HOUSTON—Veterans who have experienced acute coronary syndrome within the past year face a substantial risk of a repeat event. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly reduce that risk, but determining who would benefit most and when they should be initiated has been challenging. 

A team led by Salim S. Virani, MD, PhD, of the Michael DeBakey VAMC in Houston, tackled those questions and determined that PCSK9 inhibitors clearly have a role in reducing mortality in high-risk veterans with acute coronary syndrome. Their analysis also demonstrated that a rigorous stepped approach to low-density lipoprotein cholesterol reduction can contribute to both improved outcomes and reduced costs for the VA.1

Two large studies have shown a 15% reduction in relative risk of major cardiovascular events with the addition of a U.S. Food and Drug Administration-approved PCSK9 inhibitor to statin therapy. The ODYSSEY Outcomes trial evaluated alirocumab; the FOURIER study assessed evolocumab.2,3

To determine the proportion of patients in the VA Health Care System might benefit from PCSK9 inhibitor therapy, the Houston team searched a national cohort and found that 164,446 veterans with a history of ACS in the system between Oct. 1, 2014 and Sept. 30, 2015. Applying the ODYSSEY Outcomes criteria brought the number eligible down to 10,342, with most of the exclusions occurring because of the diagnosis of ACS was less than four weeks before or more than 52 weeks before the index primary care visit.

This treatment window “is typical for studies including those who’ve had ACS,” Virani told U.S. Medicine. “The first month has a higher chance of complication. After one year, the risk reduces. This typically is a good timeframe or range to include ACS patients.”

While 89% of participants in the ODYSSEY Outcomes trial were taking high-intensity statins at baseline, among veterans, the rates was a little more than half that. About 50% of veterans were on high-intensity statins, 28.5% were on moderate-intensity statins, 5.3% were on low-intensity statins and 15.3% were not on any statin.

The rate of statin use within the VA roughly reflects that seen in the general population.

“ODYSSEY was a randomized controlled trial,” said study co-author Vijay Nambi, MD, PhD. “To be in the study, patients had to be on statins at a maximum tolerated dose. What we were trying to do was to evaluate how many individuals in the VA would meet ODYSSEY criteria based on cholesterol levels. The low use of high-intensity statin therapy in patients with atherosclerotic cardiovascular disease is also seen in other large healthcare systems.”

Optimizing Statins First

The current American College of Cardiology algorithm for managing LDL-C in patients with ACS and hypercholesterolemia calls for optimizing statin therapy first, with a goal of reducing LDL cholesterol to less than 70 mg/dL. If the maximum tolerated dose of a statin fails to achieve the target, providers should prescribe ezetimibe, which limits absorption of cholesterol and has been shown to improve outcomes specifically in patients with ACS.

Applying these recommendations to the VA population and assuming a 6% reduction in LDL-C and a 20% reduction with ezetimibe, the researchers determined that 33% of the veterans would likely push LDL-C to or below the target by optimizing statin therapy alone. Two-thirds would have LDL-C below 70 mg/dL if they took a high-intensity statin and added ezetimibe.

That results is comparable to the active arm of ODYSSEY Outcomes trial, the authors noted but may overstate the benefit.

“Estimates vary, but muscle side effects, such as muscle pain and weakness, have occurred in 5% to 10% in some clinical studies,” Nambi told U.S. Medicine. “A percentage of these individuals will not want to continue statins,” although some may be able to tolerate a lower dose.

In addition, adherence to statin therapy is often low. In the VA population, the researchers found that 44.5% of veterans failed to adhere to recommended statin therapy. 

Some nonadherent or statin-intolerant patients may do better on PCSK 9 inhibitors. “Tolerance has been better in studies with PCSK9 inhibitor ‘from a side effect standpoint,’” Virani said. “Also, as this is not a daily medication, that may improve adherence.” PCSK9 inhibitors are typically injected once or twice a month.

For high-risk patients who do not reach their goal of LDL-C below 70 mg/dL on high-intensity statins and ezetimibe, adding PCSK9 inhibitors to existing therapy could be considered in keeping with current guidelines, Virani noted.

Limiting the use of alirocumab to patients who have optimized other treatment options rather than prescribing it to all eligible veterans based on the ODYSSEY criteria would lead to a nearly two-thirds reduction in the cost of PCSK9 inhibitor therapy at retail prices, from $150 million to $53 million, according to the Houston team’s analysis. The calculation factors in the increase in costs associated with higher utilization of statins and ezetimibe.

“Although statin undertreatment could be a result of provider clinical inertia, patient intolerance, or refusal to take statin or high-intensity statin therapy,” the authors concluded, “our analyses suggest a modest role for proprotein convertase subtilisin/kexin type 9 inhibitors if current guideline-based lipid-lowering therapy is optimized.”

1. Virani SS, Akeroyd JM, Nambi V, Michos ED, Morris PB, Nasir K, Smith SC Jr, Stone NJ, Petersen LA, Ballantyne CM. Applicability and Cost Implications for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Based on the ODYSSEY Outcomes Trial. Circulation. 2019 Jan 15;139(3):410-412.

2. Schwartz GG, Steg PG, Szarek M, et al., on behalf of the ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes After Acute Coronary Syndrome. N Engl J Med 2018 Nov 29;379:2097-107.

3. Sabatine MS, Giugliano RP, Keech AC, et al., on behalf of the FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017 May 4;376(18):1713-1722.