Diagnosis rates of familial hypercholesterolemia (FH) remain low. We implemented FH ALERT to assess whether alerting physicians for the possibility of FH impacted additional diagnostic activity. The ...study was conducted from SYNLAB laboratory Weiden (Bavaria). Beyond common reporting of LDL-C or TC, 1411 physicians covering approximately a population of 1.5 million people were eligible to receive an alert letter (AL) including information on FH, if laboratory results exceeded thresholds as follows: adults LDL-C ≥ 190-250 mg/dl (to convert into mmol/l multiply with 0.0259), TC ≥ 250 to ≤ 310 mg/dl (probable suspicion); LDL-C > 250 mg/dl and TC > 310 mg/dl (strong suspicion). Persons below 18 years were alerted for LDL-C 140 mg/dl and TC ≥ 200 mg/dl (strong suspicion). Patients above 60 years were excluded. Our readouts were characteristics of involved physicians, rate of ALs issued, acceptance, and subsequent diagnostic activity. Physicians were mainly general practitioners in ambulatory care. 75% of the ordered tests were for TC, 25% for LDL-C. We issued 3512 ALs (~ 5% of tests) triggered by 2846 patients. 86% of eligible physicians stayed with the initiative, 32.7% were alerted, and 70% were positive upon call-center survey. We registered 101 new visitors of www.fhscore.eu and sent out 93 kits for genetics. Thereof, 26 were returned and 5 patients were positive for FH. Physicians were in general open to our approach. Although genetic testing was taken up with caution, this 3-months pilot examination resulted in a greater rate of patients with FH diagnosed than previous screening projects. Further education on FH in primary care is required to improve FH detection in the community.
Cardiovascular mortality is high in Germany. For patients with high or very high cardiovascular risk, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines ...recommend intensive lipid lowering therapy (LLT). This study aimed to assess dyslipidaemia management and achievement of the ESC/EAS guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals.
This European 18-country, cross-sectional, observational DA VINCI study (EUPAS22075) collected data during a single visit between June 2017 and November 2018 and included LLT in the preceding 12 months and the patients' most recent LDL-C measurement. Achievement of the risk-based 2016 and 2019 ESC/EAS LDL-C goals while receiving stabilized LLT was assessed. Data from the German cohort are presented here.
Seven German sites enrolled a total of 421 primary and secondary prevention patients, 327 were receiving stabilized LLT at the time of LDL-C measurement, i.e. statin monotherapy of high (16%; n = 53), moderate (49%; n = 160) or low (7%; n = 24) intensity, ezetimibe combination (18%; n = 58), proprotein convertase subtilisin/kexin type 9 antibody combination (3%; n = 9), and other LLT (7%; n = 23). The 2016 and 2019 risk-based LDL-C goals were attained by 46% (n = 149) and 28% (n = 92) of patients, respectively.
There is a large gap between ESC/EAS recommendations and LDL-C goal achievement in routine clinical practice in high and very high-risk patients in Germany. Low-to-moderate-intensity statin monotherapy was the most frequently used LLT; use of high-intensity statins and combination therapy was limited. In addition to optimizing statin intensity, combination with non-statin LLT may be needed in most of these patients.
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•This study evaluated lipid-lowering therapy use and dyslipidemia burden in Germany.•Attainment of LDL-C goals set by the 2016 and 2019 EAS/ESC guidelines was evaluated.•In Germany, more than half of patients did not achieve their 2016 LDL-C goals.•Attainment of the more stringent 2019 LDL-C goals was <30%.•Intense combination therapy in Germany could lead to better LDL-C goal attainment.
Introduction
Low-density lipoprotein cholesterol (LDL-C) is among the most important modifiable risk factors for cardiovascular disease. In very high-risk patients, the European Society of ...Cardiology/European Atherosclerosis Society guidelines recommend attaining LDL-C < 55 mg/dL. In the German cohort of the observational HEYMANS study, we aimed to describe the clinical characteristics and LDL-C control among patients initiating evolocumab.
Methods
Data was collected between 09/2016 and 05/2021 for ≤ 6 months before (retrospectively) and ≤ 30 months after evolocumab initiation (prospectively). Patient characteristics, lipid-lowering therapy (LLT), lipid values, evolocumab use, and safety were collected.
Results
Of 380 enrolled patients, 93% received evolocumab in secondary prevention and 69% had a history of statin intolerance. At study baseline, 49% did not receive any statins and LDL-C was very high (145 mg/dL). Use of evolocumab decreased LDL-C by a median of 53% within 3 months and remained stable thereafter, despite mainly unchanged background LLT. Overall, 59% attained an LDL-C level < 55 mg/dL (69% with, 49% without LLT). Persistence to evolocumab was 90.6% in months 1–12 and 93.5% in months 13–30. Adverse drug reactions were reported in 8% of patients.
Conclusion
Data from the German HEYMANS cohort corroborate previous reports on evolocumab effectiveness and safety in clinical practice. Evolocumab initiation was associated with a rapid and sustained LDL-C reduction. Persistence with evolocumab was high. Our finding that patients receiving an evolocumab/LLT combination are more likely to attain the LDL-C goal than those receiving evolocumab alone corroborates previous data showing the importance of using highly intensive therapy. Graphical abstract available for this article.
Trial Registration
ClinicalTrials.gov Identifier NCT02770131 (registration date 27 April 2016).
Graphical Abstract
Aims
Two anti‐proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, alirocumab and evolocumab, have been approved for the treatment of hypercholesterolaemia in certain ...patients. We reviewed data from Phase 3 studies to evaluate the efficacy and safety of these antibodies.
Methods
We systematically reviewed Phase 3 English‐language studies in patients with hypercholesterolaemia, published between 1 January 2005 and 20 October 2015. Congress proceedings from 16 November 2012 to 16 November 2015 were also reviewed.
Results
We identified 12 studies of alirocumab and nine of evolocumab, including over 10 000 patients overall. Most studies enrolled patients with hypercholesterolaemia and used anti‐PCSK9 antibodies with statins. The ODYSSEY FH I, FH II and HIGH FH alirocumab studies and the RUTHERFORD‐2 evolocumab study exclusively recruited patients with heterozygous familial hypercholesterolaemia. Two evolocumab studies focused mainly on homozygous familial hypercholesterolaemia (HoFH): TESLA Part B and TAUSSIG (a TESLA sub‐study); only those data for HoFH are reported here. All comparator studies demonstrated a reduction in LDL cholesterol (LDL‐C) with the anti‐PCSK9 antibodies. No head‐to‐head studies were conducted between alirocumab and evolocumab. Up to 87% of patients receiving alirocumab and up to 98% receiving evolocumab reached LDL‐C goals. Both antibodies were effective and well tolerated across a broad population of patients and in specific subgroups, such as those with type 2 diabetes.
Conclusions
Using anti‐PCSK9 antibodies as add‐on therapy to other lipid‐lowering treatments or as monotherapy for patients unable to tolerate statins may help patients with high cardiovascular risk to achieve their LDL‐C goals.
Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industry's willingness to invest in this field has declined because of the many ...challenges involved with bringing new cardiovascular drugs to market, including late-stage failures, escalating regulatory requirements, bureaucracy of the clinical trial business enterprise, and limited patient access after approval. This contrasts with the remaining burden of cardiovascular disease in Europe and in the world. Thus, clinical cardiovascular research needs to adapt to address the impact of these challenges in order to ensure development of new cardiovascular medicines.
The present paper is the outcome of a two-day workshop held by the Cardiovascular Round Table of the European Society of Cardiology. We propose strategies to improve development of effective new cardiovascular therapies. These can include (i) the use of biomarkers to describe patients who will benefit from new therapies more precisely, achieving better human target validation; (ii) targeted, mechanism-based approaches to drug development for defined populations; (iii) the use of information technology to simplify data collection and follow-up in clinical trials; (iv) streamlining adverse event collection and reducing monitoring; (v) extended patent protection or limited rapid approval of new agents to motivate investment in early phase development; and (vi) collecting data needed for health technology assessment continuously throughout the drug development process (before and after approval) to minimize delays in patient access. Collaboration across industry, academia, regulators, and payers will be necessary to enact change and to unlock the existing potential for cardiovascular clinical drug development.
A coordinated effort involving academia, regulators, industry, and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.
Summary
Objectives
To put data from our recent systematic review of phase 3 studies of anti‐proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies into the context of clinical practice.
...Methods
Data from studies previously identified by a systematic review of phase 3 studies of alirocumab and evolocumab and additional references from non‐systematic literature searches were used. We evaluated the hypothetical cardiovascular (CV) benefit in cases of typical patients in whom anti‐PCSK9 antibodies may be recommended, using preliminary major CV event (CVE) rates from long‐term clinical trials of anti‐PCSK9 antibodies and from extrapolations derived from correlation between low‐density lipoprotein cholesterol (LDL‐C) reduction and CV benefit with other lipid‐lowering therapies (LLTs).
Results
Rapid (within 1‐2 weeks) and persistent (8‐74 weeks) reductions in LDL‐C levels were achieved with anti‐PCSK9 antibodies. When combined with statins (± ezetimibe), high rates of LDL‐C goal achievement were observed (41%‐87% with alirocumab and 63%‐100% with evolocumab). In long‐term alirocumab and evolocumab studies, reductions in major CVEs of 48% and 53%, respectively, were observed. For every 38.7 mg/dL (1 mmol/L) reduction in LDL‐C, a 22% reduction in relative CVE risk is predicted. Applying these assumptions to typical patients who have high–very high risk (15%‐60% absolute 10‐year CVE risk) and elevated LDL‐C despite maximally tolerated statins, the 10‐year number needed to treat with an anti‐PCSK9 antibody to prevent one additional CVE varies from 4 to 26, depending on baseline LDL‐C levels and residual absolute CVE risk.
Conclusions
Anti‐PCSK9 antibodies effectively lower LDL‐C levels in a broad patient population. While awaiting comprehensive data from CV outcome trials, these agents should be considered in very high risk patients, such as those in secondary prevention and those with familial hypercholesterolaemia who are already receiving maximally tolerated LLTs, have not achieved their LDL‐C goal and require substantial reductions in LDL‐C.
Temozolomide (TMZ) is an oral imidazotetrazinone that is spontaneously converted to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at physiological pH. MTIC methylates DNA at the O6 position ...of guanine, although this lesion may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (AGAT). In this study, TMZ was combined with cisplatin (CDDP), because both agents have single-agent activity against melanoma and other tumor types. Additionally, CDDP has been shown to inactivate AGAT, and subtherapeutic concentrations of CDDP have been shown to increase the sensitivity of leukemic blasts to TMZ. This Phase I study sought to determine the toxicities, recommended dose, and pharmacological profile of the TMZ/CDDP combination. Patients were treated with oral TMZ daily for 5 consecutive days together with CDDP on day 1 (4 h after TMZ) every 4 weeks at the following TMZ (mg/m2/day)/CDDP (mg/m2) dose levels: 100/75, 150/75, 200/75, and 200/100. Plasma samples were obtained on days 1 and 2 to evaluate the pharmacokinetic parameters of TMZ alone and in combination with CDDP. Fifteen patients received a total of 44 courses of TMZ/CDDP. The principal toxicities of the regimen consisted of neutropenia, thrombocytopenia, nausea, and vomiting, which were intolerable in two of six new patients treated at the 200/100 mg/m2 dose level. Of five patients receiving 17 courses at the next lower dose level (200/75 mg/m2), none experienced dose-limiting toxicity. Antitumor activity was observed in patients with non-small cell lung cancer, squamous cell carcinoma of the tongue, and leiomyosarcoma of the uterus. Pharmacokinetic studies of TMZ revealed the following pertinent parameters (mean +/- SD): time to maximum plasma concentration (Tmax) = 1.1+/-0.6 h (day 1) and 1.7+/-0.9 h (day 2); elimination half-life (t1/2) = 1.74+/-0.22 h (day 1) and 2.35+/-0.70 h (day 2); and clearance (Cl(s)/F) = 115+/-27 ml/min/m2 (day 1) and 141+/-109 ml/min/m2 (day 2). TMZ drug exposure, described by the area under the plasma concentration-time curve (AUCinfinity) and the maximum plasma concentration (Cmax), was similar on days 1 and 2. On the basis of these results, the recommended doses for Phase II clinical trials are TMZ 200 mg/m2/day for 5 days with 75 mg/m2 CDDP on day 1, every 4 weeks. The addition of CDDP did not affect the tolerable dose of single-agent TMZ (200 mg/m2/day x 5 days), nor did it substantially alter the pharmacokinetic behavior of TMZ.
Aim
The PERI-DYS study aims to characterize two groups of patients with dyslipidaemia at very high CV risk: PCSK9i receivers and patients qualifying for but not receiving PCSK9i.
Methods
This is an ...observational study by office-based and clinic-based physicians, mainly cardiologists and other internists in Germany, with data extracted from patient charts. ClinicalTrials.gov identifier NCT03110432.
Results
A total of 1659 patients were enrolled across 70 sites. The majority of patients (91.0%) were reported as having mixed dyslipidaemia or non-familial or heterozygous familial hypercholesterolemia. At enrolment, 794 (47.9%) of patients were PCSK9i receivers (of these 65.9% ongoing, and 34.1% newly treated within 30 days before their baseline visit). Among PCSK9i receivers, the majority had evolocumab 140 mg (
n
= 632, 38.1% of total). PCSK9i receivers compared to non-receivers were about 2 years younger and had a lower proportion of males. In terms of comorbidities, they had (statistically significantly) more often CAD, and less often PAD, diabetes mellitus, arterial hypertension and chronic renal disease. The calculated untreated median LDL-C was 187 mg/dl (IQR 127; 270) in ongoing PCSK9i receivers, 212 mg/dl (IQR 132; 277) in newly treated PCSK9i receivers, and 179 mg/dl (IQR 129; 257) in non-receivers. Physician-reported statin intolerance was much more common in the two PCSK9i receiver groups as compared to non-receivers (67.3% versus 15.3%). Consequently, patients in the PCSK9i groups received fewer concomitant statins. Mean total cholesterol (143 vs. 172 mg/dl) and LDL-C (69 vs. 99 mg/dl) were considerably lower in ongoing PCSK9i receivers compared to non-receivers.
Conclusions
PCSK9i receivers are characterized by higher baseline LDL-C and a higher portion of statin intolerance compared to those qualified for but not-receiving PCSK9i treatment. On-treatment, LDL-C was lower in PCSK9i receivers. Ongoing follow-up will determine the prognostic importance of these findings.
The physical-functional and social-emotional health as well as survival of the elderly (≥75 years of age) haemodialysis patient is commonly thought to be poor. In a prospective, multicentre, ...non-interventional, observational study, the morbidity, mortality and quality of life (QoL) in this patient group were examined and compared with a younger cohort.
In 92 German dialysis centres, 2507 prevalent patients 19-98 years of age on haemodialysis for a median of 19.2 months were included in a drug monitoring study of darbepoetin alfa. To examine outcome and QoL parameters, 24 months of follow-up data in the age cohorts <75 and ≥75 years were analysed. Treatment parameters, adverse and intercurrent events, hospitalizations, morbidity and mortality were assessed. QoL was evaluated by means of the 47-item Functional Assessment of Chronic Illness Therapy-Anaemia score (FACT-An, version 4).
The 2-year mortality rate was 34.7% for the older cohort and 15.8% for the younger cohort. The mortality rate for the haemodialysed elderly patients was 6.2% higher in absolute value compared with the age-matched background population. A powerful predictor of survival was the baseline FACT-An score and a close correlation with the 20-item anaemia subscale (AnS) was demonstrated. While the social QoL in the elderly patients was more stable than in the younger cohort (leading to equivalent values at the end of the study period), a pronounced deterioration of physical and functional status was observed. The median number of all-cause hospital days per patient-year was 12.3 for the elderly cohort and 8.9 for the younger patient population. The overall 24-month hospitalization rate was only marginally higher in the elderly cohort (34.0 versus 33.3%).
In this observational study, the mortality rate of elderly haemodialysis patients was not exceedingly high compared with the age-matched background population. Furthermore, the hospitalization rate was only slightly higher compared with the younger age group and the median yearly hospitalization time trended lower compared with registry data. The social well-being of elderly haemodialysis patients showed a less pronounced decline over time and was equal to the score of the younger cohort at the end of the study period. The physical and functional status in the elderly patients was lower and showed a sharper decline over time. The baseline FACT-An score correlated closely with the 24-month survival probability.
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