Physicians' Academy for Cardiovascular Education

FH patients with ACS have double risk of recurrent coronary events vs non-FH ACS patients

Literature - Nanchen D et al., Circulation 2016

Prognosis of Patients with Familial Hypercholesterolemia After Acute Coronary Syndromes

Nanchen D, Gencer B, Muller O, et al.
Circulation 2016;134:698-709


FH is underdiagnosed in the general population. Several FH definitions exist, based on LDL-C levels and/or personal or family history of premature CHD [1,2]. In Europe, 8% of ACS patients are diagnosed with FH at the time of their first CV event [3,4].
No established screening strategy exists for FH. Also, prognosis data are lacking for these patients, including limited data regarding the risk of CV recurrent events in ACS patients with FH, and the benefit of statin treatment compared with placebo has not been established in a randomised controlled study [5].
This study evaluated whether an FH diagnosis in 4534 ACS patients was associated with a higher risk of recurrent coronary events, compared with ACS patients without FH, independently of CV risk factors and the severity of ACS.

Main results

  • Overall, 79.2% of ACS patients had no criteria for FH, 2.5% were identified with FH using the AHA definition, 5.5% using the Simon Broome, while 18.2% were identified with possible FH, and a further 1.6% with probable/definite FH using the Dutch Lipid Clinic definition.
  • At 1-year follow-up after hospitalisation for ACS, 153 (3.4%) died, 217 (4.8%) suffered a fatal or non-fatal MI, and 275 (6.1%) patients experienced a CV event.
  • The unadjusted rates of coronary and CV events were similar between patients with and without FH, but patients with FH were 10 years younger.
  • In a multivariable model adjusted for age, sex, BMI, current smoking, hypertension, DM, pre-existing CV disease, attendance to cardiac rehabilitation, prescription of high-intensity statins at discharge, and results of the 6-months GRACE risk score, patients with FH had an 2.46 increased risk of a recurrent coronary event compared with patients without FH, according to the AHA definition: HR: 2.46 (95% CI: 1.07-5.65; P=0.034), according to the Simon Broome definition: HR: 2.73 (95% CI: 1.46-5.11; P=0.002) and according to the probable/definite Dutch Lipid Clinic definition: HR: 3.53 (95% CI: 1.26-9.94; P=0.017).
  • Among FH patients, 98.6% were discharged on any statin and 77.3% were discharged at high-dose statins. One year after ACS, high-dose statins were still used by more than 70% of FH patients, but less than 10% reached the 70 mg/dL LDL-C target.
  • Among patients without FH, 67% were discharged on high-dose statins, and 56% were still on high-dose statins one-year after ACS, with nearly 38% reaching the 70 mg/dL LDL-C target.


FH patients hospitalised for ACS, have a two-fold increased risk of recurrent coronary events, despite high-dose statin treatment, compared with ACS patients without FH. These results suggest that FH patients need to be identified, as they are less likely to reach target LDL-C levels and more likely to suffer recurrent CV events. Moreover, they are candidates for novel lipid lowering drugs, family counselling and tailored secondary prevention.

Editorial comment [6]

In their editorial article, Kees G Hovingh and John JP Kastelein provide a historical overview of insights into FH, and point out the knowledge gaps that have been addressed by Nanchen et al. Despite a few limitations, including the lack of molecular diagnosis and stratification by genetic defect, the measurement of LDL-C after ACS for the diagnosis, and the lack of assessment of xanthomas that weigh considerably in two FH scoring systems, the study provides valuable information: ‘In summary, heFH patients are at greater risk from their LDL-C level than any individual with a similar LDL-C level, are rarely diagnosed before they have their first coronary event at a mean age of 44, have a post-ACS hazard ratio for a second event of approximately 3.5 compared with non-FH ACS patients, and only receive high-dose statin therapy in 75% of cases. Even then, very few heFH patients reach the LDL-C guideline target of 70 mg/dL, and all of these factors combined leads to their death from a recurrent event at a mean age of 60 years.’
And they conclude: ‘No formal end point trial has been or ever will be conducted in patients with heFH because this is widely considered to be unethical (patients with FH are by definition at high risk) and not feasible (the large number of FH patients to be enrolled in a clinical end point trial is impractical). As a consequence, the benefit of monoclonal antibodies against PCSK9 for heFH patients will have to be extrapolated from clinical studies conducted in other high-risk patient populations.’ …. ‘Given the still elevated LDL-C levels and the ensuing hazard ratios observed by Nanchen and coworkers in FH patients, it only can be hoped that these novel therapies will be successful in reducing CV mortality and events.’
Find this article online at Circulation


1. Gidding SS, Ann Champagne M, de Ferranti SD, et al. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 2015;132:2167-2192.
2. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769-1818.
3. Nanchen D, Gencer B, Auer R, et al. Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes. Eur Heart J. 2015;36:2438-2445.
4. De Backer G, Besseling J, Chapman J, et al. Prevalence and management of familial hypercholesterolaemia in coronary patients: An analysis of EUROASPIRE IV, a study of the European Society of Cardiology. Atherosclerosis. 2015;241:169-175.
5. Foody JM. Familial Hypercholesterolemia: An Under-recognized but Significant Concern in Cardiology Practice. Clin Cardiol. 2014;37:119-125.
6. Kees Hovingh G and Kastelein JJP. Diagnosis and Management of Individuals With Heterozygous Familial Hypercholesterolemia: Too Late and Too Little. Circulation. 2016;134:710-712

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