Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the ... more 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...
Naunyn-Schmiedeberg's Archives of Pharmacology, 1999
We studied the effects of angiotensin converting enzyme (ACE) inhibitors on angiotensin II (Ang I... more We studied the effects of angiotensin converting enzyme (ACE) inhibitors on angiotensin II (Ang II) induced growth related signalling pathways in neonatal rat cardiac fibroblasts. In BrdU proliferation assays, Ang II (10(-9)-10(-7) M) stimulated cardiac fibroblast growth in a dose-dependent fashion (maximum at 10(-7) M, 5.22 +/- 0.01-fold, n = 9). 2-2-(1-(ethoxycarbonyl)-3-phenylpropyl)[amino-oxopropyl]-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid (moexiprilat) led to a dose-dependent inhibition of the Ang II induced cardiac fibroblast growth. A less pronounced effect on cellular proliferation was seen with the ACE inhibitor enalaprilat. To elucidate the mechanisms involved in this direct antiproliferative effect of ACE inhibitors in cardiac fibroblasts, we studied the activation of mitogen-activated protein kinases [MAPKs: extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38-MAPK] and JAK/STAT janus kinases/signal transducer and activator of transcription) signal transduction pathways. Ang II (10(-7) M) caused an increase in MAPKs activity with an increased phosphorylation of ERK1/2 (1.7-fold) and p38-MAPK (3.6-fold). This effect was completely inhibited by moexiprilat (10(-7) M) and enalaprilat (10(-7) M). Stimulation with Ang II (10(-7) M) also led to an increased phosphorylation of STAT3, which is one of the key effector proteins in the JAK/STAT signalling pathway. This effect was also completely inhibited by moexiprilat (10(-7) M) and enalaprilat (10(-7) M). These data show that the ACE inhibitors moexiprilat and enalaprilat inhibit Ang II induced proliferation of cardiac fibroblasts according to their relative potency of ACE inhibition in vitro. This novel effect of ACE inhibitors is accompanied by blocking the Ang II induced activation of several intracellular signal transduction pathways (ERK1/2, p38-MAPK and STAT3).
Data on left atrial/left atrial appendage (LA/LAA) thrombus resolution after non-vitamin K antago... more Data on left atrial/left atrial appendage (LA/LAA) thrombus resolution after non-vitamin K antagonist (VKA) oral anticoagulant treatment are scarce. The primary objective of X-TRA was to explore the use of rivaroxaban for the resolution of LA/LAA thrombi in patients with nonvalvular atrial fibrillation (AF) or atrial flutter, with the CLOT-AF registry providing retrospective data after standard-of-care therapy in this setting. X-TRA was a prospective, single-arm, open-label, multicenter study that investigated rivaroxaban treatment for 6 weeks for LA/LAA thrombus resolution in patients with nonvalvular AF or atrial flutter and LA/LAA thrombus confirmed at baseline on a transesophageal echocardiogram (TEE). CLOT-AF retrospectively collected thrombus-related patient outcome data after standard-of-care anticoagulant treatment for 3 to 12 weeks in patients with nonvalvular AF or atrial flutter who had LA/LAA thrombi on TEE recorded in their medical file. In X-TRA, patients were predomin...
Circulation. Cardiovascular quality and outcomes, 2015
Among patients with atrial fibrillation (AF), women are at higher risk of stroke than men. Using ... more Among patients with atrial fibrillation (AF), women are at higher risk of stroke than men. Using prospective cohort data from a large global population of patients with nonvalvular AF, we sought to identify any differences in the use of anticoagulants for stroke prevention in women and men. This was a prospective multicenter observational registry with 858 randomly selected sites in 30 countries. A total of 17 184 patients with newly diagnosed (≤6 weeks) nonvalvular AF and ≥1 additional investigator-defined stroke risk factor(s) were recruited (March 2010 to June 2013). The main outcome measure was the use of anticoagulants (vitamin K antagonists, factor Xa inhibitors, and direct thrombin inhibitors) for stroke prevention at AF diagnosis. Of 17 184 patients enrolled, 43.8% were women. More women than men were at moderate-to-high risk of stroke (CHADS2 score ≥2: 65.1% versus 54.7%). Rates of anticoagulant use were not different overall (60.9% of men versus 60.8% of women) and in pati...
There are still many unresolved issues concerning patient outcomes and prognostic factors in pati... more There are still many unresolved issues concerning patient outcomes and prognostic factors in patients with atrial fibrillation (AF) and left atrial/left atrial appendage (LA/LAA) thrombi. Rivaroxaban (Xarelto®), a potent and highly selective oral, direct factor Xa inhibitor, is a new therapeutic option in this setting. The planned study program will consist of a prospective interventional study (X-TRA) and a retrospective observational registry (CLOT-AF). The primary objective of the X-TRA study is to explore the efficacy of rivaroxaban in the treatment of LA/LAA thrombi in patients with nonvalvular AF or atrial flutter, scheduled to undergo cardioversion or AF ablation, in whom an LA/LAA thrombus has been found on transesophageal echocardiography (TEE) before the procedure. The primary end point is the complete LA/LAA thrombus resolution rate at 6 weeks of end of treatment confirmed by TEE. The secondary objectives are to describe categories of thrombus outcome in patients (resolved, reduced, unchanged, larger, or new) confirmed on TEE at the end of treatment (after 6 weeks of treatment), incidence of the composite of stroke and noncentral nervous system systemic embolism at the end of treatment and during follow-up, and incidence of all bleeding at the end of treatment and during follow-up. The objective of the CLOT-AF registry is to provide retrospective thrombus-related patient outcome data after standard-of-care anticoagulant treatment in patients with nonvalvular AF or atrial flutter, who have TEE-documented LA/LAA thrombi. The data will be used as a reference for the prospective X-TRA study. In conclusion, X-TRA and CLOT-AF will provide some answers to the many unresolved issues concerning patient outcomes and prognostic factors in patients with AF and LAA thrombi. Results from this study program would provide the first prospective interventional study (X-TRA) and a large international retrospective observational registry (CLOT-AF) on the prevalence and natural history of LA/LAA thrombi. Unique data on clot resolution with rivaroxaban in a prospective cohort would be obtained in X-TRA.
Rivaroxaban demonstrated superior efficacy and a similar safety profile to enoxaparin for the pre... more Rivaroxaban demonstrated superior efficacy and a similar safety profile to enoxaparin for the prevention of venous thromboembolism in the phase III RECORD programme in patients undergoing elective hip or knee replacement surgery. The XAMOS study investigated adverse events, including bleeding and thromboembolic events, in patients receiving rivaroxaban for thromboprophylaxis in routine clinical practice. XAMOS was a non-interventional, open-label cohort study in patients undergoing major orthopaedic surgery of the hip or knee (predominantly elective arthroplasty), in which rivaroxaban was compared with other pharmacological thromboprophylaxis. All adverse events were documented, including symptomatic thromboembolic and bleeding events. Crude and adjusted incidences based on propensity score subclasses were calculated and compared between the rivaroxaban and standard-of-care groups. A total of 17,701 patients were enrolled from 252 centres in 37 countries. Crude incidences of symptomatic thromboembolic events three months after surgery in the safety population were 0.89% in the rivaroxaban group (n=8,778) and 1.35% in the standard-of-care group (n=8,635; odds ratio [OR] 0.65; 95% confidence interval [CI] 0.49-0.87), and 0.91% and 1.31% (weighted) in the propensity score-adjusted analysis (OR 0.69; 95% CI 0.56-0.85), respectively. Treatment-emergent major bleeding events (as defined in the RECORD studies) occurred in 0.40% and 0.34% of patients in the rivaroxaban and standard-of-care groups in the safety population (OR 1.19; 95% CI 0.73-1.95), and in 0.44% versus 0.33% (weighted) in the propensity score-adjusted analysis (OR 1.35; 95% CI 0.94-1.93), respectively.This study in unselected patients confirmed the favourable benefit-risk profile of rivaroxaban seen in the RECORD programme.
Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the ... more 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...
Naunyn-Schmiedeberg's Archives of Pharmacology, 1999
We studied the effects of angiotensin converting enzyme (ACE) inhibitors on angiotensin II (Ang I... more We studied the effects of angiotensin converting enzyme (ACE) inhibitors on angiotensin II (Ang II) induced growth related signalling pathways in neonatal rat cardiac fibroblasts. In BrdU proliferation assays, Ang II (10(-9)-10(-7) M) stimulated cardiac fibroblast growth in a dose-dependent fashion (maximum at 10(-7) M, 5.22 +/- 0.01-fold, n = 9). 2-2-(1-(ethoxycarbonyl)-3-phenylpropyl)[amino-oxopropyl]-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid (moexiprilat) led to a dose-dependent inhibition of the Ang II induced cardiac fibroblast growth. A less pronounced effect on cellular proliferation was seen with the ACE inhibitor enalaprilat. To elucidate the mechanisms involved in this direct antiproliferative effect of ACE inhibitors in cardiac fibroblasts, we studied the activation of mitogen-activated protein kinases [MAPKs: extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38-MAPK] and JAK/STAT janus kinases/signal transducer and activator of transcription) signal transduction pathways. Ang II (10(-7) M) caused an increase in MAPKs activity with an increased phosphorylation of ERK1/2 (1.7-fold) and p38-MAPK (3.6-fold). This effect was completely inhibited by moexiprilat (10(-7) M) and enalaprilat (10(-7) M). Stimulation with Ang II (10(-7) M) also led to an increased phosphorylation of STAT3, which is one of the key effector proteins in the JAK/STAT signalling pathway. This effect was also completely inhibited by moexiprilat (10(-7) M) and enalaprilat (10(-7) M). These data show that the ACE inhibitors moexiprilat and enalaprilat inhibit Ang II induced proliferation of cardiac fibroblasts according to their relative potency of ACE inhibition in vitro. This novel effect of ACE inhibitors is accompanied by blocking the Ang II induced activation of several intracellular signal transduction pathways (ERK1/2, p38-MAPK and STAT3).
Data on left atrial/left atrial appendage (LA/LAA) thrombus resolution after non-vitamin K antago... more Data on left atrial/left atrial appendage (LA/LAA) thrombus resolution after non-vitamin K antagonist (VKA) oral anticoagulant treatment are scarce. The primary objective of X-TRA was to explore the use of rivaroxaban for the resolution of LA/LAA thrombi in patients with nonvalvular atrial fibrillation (AF) or atrial flutter, with the CLOT-AF registry providing retrospective data after standard-of-care therapy in this setting. X-TRA was a prospective, single-arm, open-label, multicenter study that investigated rivaroxaban treatment for 6 weeks for LA/LAA thrombus resolution in patients with nonvalvular AF or atrial flutter and LA/LAA thrombus confirmed at baseline on a transesophageal echocardiogram (TEE). CLOT-AF retrospectively collected thrombus-related patient outcome data after standard-of-care anticoagulant treatment for 3 to 12 weeks in patients with nonvalvular AF or atrial flutter who had LA/LAA thrombi on TEE recorded in their medical file. In X-TRA, patients were predomin...
Circulation. Cardiovascular quality and outcomes, 2015
Among patients with atrial fibrillation (AF), women are at higher risk of stroke than men. Using ... more Among patients with atrial fibrillation (AF), women are at higher risk of stroke than men. Using prospective cohort data from a large global population of patients with nonvalvular AF, we sought to identify any differences in the use of anticoagulants for stroke prevention in women and men. This was a prospective multicenter observational registry with 858 randomly selected sites in 30 countries. A total of 17 184 patients with newly diagnosed (≤6 weeks) nonvalvular AF and ≥1 additional investigator-defined stroke risk factor(s) were recruited (March 2010 to June 2013). The main outcome measure was the use of anticoagulants (vitamin K antagonists, factor Xa inhibitors, and direct thrombin inhibitors) for stroke prevention at AF diagnosis. Of 17 184 patients enrolled, 43.8% were women. More women than men were at moderate-to-high risk of stroke (CHADS2 score ≥2: 65.1% versus 54.7%). Rates of anticoagulant use were not different overall (60.9% of men versus 60.8% of women) and in pati...
There are still many unresolved issues concerning patient outcomes and prognostic factors in pati... more There are still many unresolved issues concerning patient outcomes and prognostic factors in patients with atrial fibrillation (AF) and left atrial/left atrial appendage (LA/LAA) thrombi. Rivaroxaban (Xarelto®), a potent and highly selective oral, direct factor Xa inhibitor, is a new therapeutic option in this setting. The planned study program will consist of a prospective interventional study (X-TRA) and a retrospective observational registry (CLOT-AF). The primary objective of the X-TRA study is to explore the efficacy of rivaroxaban in the treatment of LA/LAA thrombi in patients with nonvalvular AF or atrial flutter, scheduled to undergo cardioversion or AF ablation, in whom an LA/LAA thrombus has been found on transesophageal echocardiography (TEE) before the procedure. The primary end point is the complete LA/LAA thrombus resolution rate at 6 weeks of end of treatment confirmed by TEE. The secondary objectives are to describe categories of thrombus outcome in patients (resolved, reduced, unchanged, larger, or new) confirmed on TEE at the end of treatment (after 6 weeks of treatment), incidence of the composite of stroke and noncentral nervous system systemic embolism at the end of treatment and during follow-up, and incidence of all bleeding at the end of treatment and during follow-up. The objective of the CLOT-AF registry is to provide retrospective thrombus-related patient outcome data after standard-of-care anticoagulant treatment in patients with nonvalvular AF or atrial flutter, who have TEE-documented LA/LAA thrombi. The data will be used as a reference for the prospective X-TRA study. In conclusion, X-TRA and CLOT-AF will provide some answers to the many unresolved issues concerning patient outcomes and prognostic factors in patients with AF and LAA thrombi. Results from this study program would provide the first prospective interventional study (X-TRA) and a large international retrospective observational registry (CLOT-AF) on the prevalence and natural history of LA/LAA thrombi. Unique data on clot resolution with rivaroxaban in a prospective cohort would be obtained in X-TRA.
Rivaroxaban demonstrated superior efficacy and a similar safety profile to enoxaparin for the pre... more Rivaroxaban demonstrated superior efficacy and a similar safety profile to enoxaparin for the prevention of venous thromboembolism in the phase III RECORD programme in patients undergoing elective hip or knee replacement surgery. The XAMOS study investigated adverse events, including bleeding and thromboembolic events, in patients receiving rivaroxaban for thromboprophylaxis in routine clinical practice. XAMOS was a non-interventional, open-label cohort study in patients undergoing major orthopaedic surgery of the hip or knee (predominantly elective arthroplasty), in which rivaroxaban was compared with other pharmacological thromboprophylaxis. All adverse events were documented, including symptomatic thromboembolic and bleeding events. Crude and adjusted incidences based on propensity score subclasses were calculated and compared between the rivaroxaban and standard-of-care groups. A total of 17,701 patients were enrolled from 252 centres in 37 countries. Crude incidences of symptomatic thromboembolic events three months after surgery in the safety population were 0.89% in the rivaroxaban group (n=8,778) and 1.35% in the standard-of-care group (n=8,635; odds ratio [OR] 0.65; 95% confidence interval [CI] 0.49-0.87), and 0.91% and 1.31% (weighted) in the propensity score-adjusted analysis (OR 0.69; 95% CI 0.56-0.85), respectively. Treatment-emergent major bleeding events (as defined in the RECORD studies) occurred in 0.40% and 0.34% of patients in the rivaroxaban and standard-of-care groups in the safety population (OR 1.19; 95% CI 0.73-1.95), and in 0.44% versus 0.33% (weighted) in the propensity score-adjusted analysis (OR 1.35; 95% CI 0.94-1.93), respectively.This study in unselected patients confirmed the favourable benefit-risk profile of rivaroxaban seen in the RECORD programme.
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