J Am Coll Cardiol. 2016 Jul 19;68(3):252-60. doi: 10.1016/j.jacc.2016.04.054.

Statins in Familial Hypercholesterolemia: Consequences for Coronary Artery Disease and All-Cause Mortality.

Besseling J1, Hovingh GK1, Huijgen R1, Kastelein JJ2, Hutten BA3.
  • 1Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
  • 2Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: j.j.kastelein@amc.nl.
  • 3Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands.

 

Abstract

BACKGROUND:

A statin-induced reduction of coronary artery disease (CAD) events and mortality has not been adequately quantified in patients with heterozygous familial hypercholesterolemia (FH).

OBJECTIVES:

This study estimated the relative risk reduction for CAD and mortality by statins in heterozygous FH patients.

METHODS:

The authors included all adult heterozygous FH patients, identified by the Dutch screening program for FH between 1994 and 2013, who were free of CAD at baseline. Hospital, pharmacy, and mortality records between 1995 and 2015 were linked to these patients. The primary outcome was the composite of myocardial infarction, coronary revascularization, and death from any cause. The effect of statins (time-varying) was determined using a Cox proportional hazard model, while correcting for the use of other lipid-lowering therapy, thrombocyte aggregation inhibitors, and antihypertensive and antidiabetic medication. The authors applied inverse-probability-for-treatment weighting (IPTW) to account for differences at baseline between statin users and never-users.

RESULTS:

The authors obtained medical records of 2,447 patients, of whom 888 were excluded on the basis of age <18 years or previous CAD. Simvastatin 40 mg and atorvastatin 40 mg accounted for 23.1% and 22.8% of all prescriptions, respectively. Statin users (n = 1,041) experienced 89 CAD events and 17 deaths during 11,674 person-years of follow-up versus statin never-users (n = 518), who had 89 CAD events and 17 deaths during 4,892 person-years (combined rates 8.8 vs. 5.3 per 1,000 person-years, respectively; p < 0.001). After applying IPTW and adjusting for other medications, the hazard ratio of statin use for CAD and all-cause mortality was 0.56 (95% confidence interval: 0.33 to 0.96).

CONCLUSIONS:

In patients with heterozygous FH, moderate- to high-intensity statin therapy lowered the risk for CAD and mortality by 44%. This is essential information in all cost-effectiveness studies of this disorder, such as when evaluating reimbursement of new lipid-lowering therapies. Copyright © 2016 American College of Cardiology Foundation.

KEYWORDS: intensity; inverse-probability-of-treatment-weighting; lipid lowering

PMID: 27417002

 

Supplement

 

Familial hypercholesterolemia, a hereditary disorder of low-density lipoprotein (LDL) cholesterol metabolism, affects 1 in 250 persons and is characterized by increased levels of LDL cholesterol.1–3 Patients with heterozygous familial hypercholesterolemia are at 3-4 fold higher risk for coronary artery disease (CAD) and tend to develop CAD on average ten years earlier in life than unaffected persons.3,4 Statins lower LDL cholesterol in patients with heterozygous familial hypercholesterolemia5 approximately to the same extent as in the general population.6 In the latter, the average relative risk reduction of statins for CAD is estimated to be 22% per mmol/L.6,7 This estimate is, however, unknown in heterozygous familial hypercholesterolemia patients, since it is considered unethical to withhold treatment from these patients. Randomized controlled trials are therefore not available.

 

There is a clear need to know to what extent statins reduce the risk for CAD and how large the residual CAD risk is in these patients because new classes of LDL cholesterol lowering therapy (e.g. antibodies to proprotein convertase subtilisin/kexin type 2 [PCSK9]) will be evaluated for approval in heterozygous familial hypercholesterolemia patients who do not reach treatment targets despite statin therapy. The objective of current study was therefore to estimate the relative risk reduction for CAD and mortality by statins in heterozygous familial hypercholesterolemia patients.

 

In our large cohort of patients with heterozygous familial hypercholesterolemia, we found that medium- to high intensity statin therapy was associated with a relative risk reduction of approximately 44% for the primary prevention of CAD and all-cause mortality. Furthermore, a non-significant positive association between off-treatment LDL cholesterol levels and relative risk reduction was observed.

 

The efficacy of statin therapy in patients with familial hypercholesterolemia was previously evaluated in a retrospective cohort study.14 The authors of this study reported a relative risk reduction of 76% which is much higher than the relative reduction of 44% in our study. The main reason for this discrepancy might be found in the high untreated LDL cholesterol levels of their study population as compared to our study population (309 mg/dL versus 213 mg/dL). In fact, prior studies have shown that the higher the baseline LDL cholesterol, the greater the relative risk reduction with statin therapy.15,16 The latter is consistent with our other findings as well. Furthermore, the baseline LDL cholesterol level in our study is similar to that in large population based cohorts of patients with heterozygous familial hypercholesterolemia (200 to 236 mg/dL).17,18 We therefore deem the relative risk reduction of 44% to be applicable to heterozygous familial hypercholesterolemia patients in general.

 

In line with the association between baseline LDL cholesterol level and the extent of relative risk reduction is the lower hazard ratio of statin use for CAD and all-cause mortality in LDLR mutation carriers, compared to APOB mutation carriers. However, caution is warranted since the confidence intervals of these hazard ratios are wide and include 1.00 and the p-value for interaction is far from significant. Nonetheless, it might be suggested that LDLR mutation carriers profit more from statin use, based on their higher baseline LDL cholesterol level and therefore their absolute LDL cholesterol reduction.

 

In absolute terms, the lifetime risk for first CAD event in untreated patients with heterozygous familial hypercholesterolemia is estimated to be 103/100,000 person-years in the Netherlands.19 In theory, statins would lower this risk by 44% to 58/100,000 person-years. This is certainly an improvement, but a substantial residual risk remains in these patients compared to CAD event rates in their unaffected family members (29/100,000 person-years).19

 

Clinical relevance

The increased risk for premature CAD in heterozygous familial hypercholesterolemia, in conjunction with its high prevalence of around 1:2501,3,20, has an important impact on public health. Moreover, it is estimated that 80% of these patients will not reach LDL cholesterol levels below 100 m/dL despite efficacious therapy.21 Currently, new lipid lowering modalities, such as PCSK9 inhibitors, are evaluated by authorities for reimbursement for these patients. An important aspect in this decision is the potential for the prevention of CAD events by statins at a population level, and therefore it is important to quantify the residual CAD risk in statin treated patients. The relative risk reduction by statins is key information in this estimation. In fact, it is fundamental information in all cost-effectiveness studies in this disorder, for example when evaluating screening programs.22,23

 

In conclusion, medium to high intensity statin therapy lowers the risk of CAD and all-cause mortality by approximately 44% in patients with heterozygous familial hypercholesterolemia. 


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