The Higher the LDL-C Level, the Greater the Benefit in Mortality with Aggressive Therapy

The latest studies seem to support higher baseline LDL-C levels would justify further intensifying and already aggressive drug strategy. A more aggressive hypolipidemic therapy would involve adding far more expensive new drugs that many specialists are reluctant to accept, in terms of their cost benefit ratio.

The intensive therapy to lower LDL-C levels reduces cardiovascular death and all-cause mortality when compared against a less intensive therapy, but this benefit in mortality reduction varies according to baseline LDL-C, according to the outcomes of this meta-analyzis published in JAMA.

In fact, the benefit of intensive therapy in mortality was observed only in patients with baseline LDL-C over 100 mg/dl, which suggests the benefit of adding ezetimibe or a PCSK9 inhibitor (the only two available in the market) would be justified only in patients at the highest risk (that is, with the highest baseline LDL-C levels).

Read also: FOURIER: Efficacy of Evolocumab for Ultra-Low LDL Levels.

Baseline LDL-C levels over 100 mg/dl might justify bigger efforts in terms of drugs and costs, but what is the goal? It is rather obvious that not all patients must reach less than 70 mg/dl, less than 50 mg/dl or even less than 30 mg/dl, as some particular high-risk groups have shown.

At this point, it seems we need more thorough study of individual data, instead of relying on data from different studies. In other words, this meta-analyzis was centered on baseline LDL-C levels from several studies, quite different from each other, including different types of patients and different follow up time, among other differences. In the end, it all comes down to making conclusions based on lab figures, in this case, baseline LDL-C levels.

This meta-analyzis will soon be published in JAMA. It included 34 randomized studies with statins, ezetimibe and PCSK9 inhibitors (alirocumab and evolocumab). Eight of these studies were in primary prevention, 16 in secondary prevention and 10 included both type of patients.

Read also: Strict LDL Monitoring Helps Reduce Plaque Volume.

The meta-analyzis included studies from the 4S and the WOSCOPS (that are more than 20 years old) and the recently published FOURIER, that assessed evolocumab. It added up to a total 136,299 patients undergoing intensive drug therapy and 133,989 undergoing a less aggressive therapy.

All-cause mortality was reduced in the groups undergoing intensive therapy (7.08% vs 7.70%; RR 0.92; CI 95%, 0.88 to 0.96), while something similar was observed with cardiovascular mortality (3.48% vs 4.07%; RR 0.84; CI 95% 0.79 to 0.89). 

An intensive therapy was associated to greater all-cause mortality reduction, the higher the baseline LDL-C level, but the benefit becomes significative with 100 mg/dl cutoff (p<0.001 for the interaction).

All this should be taken into account given the large population and the cost of treatment. If ezetimibe, even the generic version, is considered expensive by most healthcare systems, what is left for the cost/benefit ratio of the new PCSK9 inhibitors?

Original Title: Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis.

Reference: Navarese EP et al. JAMA. 2018;319:1566-1579.

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