Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial.

AIM: To evaluate the effect of alirocumab on frequency of standard apheresis treatments [weekly or every 2 weeks (Q2W)] in heterozygous familial hypercholesterolaemia (HeFH). METHODS AND RESULTS: ODYSSEY ESCAPE (NCT02326220) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis. Patients were randomly assigned (2:1, respectively) to receive alirocumab 150 mg (n = 41) or placebo (n = 21) Q2W subcutaneously for 18 weeks. From day 1 to week 6, apheresis rate was fixed according to the patient's established schedule; from weeks 7 to 18, apheresis rate was adjusted based on the patient's low-density lipoprotein cholesterol (LDL-C) response in a blinded fashion. Apheresis was not performed when the LDL-C value was ≥30% lower than the baseline (pre-apheresis) value. The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks (weeks 7-18), standardized to number of planned treatments. In the alirocumab group the least square (LS) mean ± SE (95% confidence interval [CI]) per cent change in pre-apheresis LDL-C from baseline at week 6 was -53.7 ± 2.3 (-58.2 to - 49.2) compared with 1.6 ± 3.1 (-4.7 to 7.9) in the placebo group. The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab (Hodges-Lehmann median estimate of treatment difference: 0.75; 95% CI 0.67-0.83; P < 0.0001). Therefore, alirocumab-treated patients had a 0.75 (75%) additional reduction in the standardized rate of apheresis treatments vs. placebo-treated patients. During this period, 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments. Adverse event rates were similar (75.6% of patients on alirocumab vs. 76.2% on placebo). CONCLUSIONS: Lipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis, and the rate was at least halved in 92.7% of patients. Alirocumab was generally safe and well tolerated.

PEARL: A Non-interventional Study of Real-World Alirocumab Use in German Clinical Practice.

BACKGROUND: Several lipid guidelines recommend that proprotein convertase subtilisin/kexin type 9 inhibitors should be considered for patients with atherosclerotic cardiovascular disease who are inadequately treated with maximally tolerated lipid-lowering treatment. OBJECTIVES: The PEARL study assessed the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in patients with hypercholesterolemia in a real-world setting. METHODS: PEARL was an open, prospective, multicenter, non-interventional study conducted in Germany. Patients (n = 619) for whom treating physicians decided to use alirocumab 75 or 150 mg every 2 weeks according to German guidelines (low-density lipoprotein cholesterol > 1.8/2.6 mmol/L [> 70/100 mg/dL], depending on cardiovascular risk, despite maximally tolerated statin therapy with/without other non-alirocumab lipid-lowering therapy) were enrolled and followed for 24 weeks. Physicians could adjust the alirocumab dose based on their clinical judgment. The primary efficacy endpoint was low-density lipoprotein cholesterol reduction from baseline (prior to alirocumab therapy) to week 24. RESULTS: Overall, 72.8% of patients reported complete or partial statin intolerance. Mean low-density lipoprotein cholesterol was 4.7 mmol/L (180.5 mg/dL) and 2.3 mmol/L (89.8 mg/dL) at baseline and week 24, respectively. Least-squares mean percentage change from baseline to week 24 in low-density lipoprotein cholesterol was - 48.6%. Initial alirocumab dose was 75 mg in 72.9% of patients and 150 mg in 24.5% of patients; 19.6% of patients received an alirocumab dose increase (75 to 150 mg) and 1.6% of patients received a dose decrease. Adverse events were reported in 10.3% of patients, with myalgia being the most common. CONCLUSIONS: In a real-world setting in Germany, alirocumab was used in patients who had high baseline low-density lipoprotein cholesterol levels with/without statin intolerance. Efficacy and safety were consistent with findings observed in the ODYSSEY Phase III program.

Alirocumab in patients with heterozygous familial hypercholesterolemia undergoing lipoprotein apheresis: Rationale and design of the ODYSSEY ESCAPE trial.

BACKGROUND: Many patients with heterozygous familial hypercholesterolemia (HeFH) fail to reach optimal low-density lipoprotein cholesterol (LDL-C) levels with available lipid-lowering medications, including statins, and require treatment using alternative methods such as lipoprotein apheresis. OBJECTIVE: To evaluate the efficacy of alirocumab 150 mg every 2 weeks (Q2W) compared with placebo in reducing the frequency of lipoprotein apheresis treatments in patients with HeFH. METHODS: ODYSSEY ESCAPE is a randomized, double-blind, placebo-controlled, parallel-group, 18-week, phase 3 study being conducted in the United States and Germany. ODYSSEY ESCAPE will evaluate the efficacy and safety of alirocumab in approximately 63 adults with HeFH undergoing regular weekly (QW; for ≥4 weeks) or Q2W (for ≥8 weeks) lipoprotein apheresis. Patients will be randomly assigned (2:1, respectively) to receive alirocumab 150 mg subcutaneously Q2W or placebo subcutaneously Q2W (both in 1-mL injections) for 18 weeks. From day 1 to week 6, the apheresis frequency will be fixed to the individual patient's established schedule (QW or Q2W); thereafter, apheresis will be performed according to the LDL-C value at that visit: apheresis will not be performed when the LDL-C value is ≥30% lower than the baseline pre-apheresis LDL-C value. The primary end point is the frequency of apheresis treatments over a 12-week period starting at week 7. DISCUSSION: The ODYSSEY ESCAPE trial will determine whether alirocumab reduces the frequency of lipoprotein apheresis in patients with HeFH.

Excess 1-year cardiovascular risk in elderly primary care patients with a low ankle-brachial index (ABI) and high homocysteine level.

Previous studies in selected patient samples suggested a high risk for total mortality and cardiovascular (CV) morbidity associated not only with symptomatic, but also with asymptomatic peripheral arterial disease (PAD). Our aim was to assess the 1-year risk of death and CV morbidity associated with PAD in primary care. Furthermore, we quantified the strength of association between low ankle-brachial index (ABI, as indicator for PAD), plasma homocysteine (HC) levels, and various accepted PAD risk factors, and death and outcomes. In a prospective cohort study, 6880 unselected patients > or =65 years were followed up by 344 primary care physicians in Germany. At 1 year, all-cause mortality was 2.8% in patients with PAD and 0.9% in patients without PAD (odds ratio [OR] adjusted for age and gender: 2.7 [95% confidence interval: 1.7; 4.2]; multivariate adjusted OR: 2.0 [1.3; 3.3]). Mortality due to CV events was 1.6 versus 0.4% (OR: 3.7 [2.0; 6.9], adjusted OR: 2.5 [1.3; 4.9]). Patients with PAD and high HC values (> or =fourth quintile) had a markedly increased risk of premature death: OR versus no PAD/low HC level (

High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study.

We aimed to obtain reliable data on the epidemiology, co-morbidities and risk factor profile of peripheral arterial disease (PAD) in general medical practise. In the cross-sectional part of the observational German Epidemiological Trial on Ankle Brachial Index (getABI study), 344 general practitioners throughout Germany determined the ABI of consecutive, unselected patients aged 65 years or older with bilateral Doppler ultrasound measurements. Additional assessments comprised patient history with the focus on atherothrombotic diseases, physical examination, and the WHO questionnaire on intermittent claudication. A total of 6880 patients were included (42.0% male, mean age 72.5 years, mean body mass index 27.3 kg/m(2), mean systolic/diastolic blood pressure 143.7/81.3 mmHg). The prevalence of PAD for men/women as indicated by an ankle brachial index (AB1)<0.9 was 19.8/16.8%. Patients with PAD were slightly older than patients without PAD, suffered more frequently from diabetes (36.6 vs. 22.6%; adjusted OR: 1.8), hypertension (78.8 vs. 61.6%; OR: 2.2), lipid disorders (57.2 vs. 50.7%; OR: 1.3) and other coexisting atherothrombotic diseases (any cerebrovascular event: 15.0 vs. 7.6%; OR: 1.8; any cardiovascular event: 28.9 vs. 17.0%; OR: 1.5). The data highlight the high prevalence of PAD in primary care. PAD patients are characterised by a high co-morbidity, particularly with regard to other manifestations of atherothrombosis. Doppler ultrasound measurement for ABI determinations is a non-invasive, inexpensive, reliable tool in primary care and enables GPs to identify patients at risk of PAD.

Relationship between lipid parameters and the presence of peripheral arterial disease in elderly patients.

OBJECTIVE: To investigate the relationship between various lipid parameters and the presence of peripheral arterial disease (PAD). METHODS: Cross-sectional analysis of the observational epidemiological getABI study (German epidemiological trial on Ankle Brachial Index) with 6,880 unselected elderly patients in 344 primary care centers. RESULTS: In the multivariate analysis, the strength of the association between the various lipid parameters and PAD was found to be generally limited, when accounting for other risk factors. CONCLUSION: These findings are in contrast to previous studies. While lipid levels alone cannot be used for supporting the PAD diagnosis or the risk factor for these patients, this should not preclude PAD patients from receiving adequate lipid lowering treatment.

Association of low ankle brachial index with high mortality in primary care.

AIMS: We aimed to assess the increased risk of death and severe vascular events in elderly individuals with subclinical or manifest peripheral arterial disease (PAD), evidenced by low ankle brachial index (ABI < 0.9) in primary care. METHODS AND RESULTS: In this monitored prospective observational study, 6880 representative unselected patients aged >or=65 years were followed up over 3 years by 344 primary care physicians. Main outcome measures were mortality or a combined endpoint of mortality and severe vascular events. In total, 20 127 patient-years were observed. In the group of PAD patients (n=1230), 134 patients died; in the group without PAD (n=5591), 237 patients died [multivariate hazard ratio (HR) 2.0; 95% confidence interval 1.6-2.5, P<0.001]. Compared with an ABI>or=1.1, the risk of death increased linearly in the lower ABI categories: ABI 0.7-0.89, HR 1.7 (1.2-2.4, P<0.001); ABI<0.5, HR 3.6 (2.4-5.4, P<0.001). CONCLUSION: Patients with a low ABI (PAD), who can be readily identified in a primary care setting, have a substantially increased risk of death and severe vascular events. Patients with an ABI between 1.1 and 0.9 should be considered and followed up as borderline PAD cases. Particular attention should be paid to patients with PAD and previous vascular events, as their risk is markedly increased.