Dominik Lautsch

Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology

AIMS Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industrys 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. METHODS AND RESULTS 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. CONCLUSIONS 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.

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health‐related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two‐day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run‐in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.

Persistent dyslipidemia in Austrian patients treated with statins for primary and secondary prevention of atherosclerotic events - Results of the DYSlipidemia International Study (DYSIS).

ZusammenfassungHINTERGRUND: Statine reduzieren das Auftreten kardiovaskulärer Ereignisse etwa um ein Drittel. Das bedeutet, dass auch unter bestehender Behandlung mit Statinen zwei von drei Ereignissen nicht verhindert werden können. Ein Grund könnte sein, dass die Lipid Zielwerte nicht erreicht werden. In der DYSlipidemia International Study (DYSIS) wurde die Prävalenz von Dyslipidämie trotz Statinbehandlung in Österreich erhoben. PATIENTEN UND METHODEN: Zwischen April 2008 und Februar 2009 wurden 910 statinbehandelte, über 45-jährige Patienten von Allgemeinmedizinern, Kardiologen, Endokrinologen und Internisten rekrutiert. Im Rahmen einer klinischen Untersuchung wurden Lipidwerte unter bestehender Statintherapie erhoben. Die Erreichung der Zielwerte für LDL Cholesterin, bzw. normaler Werte für HDL Cholesterin und Triglyceride wurde anhand der ESC Guidelines 2007 beurteilt. Von 765 Patienten liegt das vollständige Lipidprofil inklusive Nüchern-Cholesterin, -Triglyceride, -HDL-Cholesterin und –LDL-Cholesterin vor. ERGEBNISSE: 74,5 % der Patienten erreichten – definiert nach den ESC Guidelines 2007 - zumindest einen Ziel- bzw. Normwert nicht. 52,3 % erreichten das LDL-Cholesterin-Ziel nicht (nach dem Österreichischen Lipidkonsensus 2010 56,4 %), 59,1 % hatten Gesamtcholesterinwerte über Zielwert und 42,5 % wiesen erhöhte Triglyceridwerte auf. 23 % der Patienten hatten HDL Cholesterin Level, die unterhalb jener Schwelle waren, die mit erhöhtem kardiovaskulären Risiko verbunden ist. Bei jenen Patienten, die nur einen Wert ausserhalb der Norm- bzw. Zielwerte hatten, lag die Prävalenz für LDL Cholesterin bei 24,3 %, für HDL bei 11,9 % und für Triglyceride bei 24,5 %. Bei 8,4 % der Patienten waren alle drei Lipidparameter nicht im erwünschten Bereich. SCHLUSSFOLGERUNG: Etwa drei Viertel der über einen längeren Zeitraum statinbehandelten Patienten in Österreich erreichen die international definierten Lipidzielwerte nicht. Es besteht daher der dringende Bedarf, effektivere Strategien zur besseren Kontrolle der Dyslipidämie bei statinbehandelten Patienten anzuwenden, um kardiovaskuläre Ereignisse weiter zu reduzieren.SummaryBACKGROUND: Statins reduce cardiovascular events by about one third; thus two out of three events occurring without any lipid lowering treatment still might happen under statin treatment. One reason may be that lipid targets are not met. The DYSlipidemia International Study (DYSIS) was performed to determine the prevalence of persistent dyslipidemia despite statin treatment in Austria. PATIENTS AND METHODS: Between April 2008 and February 2009, 910 outpatients on current statin treatment and aged ≥ 45 years were recruited by general practitioners, cardiologists, endocrinologists, and internists. A clinical examination was performed and lipid values were obtained under stable statin therapy. The ESC guidelines version 2007 served as criteria to judge the attainment of treatment targets for LDL cholesterol and to reach normal HDL cholesterol and triglyceride levels. In 765 patients a full lipid profile including fasting cholesterol, fasting triglycerides, HDL-cholesterol, and LDL-cholesterol could be obtained. RESULTS: Of our patients, 74.5% had at least one lipid parameter not at target. Specifically, 52.3% did not reach the LDL-cholesterol target as according to the ESC guidelines 2007 - and 56.4% as according to the Austrian lipid consensus 2010 -, 59.1% had above-target total cholesterol levels and 42.5% had elevated triglyceride levels. In 23% of the patients the HDL cholesterol was below levels associated with increased cardiovascular risk. In patients with only one single value beyond normal or targeted level, LDL cholesterol had a prevalence of 24.3%, HDL of 11.9% and triglycerides of 24.5%. In 8.4% of patients, all 3 parameters, LDL-cholesterol, HDL-cholesterol and triglycerides, were out of range. CONCLUSIONS: About three quarters of the Austrian patients under chronic statin therapy in routine clinical practice failed to meet lipid values as set by international and Austrian guidelines. There is an urgent need for more effective strategies to better control dyslipidemia in statin treated patients with the aim of further reducing cardiovascular events.

Can LDL-cholesterol targets be achieved in a population at high risk? Results of the non-interventional study ACT II

Abstract: Objective: Lowering low-density lipoprotein cholesterol (LDL-C) levels can reduce vascular clinical endpoints in outcome studies. Despite this evidence, previous cross-sectional analyses reported a mean LDL-C target attainment of <50%. This non-interventional, longitudinal study aimed to asses the rate of target attainment by intensified LDL-C lowering therapy in a high-risk population under routine medical care. Design: This was an open-label, non-interventional, observational, non-comparative longitudinal study. Methods: A total of 1682 outpatients at high cardiovascular risk, not at LDL-C target despite statin therapy, were documented. Treating physicians administered an intensified therapy at their discretion. In all, 794 patients completed all the examinations at baseline after 3 and 12 months. The achieved LDL-C reductions was evaluated based on expert consensus reflecting the 2007 guidelines issued by the European Society of Cardiology (ESC) on cardiovascular disease prevention. Registration: www.clinicaltrials.gov, identification number NCT 01381679 Results: In the study, 40.3% achieved the individual LDL-C target of <1.8 mmol/L (70 mg/dl) or <2.5 mmol/L (100 mg/dl); 73% received a simvastatin/ezetimibe fixed-dose combination; 3% received add-on ezetimibe and 23% statin therapy at maintained or increased doses; 1% received no drug treatment at all. LDL-C declined after 12 months by −31.0% (ratio 0.69, 95% CI 0.67–0.71, p < 0.001), triglycerides by −11.8% (ratio 0.88, 95% CI 0.85–0.91, p < 0.01) and high-density lipoprotein cholesterol (HDL-C) increased by 11.9% (ratio 1.12, 95% CI 1.10–1.14, p < 0.01). Conclusion: Intensified therapy was effective, but target attainment was still low at 40.3% or 13.9% with regard to the new 2011 guidelines issued by the European Atherosclerosis Society (EAS) and the ESC on dyslipidemias. Enhanced screening of LDL-C levels and the use of statins at highest tolerated dose and concomitant combination therapy is recommended in order to achieve LDL-C targets outlined by current guidelines. Limitations include the design as a non-interventional study. However, this study reflects real life conditions.

Suboptimal achievement of low-density lipoprotein cholesterol targets in French patients with coronary heart disease. Contemporary data from the DYSIS II ACS/CHD study

BACKGROUND European guidelines recommend a low-density lipoprotein cholesterol (LDL-C) target of<1.8mmol/L (70mg/dL), and/or a≥50% reduction when the target level cannot be reached, for patients at very high cardiovascular risk, and high-potency lipid-lowering therapy (LLT) in patients with an acute coronary syndrome (ACS). AIM To document the prevalence of lipid abnormalities and the achievement of lipid targets among patients surviving an ACS and in patients with stable coronary heart disease (CHD), using data from the DYSIS II study. METHODS DYSIS II was an observational cross-sectional study conducted in 21 countries (2012-2014). We report data from the French cohort, comprising patients hospitalized with an ACS and patients diagnosed with stable CHD. Data on patient characteristics, risk factors, treatments and lipid profile were collected. LDL-C target achievement was assessed based on the European guidelines endorsed by the French Society of Cardiology. RESULTS Of the 468 ACS patients, 277 (59.2%) were receiving LLT at admission to hospital; 22.6% were hospitalized for a recurrent event. Statins were used in 96.6% (450/466) of patients at discharge and in 95.1% (310/326) at 120-day follow-up, at which time 50.6% (80/158) of patients with available data achieved the LDL-C goal. Most of the 436 patients with stable CHD (97.2%) were on LLT (56.8% on high-intensity therapy); 29.2% of patients on LLT met the LDL-C treatment target<1.8mmol/L (70mg/dL). CONCLUSION These observational data show the progress made in the treatment of ACS from the acute phase up to 3 months, and highlight key areas for improvement in the prevention of recurrent events in patients with CHD in France. The use of higher intensity or combination LLT as recommended in secondary prevention are needed to increase the achievement of LDL-C treatment targets and reduce the risk of morbidity and mortality due to CHD.

How does the TRS 2°P score relate to real-world patients?

TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; Department of Molecular Medicine University of Pavia, and Cardiac Intensive Care Unit and Laboratories for Experimental Cardiology, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; Oslo University Hospital, Department of Cardiology B, and Institute of Clinical Sciences, University of Oslo, Norway; Merck&Co., Inc., Kenilworth, NJ, USA; Stiftung Institut für Herzinfarktforschung Ludwigshafen, Ludwigshafen, Germany; Department of Cardiology, Toulouse Rangueil Hospital, Toulouse University School of Medicine, Toulouse, France; and Medizinische Klinik B, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany

PERSISTENT HIGH DISTANCE TO RECOMMENDED LDL-CHOLESTEROL-TARGETS DESPITE CHRONIC STATIN TREATMENT: RESULTS OF DYSIS

International asscociations such as EAS/ESC recommend LDL-C <70 mg/dl in very high risk patients. Despite chronic statin treatment, only a minority of patients achieve this target. We examined the median distance to this treatment target. Between 2008 and 2012, consecutive statin-treated

LOW LDL-CHOLESTEROL TARGET ACHIEVEMENT IN STATIN-TREATED PATIENTS IN CLINICAL PRACTICE IN CHINA AND EUROPE: RESULTS OF THE DYSLIPIDEMIA INTERNATIONAL STUDY (DYSIS)

Statin treatment is well established for patients with dyslipidemia and high risk for cardiovascular events. Little is known about differences in patient profile and LDL target achievement between Europe and China. The cross sectional, observational study DYSIS examined lipid goal attainment among

STILL HIGH PREVALENCE OF PERSISTENT LIPID ABNORMALITIES AMONG CORONARY PATIENTS DESPITE CHRONIC STATIN THERAPY IN 2014: RESULTS OF DYSIS II ACS AND CHD

Prior studies have documented a gap between guideline recommendations and LDL-C target achievement in clinical practice. We identified real world lipid target achievements among stable CHD patients and patients surviving an ACS event. DYSIS II is a multi-country observational study conducted in

Prevalence of lipid abnormalities and cholesterol target value attainment in Egyptian patients presenting with an acute coronary syndrome

Background Effective management of hyperlipidemia is of utmost importance for prevention of recurring cardiovascular events after an acute coronary syndrome (ACS). Indeed, guidelines recommend a low-density lipoprotein cholesterol (LDL-C) level of <70 mg/dL for such patients. The Dyslipidemia International Study II (DYSIS II) – Egypt was initiated in order to quantify the prevalence and extent of hyperlipidemia in patients presenting with an ACS in Egypt. Methods In this prospective, observational study, we documented patients presenting with an ACS at either of two participating centers in Egypt between November 2013 and September 2014. Individuals were included if they were over 18 years of age, had a full lipid profile available (recorded within 24 h of admission), and had either been taking lipid-lowering therapy (LLT) for ≥3 months at time of enrollment or had not taken LLT. Data regarding lipid levels and LLT were recorded on admission to hospital and at follow-up 4 months later. Results Of the 199 patients hospitalized for an ACS that were enrolled, 147 were on LLT at admission. Mean LDL-C at admission was 127.1 mg/dL, and was not significantly different between users and non-users of LLT. Only 4.0% of patients had an LDL-C level of <70 mg/dL, with the median distance to this target being 61.0 mg/dL. For the patients with LDL-C information available at both admission and follow-up, LDL-C target attainment rose from 2.8% to 5.6%. Most of the LLT-treated patients received statin monotherapy (98.6% at admission and 97.3% at follow-up), with the mean daily statin dose (normalized to atorvastatin) increasing from admission (30 mg/day) to follow-up (42 mg/day). Conclusions DYSIS II revealed alarming LDL-C goal attainment, with none of the patients with follow-up information available reaching the target of LDL-C <70 mg/dL, either at hospital admission or 4 months after their ACS event. Improvements in guideline adherence are urgently needed for reducing the burden of cardiovascular disease in Egypt. Strategies include the effective use of statins at high doses, or combination with other agents recommended by guidelines.