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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 31, No 5, September/October 2020

250

AFRICA

The most current South African dyslipidaemia guidelines

recommend ezetimibe as a second-line treatment in combination

with a statin when the LDL-C target is not achieved with the

highest tolerated statin dose, when there is intolerance to statins

or when there is a contra-indication to a statin.

18

However, the

guidelines in place at the time of the study was conducted did

not strongly endorse ezetimibe, as no cardiovascular outcome

evidence was available for ezetimibe at the time the guidelines

were compiled.

19

Lack of cardiovascular outcome data may have

dissuaded some practitioners from prescribing ezetimibe.

Although one would expect a greater proportion of study

participants receiving ezetimibe, especially when added to the

highest possible statin dose, to reach LDL-C target, this was

not the case. This finding is not unexpected as the authors

frequently observe in clinical practice that clinicians are more

likely to prescribe ezetimibe to patients who were far from

their LDL-C goal. We have also noted that many funders in

South Africa will not reimburse ezetimibe if patients are close

to target. The use of ezetimibe may well increase as single-

pill combination tablets of ezetimibe with a potent statin

(atorvastatin or rosuvastatin) become available in South Africa,

and especially if these combination tablets are less costly than

prescribing two individual medications.

In our modelling analysis, we evaluated the impact of four

different treatment strategies in bringing patients to goal.

Because doubling the dose of a statin on average only decreases

LDL-C level by a further 6%, the statin maximisation strategy

was able to bring only 18% of those not at goal to goal. Adding

ezetimibe following statin maximisation would allow 34% of

patients previously not at goal to achieve goal. Because PCSK9

inhibitors reduce LDL-C level on average by about 60% when

added to statin therapy, the addition of a PCSK9 inhibitor to

a statin would allow over 90% of patients to reach goal. Most

patients receiving a PCSK9 inhibitor would be able to reach goal

without a statin dose increase or the addition of ezetimibe.

A simulation of various lipid-lowering strategies in American

patients with atherosclerotic cardiovascular disease using

data from a large administrative database showed that statin

intensification would bring about 67.3% of patients to an

LDL-C target of 1.8 mmol/l, while approximately 14% of

patients would require a PCSK9 inhibitor.

20

In our cohort, many

more patients would require PCSK9 inhibitors to reach target as

we selected a population that was already receiving the maximal

tolerated statin dose and specifically included patients with FH.

As PCSK9 inhibitors are costly monoclonal antibodies, access to

these drugs will be limited once they are commercially available

in South Africa.

The 2018 update of the South African dyslipidaemia

guidelines recommends considering PCSK9 inhibitor therapy

in three groups of patients: first, in patients with atherosclerotic

cardiovascular disease (coronary artery disease, symptomatic

peripheral artery disease, ischaemic stroke) at very high risk

who have substantially elevated LDL-C levels despite maximally

tolerated statin with or without ezetimibe therapy;

18

second, in

patients with FH without clinically diagnosed atherosclerotic

cardiovascular disease, at high or very high cardiovascular risk,

and with substantially elevated LDL-C levels despite maximally

tolerated statin plus ezetimibe therapy;

18

last, in patients with

atherosclerotic cardiovascular disease and at very high risk

who do not tolerate appropriate doses of at least three statins

and who have elevated LDL-C levels despite alternative lipid-

lowering therapies, such as ezetimibe.

18

Initial priority will need

to be given to those patients with the highest baseline risk and

LDL-C level in whom the number needed to treat will be the

lowest.

Limitations

Potential study sites were conveniently sampled and patients

attending these sites may not be fully representative of the

spectrum of South African patients with dyslipidaemia. Only

one study site was in the public sector and this site was based

at a tertiary-level teaching hospital. Public sector patients are

therefore not adequately represented in this study.

We were not able to objectively assess adherence to lipid-

lowering therapy and incomplete adherence may well have been

a contributing factor in some patients not at goal. We were

unable to describe the specific statin dose for 23 patients because

the information was not collected in the case report forms. This

was an error that we detected after completion of the study and

logistical issues precluded us from obtaining missing information

from sites. In our opinion it is improbable that this would make

a material difference to the results, discussion and conclusion of

this study.

For our modelling analysis, we made several assumptions,

including that patients will adhere to the prescribed therapy

perfectly and that it will be possible to up-titrate all patients to

the maximum statin dose. Because responses to lipid-lowering

therapies may be variable, some patients may show larger or

smaller decreases in LDL-C level at the various stages of our

titration algorithm, but in a large population we would expect

the average response to be close to previously published values.

Incomplete adherence would reduce the number of patients

reaching target at the various steps of our titration algorithm, as

would an inability to titrate all patients to the maximum statin

dose.

Conclusion

The majority of study participants were not at LDL-C goal

despite maximum-tolerated statin with or without ezetimibe

therapy, highlighting the importance of further treatment

intensification in this high-risk population. Currently PCSK9

inhibitors, in combination with statin, is the most effective

therapeutic strategy to reach LDL-C goals, but because of the

anticipated high cost of the drug, access will be limited in South

Africa. Despite the under-usage of ezetimibe in this study, the

addition of ezetimibe to existing maximum-tolerated statin

would result in a larger proportion of the study population

reaching target LDL-C goals, therefore contributing to a greater

reduction in atherosclerotic cardiovascular disease.

We thank the patients and investigators for their contributions.

PN, AvT and MGM are employees of Sanofi. PN, AvT and MGM do

not own stocks in Sanofi or Regeneron. Sanofi manufactures and markets

lipid-lowering therapies. Sanofi and Regeneron manufacture and market a

PCSK9 inhibitor.

Prof Dirk Jacobus Blom has received honoraria for lectures, advisory

board payments from Sanofi and Amgen and institutional payment for clini-

cal trials from Sanofi and Amgen. Prof Frederick Johan Raal has received