From the LipidSpin Editor: HOPE Springs Eternal for Intermediate-Risk Primary Prevention Patients

The annual Potpourri edition of the LipidSpin is one of my favorites. What is published typically reflects what is in the forefront of the minds of several clinical lipidologists and clinical lipid specialists.

I have spent the past several months debating how the 2016 American College of Cardiology Expert Consensus Decision Pathway, endorsed by the National Lipid Association (NLA), will change my practice.¹ I have also anticipated (fretted might be a better word) how approval of generic rosuvastatin will or will not be embraced by most insurers. I’m puzzled about the Food and Drug Administration’s decision to allow omega-3 fatty acid products to be promoted off-label. However, the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial results were what I found most appeasing.²

The HOPE trials are a series of clinical trials evaluating the long-term cardiovascular (CV) benefits of different medications. The original HOPE trial was a randomized placebo-controlled trial that demonstrated reduced risk of CV events in patients with ramipril-based therapy, even in the absence of hypertension.³

This had high impact with ACE inhibitor therapy broadly being adapted as an evidence-based recommendation in many high-risk patients. The most recently published HOPE-3 trial used a prospective randomized placebo controlled trial design to evaluate the effect of rosuvastatin 10 mg daily among 12,705 intermediate- risk primary prevention patients. After a median of 5.6 years, there was a significant 24 percent relative risk reduction in the primary CV endpoint (3.7 and 4.8 percent for rosuvastatin and placebo, respectively; p=0.002).

I am not certain why the HOPE-3 results have not received more attention. This is a landmark study and the results are impactful. Guidelines and expert recommendations have endorsement treating certain primary prevention patients. However, skeptics have questioned the benefits of statin therapy in intermediate-risk primary prevention patients who do not have diabetes.

Skeptics also cite that women and diverse patients (i.e., not white patients) have not been adequately represented in primary prevention outcome trials evaluating statin therapy. The JUPITER trial in 2008 had a reasonable number of women and non-white patients and demonstrated a significant reduction in CV events with rosuvastatin 20 mg daily versus placebo.⁴ However, JUPITER included only patients with elevated hs-CRP, which is a risk marker for CV events. The HOPE-3 included 28 percent Hispanic patients and 45 percent Asian patients. Patients were enrolled based on the “uncertainty principle,” meaning patients who were excluded had clear indications or contraindications for statin therapy. This means there was reasonable doubt of the benefits of statin therapy in the study population because they were intermediate-risk primary prevention without elevated hs-CRP or diabetes. Considering the results and the diversity of the population, the HOPE-3 expands the patient population with proven evidence that statin therapy reduces CV events.

The safety results of HOPE-3 were also important. Rosuvastatin was associated with small, but significant increase in muscle symptoms and need for cataract surgery compared to placebo. However, there was no increased risk of new onset diabetes with rosuvastatin, which is in contrast to other clinical trials. This should garner further interest. The HOPE-3 is not without limitations. There was only a 26.5 percent difference in LDL-C between rosuvastatin 10 mg daily and placebo. The study dose of rosuvastatin is moderate- intensity so this difference should have been much greater, even with some nonadherence. Nonetheless, CV events were reduced and the reduction is similar to what has been demonstrated in other clinical trials with a comparable amount of LDL-C lowering. This supports the LDL hypothesis.

The HOPE-3 trial adds to the already rich evidence base supporting statin therapy in primary prevention patients. Considering that the rate of ASCVD events seen in the placebo rate is similar to a 10-year ASCVD event rate of approximately 10 percent, these primary patients are candidates for moderate-to-high intensity statin therapy according to the 2013 American College of Cardiology/American Heart Association cholesterol guidelines.⁵ Most importantly, it provides additional data in diverse patients who are intermediate-risk. Expect to hear more about HOPE-3 in the near future.

It is a privilege to be the co-editor of LipidSpin. I hope you enjoy this Potpourri edition as much as I have!

References are listed on page 45 of the PDF.