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Thursday, May 9th 2019

08.10 – 08.15

Welcome

08.10 – 08.15
Opening of the Meeting

Paolo Ferrari, Chief Medical Officer, Ente Ospedaliero Cantonale

08.15 – 09.35

World Epidemics – Joint Session with ESC Working Group on Cardiovascular Pharmacotherapy

Chairpersons: Thomas Kahan (Stockholm, SE), Antoni Martinez-Rubio (Barcelona, ES), Hector Ventura (Miami, US), Luca Gabutti (Bellinzona, CH), Jean-Luc Eiselé (Geneva, CH)

08.15 – 08.30
Dyslipidemia – new challenges and how to achieve targets

Heinz Drexel (Feldkirch, AT)

Description

Dyslipidemia – new challenges and how to achieve targets

Heinz Drexel (Feldkirch, AT)


We live in a very active era, characterised by new approaches to attack dyslipidemia. In the last years we had a disappointment from interventions aimed to increase HDL-cholesterol. This diverted the strategies from HDL- raising back to LDL-lowering. Despite the success of statins and ezetimibe we had to admit a residual risk. Therefore, encouraged by data from mendelian randomisation studies, we now see new attempts to further lower LDL-cholesterol.

The inhibition of PCSK9 by antibodies has shown us that we can go to very low LDL-C with a very good short-term safety and with benefits on cardiovascular endpoints. Examples are FOURIER and ODYSSEY OUTCOMES. This encouraged alternative ways of interfering with LDL. The next one will be the use of small interfering RNA, the first target again is PCSK9. A further example is bempedoic acid where we have the first data now that this molecule lowers LDL-cholesterol by interfering with the endogeneous cholesterol synthesis and has a good safety profile. Bempedoic acid acts at a higher level than statins in the biochemical pathway of cholesterol synthesis.
In synopsis, the successful interventions include these four steps: (1) reduction of endogeneous cholesterol synthesis, (2) lower intracellular cholesterol induces the expression of LDL-receptors, (3) the increased number of LDL receptors on the cell surface allows for increased elimination of LDL particles from the circulation. (4) The end result is a reduced LDL-cholesterol level in the blood. It has been shown that all interventions involving increased LDL receptor expression reduce cardiovascular events.

A new field is an old field, namely triglycerides. We have now new data on omega-3-fatty acids that show in the REDUCE-IT trial benefit for patients if added to statins.
The field of lipidology has a new hype. We have many promising new approaches, mainly to lowering of LDL-cholesterol and triglycerides.

Reference: Schwartz GG et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379: 2097-2107.

08.30 – 08.45
Hypertension management in year 2019. Pending Issues

Gianfranco Parati (Milan, IT)

08.45 – 09.00
The management of patients with diabetes and heart failure: the start of a new era?

Felipe Martinez (Cordoba, AR)

09.00 – 09.15
Obesity after smoking cessation – rationale of a complex interplay

Koji Hasegawa (Kyoto, JP)

Description

Obesity after smoking cessation – rationale of a complex interplay

Koji Hasegawa (Kyoto, JP)


Background
Smoking cessation is one of the most effective ways to reduce cardiovascular disease (CVD) risk. It is astonishing that 7-28% of patients who have survived a coronary heart disease still smoke (1). As one of nicotine withdrawal syndromes, body weight gain and abdominal obesity generally occur after quitting smoking. Obesity results in an increase in various inflammatory markers. Pharmacological treatment by medications such as nicotine patches and varenicline is useful to suppress weight gain during smoking cessation. Weight gain after smoking cessation temporally increases risks of diabetes and reduce the benefit by smoking abstinence. Does weight gain after quitting smoking help exacerbate CVD?

Explanation and Comment
The α1-antitrypsin–low-density lipoprotein (AT-LDL) complex, a complex of α1-antitrypsin (AT)-oxidised LDL, is an important cardiovascular biomarker. AT-LDL levels have been shown to significantly decrease 3 months after quitting smoking. One year after quitting smoking, the serum AT-LDL levels decreased to a greater extent than the levels 3 months after quitting smoking, regardless of whether obesity increased (2). Thus, long-standing non-smoke will overcome the demerit of weight gain. A large-scale follow-up study conducted over 30 years examined weight gain after quitting smoking and the subsequent disease risk (3). This study demonstrates that, after an individual quits smoking, his or her risk of death due to CVD and any other cause significantly decreases regardless of weight gain, even if he or she gains ≥10 kg. However, individuals who do not gain weight display greater reduction in the risk of developing CVD than those who gain weight. A randomised controlled trial examined the timing of instruction in weight management when implementing a smoking cessation intervention (4). According to that trial, the rate of successfully quitting smoking decreased when instructions regarding quitting smoking and managing weight were simultaneously provided from the beginning of the intervention.

Conclusion
Supporting patients to continue smoking cessation is most crucial. Additional management of their weight is clearly beneficial, but should be performed after smoking cessation has been completed.

References

  1. Reiner Z. The importance of smoking cessation in patients with coronary heart disease. Int J Cardiol 2018; 258:26-27.
  2. Komiyama M, Shimada S, Wada H, et al. Time-dependent Changes of Atherosclerotic LDL Complexes after Smoking Cessation. J Atheroscler Thromb 2016;23:1270-1275.
  3. Hu Y, Zong G, Liu G, Wang M, Rosner B, Pan A, Willett WC, Manson JE, Hu FB, Sun Q. Smoking Cessation, Weight Change, Type 2 Diabetes, and Mortality. N Engl J Med. 2018 379:623-632
  4. Bush T, Lovejoy J, Javitz H, Torres AJ, Wassum K, Tan MM, Spring B. Simultaneous vs. sequential treatment for smoking and weight management in tobacco quitlines: 6 and 12 month outcomes from a randomized trial. BMC Public Health. 2018 May 31;18:678-690.
09.15 – 09.35
Discussion

09.35 – 10.35

A Changing Paradigm in Management of Dyslipidemia

Chairpersons: Koji Hasegawa (Kyoto, JP), Alexandre Fredenrich (Bellinzona, CH / Nice, FR ), Heinz Drexel (Feldkirch, AT)

09.35 – 09.50
The discovery of PCSK9

Catherine Boileau (Paris, FR)

09.50 – 10.05
Opportunities and barriers for the successful clinical utilisation of PCSK9

Michel Farnier (Dijon, FR)

Description

Opportunities and barriers for the successful clinical utilisation of PCSK9

Michel Farnier (Dijon, FR)


Although lowering LDL-cholesterol (LDL-C) by statin or statin plus ezetimibe combination therapy reduced the risk of atherosclerotic cardiovascular disease (ASCVD), there remains a high degree of residual risk in treated patients. Moreover, many patients on treatment have unsatisfactory LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) plays an important role in the regulation of LDL metabolism and PCSK9 inhibition has emerged as a significant therapeutic target for further lowering of LDL-C : PCSK9 inhibitory monoclonal antibodies (alirocumab or evolocumab) produced reductions in LDL-C by up to 60% with an excellent safety profile.
The potent of LDL-C lowering efficacy of PCSK9 inhibitors provides the opportunity for more aggressive LDL lowering strategies in patients with ASCVD, and two randomized clinical trials have demonstrated that both alirocumab and evolocumab reduce ASCVD events when used in combination to statin therapy for patients in secondary prevention with LDL-C > 70 mg/dL (1,2). Additional groups who stand to benefit from use of PCSK9 inhibitors are patients with familial hypercholesterolemia and high-risk patients unable to tolerate statins (3).
The major barrier with these agents in clinical practice involves their cost. Given cost-considerations and resource issues, heath care providers and payers will need to consider prioritizing those patient subgroups who may benefit the most from the use of these PCSK9 inhibitors. In addition to the setting of familial hypercholesterolemia where a strong economic argument can be made for their use, a number of subgroup analyses of randomized controlled trials have identified patient cohorts with higher event rates and greater absolute risk reduction in which PCSK9 inhibitor may be more cost-effective.
In summary, PCSK9 inhibition is a very effective strategy for lowering LDL-C and has a potential to achieve greater reductions in cardiovascular risk. The challenge is how to identify the most cost-effective strategy for their clinical use.

  1. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. for the FOURIER steering committee and investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. New Engl J Med 2017 376: 1713-22.
  2. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379: 2097-107.
  3. Landmesser U, Chapman MJ, Stock JK, Amarenco P, Belch JJF, Borén J, et al. 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J 2018; 39: 1131-43.
10.05 – 10.20
PCSK9 – Effects beyond LDL lowering

Alberico L. Catapano (Milan, IT)

10.20 – 10.35
Discussion

10.35 – 11.05

Coffee Break

11.05 – 12.05

Anti-Inflammatory Treatment in Coronary Artery Disease

Chairpersons: Filippo Crea (Rome, IT), Giuseppe Vassalli (Lugano, CH), Alberto Lorenzatti (Cordoba, AR), Konstantinos Koskinas (Bern, CH)

11.05 – 11.20
The rationale for anti-inflammatory treatment

Peter Libby (Boston, US)

11.20 – 11.35
The clinical evidence: targeting interleukin-1β: the CANTOS trial

Luigi M. Biasucci (Rome, IT)

11.35 – 11.50
A word of caution

Juan Carlos Kaski (London, GB)

Description

A word of caution

Juan Carlos Kaski (London, GB)


Atheronenesis is an inflammatory process in its own right. Rapid coronary artery disease progression and plaque disruption are associated with vascular and systemic inflammation. Moreover, inflammation has been also shown to be a key mechanism underlying coronary microvascular dysfunction leading to microvascular angina. Patients suffering from chronic inflammatory conditions, particularly those triggered by autoimmune mechanisms, are at a higher risk of coronary artery disease and cardiovascular events. C-reactive protein has been postulated to be a marker of both inflammation and coronary artery disease and disease progression. Although anti-inflammatory interventions should in theory improve cardiovascular outcomes, drugs such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAID) have been shown to be potentially harmful in the context of the acute coronary syndrome. Colchicine, on the contrary, has been effective in patients with stable coronary artery disease, albeit in studies involving small numbers of patients. The Low-Dose Colchicine (LoDoCo) study (1), which tested this anti-inflammatory agent for the secondary prevention of cardiovascular events in 532 patients, resulted in significant beneficial cardiovascular effects, but with a high rate of gastrointestinal side effects. Colchicine is currently being assessed in a large study of patients with stable coronary artery disease (NCT02551094).

A monoclonal antibody (canakinumab) targeting interleukin-1β resulted in significant beneficial effects, as shown by the CANTOS study (2). Patients included in CANTOS were high-risk secondary prevention patients, who despite being on high-intensity statin therapy, continued to have elevated CRP levels. Of interest, cancer mortality -particularly lung cancer - was significantly lower in patients treated with canakinumab v. placebo. Importantly, however, there was a significantly increased risk of death with canakinumab caused by infection or sepsis, compared with events in the placebo arm (0.31 vs 0.18 events per 100 patient years; P = 0.02). Neutropenia and thrombocytopenia were more common in patients treated with canakinumab.

The Cardiovascular Inflammation Reduction Trial (CIRT), recently published in the New England Journal of Medicine (3), showed that methotrexate had no beneficial effects on cardiovascular outcomes or on interleukin-1β, interleukin-6, or C-reactive protein (CRP) levels in patients with ischaemic heart disease. In CIRT, patients with previous MI or multivessel coronary artery disease in addition to type 2 diabetes or metabolic syndrome were randomised to receive low-dose methotrexate (15-20 mg) or matching placebo. The trial was stopped by the Data and Safety Monitoring Board for futility after a median of 2.3 years. From an objective perspective, despite the overwhelming data supporting the role of inflammation in atherogenesis, treatment strategies have so far been rather disappointing with the exception of canakinumab in CANTOS -a proof of concept study- which showed a small benefit on clinical outcomes and a significant increase in risk of death mainly associated with sepsis. Methotrexate treatment, in CIRT, was “neutral” regarding cardiac events but there were significantly more adverse events with methotrexate, compared with placebo and a higher incidence of non-basal-cell skin cancers. Colchicine is currently being tested in a large study.

From an optimistic perspective, the inflammation hypothesis remains viable, particularly the interleukin-1β to interleukin-6 pathway, as supported by vascular biology research and the CANTOS results. The cost of potentially effective treatments i.e. monoclonal antibodies, however, is extremely high and this will limit their use in clinical practice. Although at present there is little data that support therapeutic strategies for IHD based on anti-inflammatory agents, scientists, clinicians and trialists should be encouraged to continue the search for suitable pharmacological therapies able to effectively tackle pro-inflammatory mechanisms to reduce cardiovascular events. Caution, however, is necessary when interpreting available treatment data and when designing future studies in order that truly meaningful data can be gathered, with true translational impact.

  1. Nidorf SM, Eikelboom JW, Budgeon CA et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404–10
  2. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab of atherosclerotic disease. N Engl J Med 2017; 377:1119-1131
  3. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019; 380:752-762
11.50 – 12.05
Discussion

12.05 – 12.30

KEY LECTURE – CARDIOVASCULAR PHARMACOTHERAPY IN THE ELDERLY
LECTURE SPONSORED BY Daiichi Sankyo

Chairpersons: Juan Carlos Kaski (London, GB), Edgardo Escobar (Santiago, CL), Maurizio Volterrani (Rome, IT), Alessandro Ceschi (Lugano, CH)

12.05 – 12.20
Polypharmacy: what the clinical cardiologist should be aware of

Stephan Krähenbühl (Basel, CH)

12.20 – 12.30
Discussion

12.30 – 13.30

Lunch

12.30 – 13.30

PCSK9 INHIBITORS: HOW TO BRIDGE FROM HIGH CLINICAL VALUE TO ACCESS FOR PATIENTS?
Satellite Working Lunch Session - organized by AMGEN

Chairpersons: Augusto Gallino (Bellinzona, CH), Stefan Windecker (Bern, CH), Walter Riesen (Diessenhofen, CH)

12.30 – 12.35
Welcome and Introduction

Augusto Gallino (Bellinzona, CH), Stefan Windecker (Bern, CH)

12.35 – 12.50
PCSK9 Inhibitors: Discrepancies between science and reimbursement in secondary prevention

Christian Mueller (Basel, CH)

12.50 – 13.05
Optimizing cardiovascular outcomes with PCSK9 Inhibitors: start now before a potential next MI or stroke

François Mach (Geneva, CH)

13.05 – 13.15
Patients to consider for PCSK9 Inhibitor treatment

Isabella Sudano (Zurich, CH), Konstantinos Koskinas (Bern, CH)

13.15 – 13.30
Panel Discussion and Closing Remarks

13.30 – 14.20

Medical vs Invasive Treatment Strategies in Stable Coronary Artery Disease: Debate Session

Chairpersons: Juan Carlos Kaski (London, GB), Olivier Muller (Lausanne, CH), Koji Hasegawa (Kyoto, JP)

13.30 – 13.45
Are percutaneous coronary interventions needed in patients with stable angina?

Filippo Crea (Rome, IT)

13.45 – 14.00
Missed opportunities for successful myocardial revascularisation in stable coronary artery disease

Stefan Windecker (Bern, CH)

14.00 – 14.05
Rebuttal Filippo Crea (Rome, IT)

14.05 – 14.10
Rebuttal Stefan Windecker (Bern, CH)

14.10 – 14.20
Discussion

14.20 – 15.20

Emerging Indications for New Oral Anticoagulation in Stable Coronary Artery Disease

Chairpersons: Gheorghe Dan (Bucharest, RO), Antoni Martinez-Rubio (Barcelona, ES), Roberto Corti (Zurich, CH)

14.20 – 14.35
Rivaroxaban; from research to medicine

Elisabeth Perzborn (Wuppertal, DE)

Description

Rivaroxaban; from research to medicine

Elisabeth Perzborn (Wuppertal, DE)


Heparins and VKA have been the mainstay of anticoagulant therapy for more than 60 years. These traditional anticoagulant agents, affecting multiple coagulation factors, are associated with several limitations. These shortcomings have spurred the search for oral small-molecule inhibitors that specifically target directly a single coagulation factor, such as factor Xa (FXa) or thrombin resulting in a dramatic change of the landscape of anticoagulation by NOAKs (non-vitamin K-antagonistic oral anticoagulants). The direct thrombin inhibitor dabigatran (Pradaxa®) and the direct Factor Xa (FXa) inhibitors, rivaroxaban (Xarelto®), apixaban (Eliquis®) and edoxaban (Lixiana®, Savaysa®) are the first alternative to VKA for oral anticoagulation. Rivaroxaban was the first oral FXa inhibitor licensed for VTE prevention and treatment.

This overview summarizes the history of rivaroxaban focusing on the rational of the preclinical FXa program, compound finding and chemical optimization program, show the way how we succeed in the synthesis of rivaroxaban and give a brief overview of the pharmacological profile of rivaroxaban.

The serine protease FXa was selected as target as it is known to be the primary site of amplification in the coagulation process i.e. one molecule of FXa produced about 1000 molecules of thrombin. When we initiated the FXa program in 1998, no orally active FXa inhibitors with sufficient antithrombotic activity were known. All known potent inhibitors contained highly basic, positively charged residues, such as amidines, which act as mimics for an arginine present in prothrombin, the natural substrate of FXa. However, strongly basic residues contribute to poor oral absorption.

High-throughput screening of approximately 200,000compounds revealed several hits that selectively inhibited the cleavage of a chromogenic substrate by human FXa [1].

The chemical optimization started with the most potent hit. However, we could not achieve the target pharmacokinetic profile, as compounds with high potency showed generally low bioavailability. But we learned that the non-basic chlorothiophene moiety was essential for potent FXa inhibition. When re-evaluating the HTS hits by similarity considerations, we identified oxazolidinone derivatives containing a thiophene moiety as weak FXa inhibitors with good oral bioavailability. Applying our experience we introduced the chlorothiophene moiety resulting in a lead compound with more than 200-fold improved potency and high oral bioavailability and which did not comprise a basic group. This significant breakthrough led to the synthesis of rivaroxaban in 2000.

The mode of action of rivaroxaban is the direct, selective and competitive inhibition of human FXa [2]. In various well-established preclinical animal models of venous and arterial thrombosis, rivaroxaban showed dose dependent antithrombotic activity. Rivaroxaban has shown predictable pharmacokinetics and pharmacodynamics across a wide range of doses in healthy individuals [3].

The encouraging findings from preclinical and early clinic studies led to the investigation of rivaroxaban in late clinical studies for the prevention and treatment of thromboembolic diseases. 275,000 patients were included in the study program. Across all indications rivaroxaban is approved in more than 130 countries.

1. Roehrig S, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer KH, Reinemer P, Perzborn E. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem. 2005; 48:5900-8
2. Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer KH, Straub A. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939-an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005;3:514-21
3. Kubitza D, Perzborn E, Berkowitz SD. The discovery of rivaroxaban: translating preclinical assessments into clinical practice. Front Pharmacol. 2013;4:145

14.35 – 14.50
NOACs in acute coronary syndrome and after coronary stent in patients with atrial fibrillation

Giovanni B. Pedrazzini (Lugano, CH)

14.50 – 15.05
Advances in anticoagulant therapies; from Aspirin to NOACs

Salim Yusuf (Hamilton, CA)

15.05 – 15.20
Discussion

15.20 – 15.50

Coffee break

15.50 – 16.35

Antithrombotic Treatment in Acute Coronary Artery Disease in the World of Emerging Stents

Chairpersons: Felipe Martinez (Cordoba, AR), Doreen Tan (Singapore, SGP), Daniel Suerder (Lugano, CH)

15.50 – 16.05
State of art secondary prevention with antithrombotics

Marco Valgimigli (Bern, CH)

16.05 – 16.20
Will emerging stents simplify antithrombotic treatment?

Marco Roffi (Geneva, CH)

16.20 – 16.35
Discussion

16.35 – 17.30

PCSK-9 INHIBITION: INSIGHTS FROM THE ODYSSEY OUTCOMES TRIAL
A SANOFI SYMPOSIUM

Chairpersons: Heinz Drexel (Feldkirch, AT), Alvaro Sosa-Liprandi (Buenos Aires, AR), Stefan Windecker (Bern, CH)

16.35 – 16.50
Effect of Alirocumab on cardiovascular events and all-cause mortality

Christian Mueller (Basel, CH)

16.50 – 17.05
Advances in targeting LDL and Lp(a)- Causal Risk Factors for Atherosclerosis

Peter Libby (Boston, US)

17.05 – 17.20
Patients to consider for Aliricumab treatment

Alberico L. Catapano (Milan, IT)

17.20 – 17.30
Discussion

17.30 – 18.00

Distinguished Eugene Braunwald Lecture

Chairpersons: Juan Carlos Kaski (London, GB), Filippo Crea (Rome, IT), Ludwig K. von Segesser (Lausanne, CH), Augusto Gallino (Bellinzona, CH)

17.30 – 17.50
The Inclisiran (RNAi of PCSK9) trial: an avenue for postponing CAD until the age of 100?

Eugene Braunwald (Boston, US)

17.50 – 18.00
Discussion

18.00 – 18.30

Neufeld Lecture

Chairpersons: Juan Carlos Kaski (London, GB), Tiziano Moccetti (Lugano, CH), Koji Hasegawa (Kyoto, JP), Augusto Gallino (Bellinzona, CH)

The Polypill: A simple, inexpensive approach to reduce mortality and morbidity worldwide

Salim Yusuf (Hamilton, CA)