of the drugs show them to be effective in treating cardiovascular disease. But for now, statins are the only cholesterol medications proven — and FDA-approved as — effective in patients with cardiovascular disease.

For more on our recommendations on treating high cholesterol and on the appropriate use of statins, see New Cholesterol Treatment Guidelines Recommend Statins for More Patients in the November 2014 issue of Worst Pills, Best Pills News, and Studies Cast Doubt on the Benefits of Raising HDL ("Good") Cholesterol in the May 2015 issue.

References

[1] Jarcho JA, Keaney JF. Proof that lower is better — LDL cholesterol and IMPROVE-IT. N Engl J Med. 2015;372(25):2448-2450.

[2] Kolata G. Study finds alternative to anti-cholesterol drug. The New York Times. November 17, 2014. http://www.nytimes.com/2014/11/18/health/study-finds-alternative-to-statins-in-preventing-heart-attacks-and-strokes.html?_r=2. Accessed November 25, 2015.

[3] Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.

[4] Food and Drug Administration. Briefing Document for the Endocrinologic and Metabolic Drugs Advisory Committee for Praluent, at PDF page 50. June 9, 2015. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM449865.pdf. Accessed November 25, 2015.

[5] Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.

[6] Food and Drug Administration. FDA news release: FDA approves Praluent to treat certain patients with high cholesterol. July 24, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. Accessed November 25, 2015.

[7] Food and Drug Administration. FDA news release: FDA approves Repatha to treat certain patients with high cholesterol. August 27, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm. Accessed November 25, 2015.

[8] Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.

[9] Food and Drug Administration. December 14, 2015: Endocrinologic and Metabolic Drugs Advisory Committee Meeting Announcement. http://www.fda.gov/AdvisoryCommittees/Calendar/ucm472456.htm. Accessed December 17, 2015.

[10] Public Citizen. Testimony Before the FDA's Endocrinologic and Metabolic Drugs Advisory Committee Regarding Simvastatin/Ezetimibe. December 14, 2015. http://www.citizen.org/documents/2292.pdf. Accessed December 15, 2015.

[11] Clarke T. Merck fails to win FDA panel backing for Vytorin heart claim. Reuters. December 14, 2015. http://www.reuters.com/article/us-merck-zetia-fda-idUSKBN0TX2IL20151215. Accessed December 15, 2015.

[12] Food and Drug Administration. FDA news release: FDA approves Praluent to treat certain patients with high cholesterol. July 24, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. Accessed November 25, 2015.

[13] Food and Drug Administration. FDA news release: FDA approves Repatha to treat certain patients with high cholesterol. August 27, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm. Accessed November 25, 2015.

[14] Public Citizen. Testimony Before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Regarding Evolocumab. June 10, 2015. http://www.citizen.org/hrg2264. Accessed November 25, 2015.

[15] Public Citizen. Testimony Before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Regarding Alirocumab. June 9, 2015. http://www.citizen.org/hrg2263. Accessed November 25, 2015.

[16] Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in whom? N Engl J Med. 2015;372(16):1564-1565.

[17] Clinicaltrials.gov. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER). NCT01764633. https://clinicaltrials.gov/ct2/show/record/NCT01764633. Accessed November 25, 2015.

[18] Clinicaltrials.gov. ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab SAR236553 (REGN727). NCT01663402. https://clinicaltrials.gov/ct2/show/record/NCT01663402. Accessed November 25, 2015.

[19] Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in whom? N Engl J Med. 2015;372(16):1564-1565.

[20] Public Citizen. Testimony Before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Regarding Alirocumab. June 9, 2015. http://www.citizen.org/hrg2263. Accessed November 25, 2015.