While the absolute risk reduction for the composite endpoints was not reported, it was calculated to be 1.5% based on the results that were reported. As with many similar studies, this small decrease in risk is magnified by the authors when they report only the relative risk reductions, which range from 15% to 20%, depending on the composite endpoint evaluated. When the outcomes of the composite endpoints were evaluated independently, there were no significant differences in cardiovascular death between the placebo and the evolocumab groups.
Likewise, death from any cause, hospitalizations for unstable angina, or the composite of death or hospitalizations for worsening heart failure were not significantly different between groups.
While cardiovascular mortality was not a primary endpoint evaluated, surely, we’ll be hearing pharmaceutical reps cite the relative risk reductions ad nauseam. So it is important to consider that while there were significant reductions in the primary and secondary composite endpoints, this trial did not show an improvement in cardiovascular mortality when it was evaluated independent from the composite endpoints.
While it is important to note that the trial was not designed to evaluate cardiovascular mortality, when considering this expensive drug for our patients we should keep in mind that its effect on mortality remains unknown. Despite its fantastic efficacy at reducing LDL, non-fatal MI, or stroke these reduction did not translate into a mortality benefit during the study period.
The authors explained that the data suggest that clinically significant reductions in LDL levels require time to translate into clinical benefit, because the greatest differences between the groups were found in the second year of follow-up. The implication is obviously that we should treat patients for longer periods of time. Unfortunately, we need a longer study in order to support that claim with sufficient evidence.
At the current price of the drug, and lacking sufficient mortality data, treating patients for longer periods of time with expensive PCSK9 inhibitors is likely to result in increasing the financial burden on our high-risk patients with minimal clinical benefit in reducing non-fatal MI and stroke but unknown mortality benefit.
There is no doubt that, based on the available data, PCSK9 inhibitors do decrease LDL levels more significantly than any other drug currently available in our arsenal, and they do decrease the incidence of non-fatal MI and stroke over high dose statin’s alone.
However, with an estimated price tag of around $14,000 per year3 ,would treating all high-risk patients who simply do not meet their lipid goals by adding a PCSK9 inhibitor to their treatment be cost effective — especially for an absolute risk reduction for a composite endpoint of only 1.5% and thus far no significant reduction in risk for cardiovascular death. With that said, there is no evidence that a patient without coronary heart disease or familial hypercholesterolemia should even be considered for this drug.
With the trial’s reported number needed to treat (NNT) of 74 individuals over a 2 year period, it would cost an estimated $2,072,000 to prevent one event based on the study authors’ secondary composite endpoint, an estimated $2,333,333 to prevent one nonfatal MI, and approximately $7,000,000 over 2 years to prevent a stroke.
Just for comparison, the cost to prevent one cardiovascular death with a statin would cost anywhere between $85,000 to $300,000 depending on the risk levels of the individuals being treated.4
Needless to say, despite their efficacy at lowering LDL, PCSK9 inhibitors are probably not yet a cost-effective solution. Widespread adoption of this drug would be costly and would significantly add to the economic burden of our patients and the struggling American healthcare system.
While this trial does make progress toward answering some of the crucial questions surrounding PCSK9 inhibitors, the trial was not designed to show mortality benefits in patients already at high risk. Trials involving longer outcomes are still needed to evaluate whether adopting the widespread use of PCSK9 inhibitors in high-risk patients with clinical atherosclerosis and suboptimal LDL levels will result in clinically significant reductions in cardiovascular mortality.
Further, while the reduction of LDL levels to 30 mg/dL in this study appeared to be safe, longer trials are still needed to test this conclusion. As the authors suggested — it takes time to see a clinical benefit. Likewise, if there are significant consequences to having such low LDL levels, I imagine those would take some time to become clinically evident as well.
- Nissen SE. Global assessment of plaque regression with a PCSK9 antibody as measured by intravascular ultrasound – GLASGOV. Abstract Presented At: American Heart Association Annual Scientific Sessions (AHA 2016); November 12-16, 2017; New Orleans, LA.
- Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease [published online March 2017]. N Engl J Med. doi: 10.1056/NEJMoa1615664
- Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA. 2016;316(7):743-753. doi: 10.1001/jama.2016.11004
- Thompson A, Temple NJ. The case for statins: has it really been made? J R Soc Med. 2004;97(10):461-464. doi: 10.1258/jrsm.97.10.461
This article originally appeared on Medical Bag