August 29 - September 2 , 2009
Barcelona
INTRODUCTION
August 29-September 2, 2009
Barcelona, Spain
Barcelona is the birthplace and residence of the writer signing this report, who apologizes herewith if any bias towards this beautiful sunny, warm (perhaps a bit too warm during the meeting) city is expressed in this text, which aims to summarize everything new regarding pharmacological treatment for cardiac and vascular diseases as discussed during the meeting of the European Society of Cardiology. Although the meeting was not held in Barcelona proper, but in the neighboring town of L’Hospitalet del Llobregat, Barcelona was the reference for the vast majority of attendees, who could not enjoy the impressive architecture, beaches, museums, landmarks or shops because of the intense pace of the meeting, but could at least enjoy very nice restaurants in gorgeous places tucked away in amazing corners throughout the streets and avenues around the Catalan capital.
Amazing is also an appropriate adjective to describe the increasing number of highly effective, reliable therapies available for cardiovascular diseases, as well the increasing number of preventive strategies with a demonstrated impact on cardiovascular risk. No less astonishing is the general lack of compliance with healthy lifestyles and the common underuse of medications, not just in primary cardiovascular prevention, but also in high-risk patients known to respond to guideline-mandated therapies with increased likelihood for survival. An example of this is the lack of adherence with dual antiplatelet therapy after a coronary stent implantation, with either underuse of drugs or excessive treatment duration [Bampali, T.H. et al., Abst P1552]. Underuse has been described with antihypertensive medications, statins, antianginals, anticoagulants, antiplatelets and indeed most of the available therapies indicated for the welfare of patients.
An interesting observation reported during this year’s meeting was that, according to a study in Korea, very low levels of LDL-cholesterol are not associated with a decrease but rather an increase in the likelihood for death in patients suffering from an acute myocardial infarction [Lee, J.H. et al., Abst P420], which contradicts the conventional motto of “the lower the better” and adds to last year’s observations related to a J-curve also relating mortality and blood pressure. In a totally unrelated manner, and as an addition to adverse cardiovascular risk factors, a study in Singapore confirmed that sleeping less than 5 hours per day is associated with increased prevalence of coronary artery calcifications, at least in male Asian individuals [Tan, S.Y. et al., Abst P1365]. As a final curiosity among the many presentations and discussions during this year’s meeting in Barcelona ─ made more relevant to this reporter by the fact that in addition to medical reporting, he also plays piano in music concerts ─ is that music therapy was identified as beneficial in patients with acute myocardial infarction because of its effect in reducing blood pressure, lowering heart rate and preventing coronary events [Mitrovic, P.M. et al., Abst P2126].
HEART FAILURE
With no difference in efficacy between Caucasian and Afro-Caribbean populations [Edwards, C.P. et al., Abst P2508], beta-blockers are used extensively [Cohen-Solal, A. et al., Abst P2521] and have become the mainstay in the treatment of heart failure, and should be continued in case of acute decompensation to maximize benefit without delaying or impairing recovery from the acute episode [Jondeau, G. et al., Abst P2485]. Furthermore, at least with bisoprolol, the CIBIS II study demonstrated a survival benefit in patients with heart failure regardless of renal function status [Castagno, D. et al., Abst 2477], whereas carvedilol, a beta-blocker that induced greater additional positive effects on elastic artery stiffness compared to metoprolol [Ozova, E.M. et al., Abst P2497], also improved left ventricular hemodynamics in experimental models of acute myocardial infarction [Cimmino, G. et al., Abst P3377]. Carvedilol also improved survival in chronic, postischemic heart failure regardless of heart rate, while ivabradine used as comparator improved prognosis only in patients with a heart rate over 70 beats/minute [Tumasyan, L.R. et al., Abst P2498]; ivabradine also showed potential for improving hypertensive cardiac remodeling through modulation of connective tissue growth factor [Velkoska, E. et al., Abst P3382], and was confirmed safe and effective for reducing heart rate and angina attacks in patients over 80 years of age [Koester, R. et al., Abst P4510]. Moreover, because of its rate-lowering effect, ivabradine was considered a valid alternative to beta-blockers for computed tomographic coronary angiography, regarding image quality and motion artifacts [Perez De Isla, L. et al., Abst P3039; Marcos-Alberca Moreno, P. et al., Abst P4563], and also for performing coronary surgical interventions in patients with conduction abnormalities [Iliuta, L. et al., Abst 5242]. As in the case of bisoprolol, nevibolol was also confirmed safe and effective in patients with impaired renal function, in this particular case in the elderly [Kotecha, D. et al., Abst P2493] and nevibolol, but not atenolol, also inhibited T-cell activation during experimental myocardial ischemia, adding pleiotropic favorable cardiac activities to the known pharmacological spectrum of this particular beta-blocker [Gasser, S. et al., Abst P4531].
However, beta-blockers are not the only effective drugs in the therapeutic armamentarium. As an example, trimetazidine was shown to improve the electrocardiographic dispersion in patients with chronic, postischemic heart failure [Cera, M. et al., Abst P2504] and enhanced the benefits of exercise training on physical work capacity and left ventricular remodeling in patients with dilated cardiomyopathy [Gad, M. et al., Abst P2500], while, although underused according to retrospective survey data, eplerenone was described as able to reduce heart failure-related hospitalizations and complications [Gheorghiade, M. et al., Abst P2502], showed an overall beneficial effect on endothelial function [Tiritilli, A. et al., Abst P2517] and myocardial collagen turnover [Mak, G. et al., Abst 5047] and improved experimental coxsackievirus B3-induced myocarditis in animal models [Ukimura, A. et al., Abst 5229]. In addition, levosimendan was equieffective to dobutamine for improving left ventricular function in patients with heart failure on beta-blocker therapy [Cavusoglu, Y. et al., Abst P1723] (Fig. 1), but despite similar improvements in left ventricular systolic function, only levosimendan improved diastolic function and induced a greater decrease in neurohormonal activation, lacking the proarrhythmic and chronotropic effect of dobutamine [Duman, D. et al., Abst P2173; Duman, D. et al., Abst P5698]. Furthermore, levosimendan was suggested safe and effective for improving postoperative outcomes in critically ill patients with low cardiac output syndrome undergoing cardiac surgical procedures, with improved in-hospital outcomes and one-year survival [Cattaneo, P. et al., Abst P853], and proved a feasible option for slowing heart rate during high-risk cardiac surgery [Lahtinen, P. et al., Abst 3644].
Fig. 1. Change in the left ventricular ejection fraction at the end of a 15-minute infusion of levosimentan or dobutamine in patients with heart failure on beta-blocker therapy [Cavusoglu, Y. et al., Abst P1723].
A number of natriuretic peptides have been developed and tested for activity in heart failure, including, as reported during this year’s meeting sessions, CD-NP, which showed renal enhancing properties in chronic heart failure patients with elevated blood pressure and low ejection fraction [Lieu, H.D. et al., Abst P2490].
Improvements in pulmonary capillary wedge pressure in patients with congestive heart failure were obtained by treatment with nicorandil and nitroglycerin, without differences between the two agents, but nicorandil showed reduced hemodynamic tolerance, better maintaining activity for 48 hours [Singh, V. et al., Abst P2503] (Fig. 2). Symptomatic and functional benefits in patients with moderate to severe heart failure were also attained by growth hormone replacement therapy in patients showing growth hormone deficiency [Cittadini, A. et al., Abst P2496].
Fig. 2. Change in pulmonary capillary wedge pressure during 48 hours after administration of nicorandil or nitroglycerin [Singh, V. et al., Abst P2503].
Currently under clinical development, a phase IIb study with relaxin in patients with acute heart failure and normal blood pressure demonstrated rapid improvements in dyspnea and overall symptoms of the disease [Metra, M. et al., Abst P2489] (Fig. 3).
Fig. 3. Percent of patients with marked improvement in the Likert’s dyspnea scale scores within 24 hours of treatment with relaxin or placebo [Metra, M. et al., Abst P2489].
Acting by stimulation of guanylate cyclase, BAY-60-4552 induced potent vasodilatation, reduced pre- and afterload and improved ejection fraction in patients with biventricular failure [Mitrovic, V. et al., Abst P1577]; sharing the same mechanism of action, HMR-1766 improved postischemic remodeling as effectively as but synergistically with angiotensin-converting enzyme inhibitors [Bauersachs, J. et al., Abst P2482] and alone or combined with ramipril reversed intramural coronary artery remodeling in hypertensive conditions [Varela Carver, A. et al., Abst P4744]. Regarding experimental findings, chronic activation of guanylate cyclase with apaciguat resulted in improvements of endothelial function and reductions of platelet activation in models of congestive heart failure [Schaefer, A. et al., Abst 385].
In addition, blockade of sarcoplasmic calcium transport by K-201 was associated with attenuation of sarcoplasmic reticulum calcium leak-dependent sodium accumulation in cardiomyocytes, suggesting potential as a treatment for heart failure and cardiac arrhythmia [Heinzel, F.R. et al., Abst P562]. In the setting of beta1-receptor antibody-induced cardiomyopathy, potential in the experimental arena was suggested for immunotherapy with epitope-mimicking cyclopeptides [Merkl, M. et al., Abst P1569]. Further experimental studies suggested potential for recombinant periostin for improving cardiac function in models of ischemic cardiomyopathy [Ladage, D. et al., Abst P1692], and for AAV-BARKct gene therapy in models of pacing-induced heart failure [Byrne, M. et al., Abst P1689]. In a similar way, AAV-HCN4 gene transfer was able to overcome loss of ventricular activity secondary to atrioventricular block [Murakoshi, N. et al., Abst 1923].
In the specific case of peripartum cardiomyopathy, benefits were attributed to bromocriptine, which added to standard therapy improved left ventricular systolic and diastolic function and six-month survival without detrimental effects on the neonates in a randomized study including 10 pregnant women and their 21 offspring [Sliwa, K. et al., Abst 341] (Fig. 4). In the case of cardiomyopathy in Fabry’s disease, agalsidase alfa replacement delayed cardiac disease, suggesting potential for preventive therapy in the absence of left ventricular hypertrophy [Serra, V. et al., Abst 343].
Fig. 4. Change in the left ventricular ejection fraction at 6 months in pregnant women with peripartum cardiomyopathy receiving or not add-on bromocriptine [Sliwa, K. et al., Abst 341].
In the context of adjuvant therapies, use of epoetin to control anemia in heart failure patients resulted in improved exercise performance and reduced symptoms and clinical outcomes according to a meta-analysis of 11 randomized clinical trials [Kotecha, D. et al., Abst 1102], although a further meta-analysis demonstrated good tolerability and effective control of anemia with erythropoiesis-stimulating factors, without evidence of clinical benefit on heart failure [Canario-Almeida, F. et al., Abst P2491] and in the experimental arena, preconditioning with erythropoietin effectively prevented reperfusion injuries after experimental ischemia [Treguer, F. et al., Abst P4492; Jo, Y. et al., Abst P4499]. On an independent basis, coadministration of low-dose furosemide and low-dose dopamine was suggested as a feasible option for preventing worsening of renal function and hypopotassemia during hospitalization for acute, decompensated heart failure [Giamouzis, G. et al., Abst P2513].
CARDIAC ARRHYTHMIA
While continuous amiodarone therapy was associated with better maintenance of sinus rhythm compared to episodic treatment [Ahmed, S. et al., Abst P2432] and it proved synergistic with beta-blockers in terminating ventricular tachycardia without the need for electroshock [Jimenez-Candil, J. et al., Abst P3297], the agent was deemed superior to sotalol, as it did not modify the action potential duration, which was significantly prolonged by the beta-blocker [Frommeyer, G. et al., Abst P2418]. However, common adenosine resistance was identified in patients on amiodarone therapy [Nedios, S. et al., Abst P403], whereas concomitant use of beta-blockers did not enhance the effectiveness of the agent in maintaining sinus rhythm in patients with persistent atrial fibrillation [Mezzetti, M. et al., Abst P771]. On the other hand, novel data from the ATHENA study confirming the positive impact of dronedarone on atrial fibrillation/flutter-related hospitalizations [Page, R.L. et al., Abst 2781] and cardiovascular hospitalizations in patients with coronary artery disease [Crijns, H.J.G.M. et al., Abst 2779] were reported, while spironolactone was a useful up-stream option for preventing atrial fibrillation in patients with recurrent arrhythmia [Dabrowski, R. et al., Abst P4859].
Both propafenone and flecainide increased inward-rectifying potassium currents in isolated cells transfected with human channel, which could be one of the mechanisms for the ventricular proarrhythmic effect of these class Ic antiarrhythmics [Caballero, R. et al., Abst P579]; in fact the proarrhythmic effect of flecainide in patients with atrial fibrillation resulted in an annualized incidence of sudden death or ventricular arrhythmia of 3% [Almroth, H. et al., Abst 2784]. On the contrary, oral vernakalant was suggested as a feasible approach for preventing postcardioversion atrial fibrillation recurrence based on the results of a double-blind, placebo-controlled trial [Torp-Pedersen, C. et al., Abst 2780] (Fig. 5), and flecainide, like verapamil, was shown to counteract the proarrhythmogenic effect of dofetilide in inducing torsades de pointes [Oros, A. et al., Abst P3312]. In the experimental setting, normalization of action potential duration during exposure to angiotensin II was demonstrated in cardiac cells treated with ranolazine [Casini, S. et al., Abst P567], and possibly through a related mechanism, the agent proved to reduce the frequency of ventricular tachycardia during percutaneous interventions for non-ST segment-elevated acute coronary syndromes [Karwatowska-Prokopczuk, E. et al., Abst P3295].
Fig. 5. Percent of patients in sinus rhythm at day 90 after postcardioversion treatment with vernakalant or placebo [Torp-Pedersen, C. et al., Abst 2780].
An interesting report from a 10-year study in 68 patients with Brugada’s syndrome was presented during the meeting demonstrating that, without compromising safety, quinidine could be a therapeutic alternative able to prevent ventricular fibrillation and avoid the need for implantable cardioverter defibrillators [Fourey, D. et al., Abst 1117]; oral quinidine administration was indeed associated with reduced likelihood for electrical storm without adverse events in a further study in five patients with the syndrome [Sciarra, L. et al., Abst P4151]. Regarding the long-QT syndrome, although beta-blockers had a minimal effect, lappaconitine did show potential for shortening the QT interval [Chuprova, S. et al., Abst P4165].
In the experimental arena, bepridil was related to attenuation of the risk for stretch-induced arrhythmia through an effect on calcium-regulated potassium channels [Iribe, G. et al., Abst P408], whereas nicorandil shortened the action potential and decreased repolarization dispersion in models of long-QT syndrome [Brunner, M. et al., Abst P405]. In further in vitro studies, use-dependent blockade of late sodium currents by ranolazine was demonstrated [Rajamani, S. et al., Abst P404]. Furthermore, attenuation of tachycardia-induced electrical remodeling was demonstrated upon treatment with dexamethasone in models of atrial fibrillation [Laszlo, R. et al., Abst P555]. In that respect, the adenosine A2 receptor blocker ZM-241385 was shown to stabilize rate-dependent beat-to-beat responses of L-type calcium channels in atrial cardiomyocytes [Molina, C.E. et al., Abst P578], while the alpha1A-agonist methoxamine inhibited early afterdepolarization in experimental animals, suggesting antiarrhythmic potential [Yamagishi, S. et al., Abst P3303].
Arrhythmia is a common complication of chronic heart failure, but attenuation of the proarrhythmic status in experimental animal models was demonstrated with the sodium/calcium exchanger NCX1 inhibitor SEA-0400, increasing the list of putative preventive approaches [Milberg, P. et al., Abst P565].
CORONARY ARTERY DISEASE
Dual antiplatelet therapy is standard in patients with acute coronary syndromes or stable coronary artery disease and individuals at risk for ischemic heart disease, and is indicated in patients who have undergone percutaneous coronary interventions, to the extent that discontinuation of antiplatelet therapy after coronary stent implantation was related to a marked increase in the risk of suffering an adverse cardiovascular event [Bampali, T.H. et al., Abst P658; Rossini, R. et al., Abst P1551], whereas lower risk of death or myocardial infarction was apparent after coronary stent implantation in patients maintaining clopidogrel for at least 12 months [Zahger, D. et al., Abst P2086] or in patients undergoing percutaneous coronary interventions of complex saphenous vein graft lesions with drug-eluting stent implantation treated with “prolonged” dual antiplatelet therapy for at least 12 months [Ruggiero, N.J. et al., Abst P4733], although the risk of bleeding should be considered [Serebruany, V.L. et al., Abst P2084], being more common in females, patients with a history of peptic ulcer and subjects with prior myocardial infarction [Rossini, R. et al., Abst P2094]. Aspirin is probably the most universally prescribed drug, and is the mainstay of cardiovascular treatment and prevention, with novel analyses revealing a role in protecting against endothelial damage through lectin-like oxidized LDL receptor-1 blockade [Chang, P.Y. et al., Abst P2229]. Clopidogrel is the most commonly used antiplatelet agent in dual combinations with aspirin, and according to new clinical results and observations reported during this year showed marked antiinflammatory effects besides lowering platelet activity, with reductions in interleukin-1alpha, -2, -6 and -13, tumor necrosis factor-alpha and -beta and C-reactive protein levels demonstrated in 110 patients undergoing coronary stent implantation [Tantry, U.S. et al., Abst P681] and improvements in endothelial function and nitric oxide bioavailability in experimental models of heart failure [Schaefer, A. et al., Abst P3966]. In fact, administration of clopidogrel to patients with acute coronary syndrome translated into attenuation of platelet-mediated inflammatory responses in further studies, an effect that was related to reduced expression of membrane CD40 ligand, platelet-derived microparticle release and platelet-leukocyte interactions [Kalantzi, K. et al., Abst P1319], although without a clear impact on ischemia during exercise stress [Jovin, I.S. et al., Abst P4574]. In that particular regard, responsiveness to clopidogrel showed dependence upon CYP2C19 [Gurbel, P.A. et al., Abst P676; Collet, J.P. et al., Abst 5200] and adrenergic alpha2A-receptor [Cuisset, T. et al., Abst 5117] genotype. Concomitant use of proton pump inhibitors increased the risk of adverse cardiovascular events in patients receiving clopidogrel [Banerjee, S. et al., Abst P653; Sarafoff, N. et al., Abst 894; Lanas, A. et al., Abst P2095; Zuern, C.S. et al., Abst 2680], although no significant impact on thromboembolic events could be demonstrated in two cohorts of patients receiving dual antiplatelet therapy [Jarai, R. et al., Abst P675; Gaspar, A. et al., Abst 2679] and in fact no safety concern arose during dual antiplatelet therapy with aspirin and clopidogrel in patients undergoing drug-eluting stent implantation while treated with proton pump inhibitors [Rossini, R. et al., Abst P4532]. Decreased antiplatelet effectiveness of clopidogrel was also documented upon concomitant administration of esomeprazole and phenprocoumon (which also increased serum levels of inactive uncarboxylated matrix Gla protein, suggesting deficiency of calcification inhibitor [Koos, R. et al., Abst P5383]), but not ranitidine [Moceri, P. et al., Abst 895; Sibbing, D. et al., Abst 5114], and upon using nonionic contrast media in patients on chronic clopidogrel therapy [Sarkis, A. et al., Abst P4857]. On the other hand, concomitant use of dual antiplatelet and anticoagulant therapy after coronary stent implantation increased the risk of bleeding complications, calling for caution in patients already anticoagulated at the time of intervention [Hoffmann, A. et al., Abst P669], and in fact use of warfarin in patients undergoing stent implantation translated into common bleeding complications in further studies [Annala, A.P. et al., Abst P682], whereas triple therapy with aspirin, clopidogrel and tirofiban improved antiplatelet responses and clinical outcomes in the On-TIME trial [Smit, J.J.J. et al., Abst P1311]. Furthermore, the use of more than three concomitant antiplatelet and/or anticoagulant agents was concluded to offer no additional benefit, while increasing the risk of bleeding in a pooled analysis of 64 randomized trials [Petr, R. et al., Abst P1272], but this should be considered along with the occurrence of resistance or underresponsiveness to aspirin and clopidogrel [Addad, F. et al., Abst P1326; Pettersen, A.A. et al., Abst P2088; Sharp, A.S.P. et al., Abst P2087; Bellemain, A. et al., Abst P2083; Thuaire, C. et al., Abst P2112], a phenomenon described, at least in the case of clopidogrel, in patients with reduced renal function [Angiolillo, D.J. et al., Abst P1316] or carrying the CYP2C19*2 gene variant [Aleil, B. et al., Abst P2090; Worrall, A. et al., Abst P2089], and the poorer clinical outcomes after acute coronary syndromes in patients with suboptimal response to dual antiplatelet therapy [Milicic, D. et al., Abst P1308; El Ghannudi, S. et al., Abst P1312; Mangiacapra, F. et al., Abst P1334; Marcucci, R. et al., Abst P1325; Lee, K.H. et al., Abst P2091] (not confirmed in all trials, as no statistically significant differences between responders and not responders were seen in a particular study [Range, G. et al., Abst 4989]), although no impact of clopidogrel underresponsiveness on the risk of restenosis after drug-eluting stent implantation could be demonstrated in a series of more than 1,000 patients [Schulz, S. et al., Abst P1332]. To counteract this problem, continued administration of clopidogrel for at least 30 days was noted to significantly improve antiplatelet responses in patients with initial clopidogrel resistance developing acute coronary syndromes [Kalantzi, K. et al., Abst P1315]. Use of higher doses of clopidogrel has also been advocated, although according to some authors the protocol is too time-consuming when compared with the availability and higher antiplatelet reliability of prasugrel [Collet, J.P. et al., Abst P1333], whereas loading doses higher than 300 mg proved safe and effective in some studies, including one in very elderly patients over 75 years of age [Simon, T. et al., Abst P5301], but did not improve outcomes in patients with acute coronary syndromes not undergoing percutaneous interventions, while increasing the risk of bleeding complications in other studies [Pizzi, C. et al., Abst P2092; Widimsky, P. et al., Abst P3821; Widimsky, P. et al., Abst 5201; Mrdovic, I. et al., Abst P5269]; nonetheless, higher loading and maintenance doses have been advocated as a means for improving outcomes in patients with increased platelet reactivity [Trenk, D. et al., Abst 5116]. Add to this that discontinuation of clopidogrel was not associated with rebound phenomena, and had no impact on platelet reactivity or clinical outcomes other than stopping inhibition [Sibbing, D. et al., Abst P1313; Lemesle, G. et al., Abst 2681], and that a patient information card discussing the benefits and risks of clopidogrel improved patient knowledge and persistence with treatment [Bhattacharyya, S. et al., Abst P2085]. Of interest also, cangrelor impaired the binding of clopidogrel and prasugrel active metabolites to the P2Y12 receptor [Buckland, R. et al., Abst P1310]. Elinogrel, a novel alternative to prasugrel, was tested feasible in a first in-patient study, showing rapid antiplatelet activity in patients exhibiting resistance to high-dose clopidogrel [Gurbel, P.A. et al., Abst 2678], the agent showing activity against clopidogrel-insensitive P2Y12 receptors [Haberstock-Debic, H. et al., Abst 5115].
However, anticoagulants are useful in many instances and cannot be ruled out as an approach for coronary artery disease even in patients undergoing invasive therapies, and some agents may confer specific additional benefits, such as the angiogenic and vasculogenic effect demonstrated with bemiparin in an in vitro, endothelial cell culture assay [Di Stefano, R. et al., Abst P1273]; vasculo-angiogenic responses were also demonstrated with the antiplatelet agent cilostazol [Chao, T.H. et al., Abst P2195]. A first clinical application study described during the meeting revealed the feasibility and benefits of anticoagulation with RB-006 followed by reversal with RB-007, permitting individualized prevention of thrombosis while maintaining homeostasis [Cohen, M.G. et al., Abst P686]. On the other hand, confirmation of the safety and efficacy of fondaparinux in patients undergoing percutaneous coronary interventions was obtained in a new study discussed in Barcelona [Schiele, F. et al., Abst 5209].
Besides antiplatelet and classical anticoagulant therapies, a number of modern therapies have been developed and proved effective in the management of acute coronary syndromes, among which glycoprotein IIb/IIIa inhibitors were shown to improve outcomes in clopidogrel-nonresponding patients [Cuisset, T. et al., Abst 5119]. These include abciximab, which compared to placebo reduced by 30% the risk of repeated myocardial infarction at 6-12 months in patients with acute ST segment-elevated myocardial infarction undergoing nonemergent percutaneous coronary interventions according to a new meta-analysis [Ferrante, G. et al., Abst P1271] but was associated with improved outcomes upon intracoronary compared to intravenous bolus administration [Iversen, A. et al., Abst 5206]. The small-molecule gpIIb/IIIa blockers tirofiban and epitifibatide are a valid pharmacological alternative to abciximab as adjuvant pharmacotherapy in patients undergoing percutaneous coronary interventions, according to a meta-analysis of randomized clinical trials [Ottani, F. et al., Abst P5267]: tirofiban significantly improved ST segment resolution and reduced the risk of myocardial infarction when given preadmission to elderly or diabetic patients undergoing percutaneous coronary interventions [Timmer, J.R. et al., Abst P5264; Van Houwelingen, K.G. et al., Abst P5312] and eptifibatide, when substituted for abciximab, did not result in poorer long-term outcomes [Koutouzis, M. et al., Abst P3223]. However, use of bivalirudin monotherapy was as effective as unfractionated heparin combined with glycoprotein IIb/IIIa inhibitors in patients with ST segment-elevated myocardial infarction undergoing drug-eluting stent implantation with background antiplatelet therapy with aspirin and clopidogrel, although mortality was lower with bivalirudin compared to the control group [Trivisonno, A. et al., Abst 5211; Stone, G.W. et al., Abst 5210]. In addition, results were presented with rivaroxaban, which showed greater antithrombotic effects at low doses when coadministered with aspirin and clopidogrel [Perzbon, E. et al., Abst P2106] (the agent is currently being compared to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation in the ROCKET AF study [Patel, M. et al., Abst P4198]), and ARC-1779, which without impairing platelet activation or aggregation, showed antithrombotic potency comparable to abciximab when added to aspirin/clopidogrel [Aizamenti Aizpurua, D. et al., Abst P2093]. Additional studies confirmed the anticoagulant activity of edoxaban in healthy volunteers [Samama, M.M. et al., Abst P2105] and the significant antiplatelet activity of the protease-activated receptor-1 blocker E-5555 in both healthy volunteers and patients with coronary artery disease [Serebruany, V.L. et al., Abst P2097]. A mechanistic investigation related to anticoagulant agents demonstrated inhibition of thrombus-induced thrombogenicity by the direct thrombin inhibitor dabigatran, but not the factor Xa inhibitors rivaroxaban and apixaban [Van Ryn, J. et al., Abst P2110] (note that dabigatran was reported as effective as unfractionated heparin or low-molecular-weight heparins in preventing mechanical valve thrombosis in in vitro assessments [Maegdefessel, L. et al., Abst P2408]). In the preclinical arena, prevention of carotid thrombosis in experimental animal models was obtained with the synthetic cyclic peptide (S,S)-PSRCDCR-NH2 [Roussa, V. et al., Abst P2103], whereas mechanistic data with the novel direct thrombin inhibitor AZD-0837 revealed a correlation between pharmacokinetic exposure and decrease in D-dimer levels in patients with atrial fibrillation [Lip, G.Y.H. et al., Abst P4851].
In addition, antianginal agents are available and useful in a number of settings, and in fact both nitrates and calcium channel blockers were related with reduced risk for sudden death in patients with variant angina [Park, H.W. et al., Abst P4152]. Examples of this include the favorable results upon preprocedural administration of nicorandil in patients undergoing percutaneous coronary interventions, resulting in effective prevention of slow coronary flow phenomenon [Kawai, Y. et al., Abst P1514] and prevention of cardiovascular death [Horinaka, S. et al., Abst 2825], or the prolongation of total exercise time in patients with exercise-induced ischemia and chronic stable angina treated with allopurinol [Noman, A. et al., Abst 2815]. A further observation was that of enhanced reactive hyperemia in patients with coronary artery disease treated with pentaerithryl tetranitrate [Ostad, M.A. et al., Abst P2238]. The same was noted with diltiazem and verapamil, with superiority over nitroglycerin [Huang, D. et al., Abst P1534], whereas ivabradine improved coronary blood flow and flow reserve [Skalidis, E.I. et al., Abst P4749], reduced post-percutaneous coronary intervention angina [Koester, R. et al., Abst 2824], delayed ischemia-induced ventricular fibrillation (and did so more effectively than propranolol) [Timour Chah, Q. et al., Abst P4500], was able to safely terminate sinoatrial tachycardia [Borbola, J. et al., Abst P3344], improved systolic performance and enhanced the expression of FK506-binding protein-12 after reperfusion from a myocardial infarction [Couvreur, N. et al., Abst P2474], reduced heart rate without affecting energy-producing pathways in isolated hearts [Lauzier, B. et al., Abst P1397] and, in experimental hypercholesterolemic animals, attenuated diastolic dysfunction and atrial fibrosis and reduced heart rate [Busseuil, D. et al., Abst P2499]; however, despite the marked benefits it afforded to patients with heart failure, confirmed also in experimental animal models [Mulder, P. et al., Abst P2510], ivabradine did not translate into cost-effectiveness [Wynn, G.J. et al., Abst P2515]. As additional observations, treatment with perhexiline was shown to improve symptoms in patients with heart failure and refractory angina, renewing the interest in old drugs [Phan, T. et al., Abst P2494], but in exactly the same context, patients with ischemic cardiomyopathy and angina, improvements in exercise capacity and cardiac function were obtained with the novel cardiac myosin activator CK-1827452 [Greenberg, B. et al., Abst P2519; Goldman, J.H. et al., Abst P2512] (Fig. 6). Moreover, intracoronary infusion of the cytoprotectors Neoton or Mexicor prior to recanalization for acute myocardial infarction significantly improved left ventricular function and the clinical outcomes [Iosseliani, D. et al., Abst 2826]. On the contrary, tranilast showed no activity against remodeling and mortality after chronic, extensive myocardial ischemia in experimental animals [Betge, S.& Figulla, H.R., Abst P2522].
Fig. 6. Percent of patients reaching stage 4 or above during exercise tolerance testing after treatment with CK-1827352 (oral daily dosing for 7 days after an initial 20-hour intravenous infusion) or placebo [Greenberg, B. et al., Abst P2519].
Adjuvant therapies may also have a role, as exemplified by the improved left ventricular ejection fraction demonstrated in patients receiving chronic low-dose epoetin beta therapy after percutaneous coronary intervention [Bergmann, M. et al., Abst 2020].
In the preclinical, experimental arena, the mitochondrial translocator protein blocker TRO-40303 was confirmed active in preventing ischemia/reperfusion injuries and promoting functional recovery partly through prevention of mitochondrial permeability transition pore opening, suggesting putative usefulness as cardioprotectant [Schaller, S. et al., Abst P1384; Augeul, L. et al., Abst P4491], whereas granulocyte colony-stimulating factor alone or combined with the CD26 inhibitor diprotin A enhanced cell homing and improved cardiac function after an experimental myocardial infarction [Theiss, H.D. et al., Abst 2915; Brunner, S. et al., Abst 2912] and prevented arterial remodeling after angioplasty [Zhang, X.H. et al., Abst P4503], but adversely reduced the myocardial repolarization reserve and had no benefit on arrhythmia in models of heart failure [Milberg, P. et al., Abst P4640]. Other compounds that were shown to possess cardioprotective activity by limiting infarct size and/or preventing ischemia/reperfusion injuries in experimental models included the calpain inhibitor MDL-28170 [Sartorio, C.L. et al., Abst P1387], the cannabinoid receptor blocker R1-methanandamine [Kaseeckert, S.A. et al., Abst P1394], the adenosine A2b receptor blocker MRS-1754 [Simonis, G. et al., Abst P4502], the bradykinin B2 receptor blocker icatibant [Koike, M.K. et al., Abst P4498], the glycogen synthase kinase-3 inhibitor SB-216763 [Couvreur, N. et al., Abst P4494] and intravenous immunoglobulin [Ueno, K. et al., Abst 5143], while both rilonacept [Abbate, A. et al., Abst P3367] and the myeloid differentiation factor-88 inhibitor IMG-2005 [Van Tassell, B. et al., Abst P2124] attenuated ventricular remodeling and cardiomyocyte apoptosis after an experimental myocardial infarction without affecting scar formation; the contrary was true for ketamine, which at high but not low doses abolished the cardioprotective effect of diazoxide preconditioning [Muntean, D. et al., Abst P1395]. Prevention of ischemia/reperfusion injuries was also obtained with the organ-preserving solution custodial-n [Loganathan, S. et al., Abst P2324].
Drug-eluting stents
Although with differences in individual trial results, the burden of available data justifies the use of drug-eluting stents as superior to bare metal stents regarding clinical outcomes, despite a risk for late thrombosis, hypercoagulability, systemic and vascular inflammation, stent fracture, delayed neointimal formation and incomplete stent apposition and poorer results in higher risk populations, including notably obese or diabetic patients or subjects with atrial fibrillation, without meaningful differences between sirolimus- and paclitaxel-eluting stents [Akin, I. et al., Abst P646; Flores Rios, X. et al., Abst P641; Willich, S. et al., Abst P642; Toelg, R. et al., Abst P643; Tiroch, K. et al., Abst P644; Wang, Z.J. et al., Abst P651; Kimura, T. et al., Abst P656; Marin Ortuno, F. et al., Abst P657; Nakamura, S. et al., Abst P672; Koch, W. et al., Abst P670; Kadota, K. et al., Abst P668; Bental, T. et al., Abst P667; Akin, I. et al., Abst P666; Valenti, R. et al., Abst P665; Hosogi, S. et al., Abst P691; Mehilli, J. et al., Abst P684; Kimura, M. et al., Abst P688; Takahashi, S. et al., Abst P689; Otsuru, S. et al., Abst P690; Zuern, C.S. et al., Abst P695; Kitahara, H. et al., Abst P693; Mukawa, H. et al., Abst P692; Gonzalo Lopez, N. et al., Abst 897; Ito, T. et al., Abst P1366; Nakamura, S. et al., Abst P1467; Flores Rios, X. et al., Abst P1499; Flores Rios, X. et al., Abst P1500; Combescure, C. et al., Abst P1492; Steigerwald, K. et al., Abst P1512; Atary, J.S. et al., Abst P1506; Habara, M. et al., Abst P1505; Siddique, A. et al., Abst P1504; Fukushima, K. et al., Abst P1503; Gerber, R.T. et al., Abst P1544; Miyamoto, Y. et al., Abst P1537; Arfanakis, D.A. et al., Abst P1547; Yamaguchi, K. et al., Abst P1558; Balakrishnan Nair, S. et al., Abst P1554; Choi, B.J. et al., Abst P1553; Assali, A.E.L.R. et al., Abst P1550; Patsa, C. et al., Abst P2321; Boudriot, E. et al., Abst 2928; Byrne, R. et al., Abst 2929; Mehilli, J. et al., Abst 2931; Pracon, R. et al., Abst 2933; Zhang, F. et al., Abst 2927; De La Torre Hernandez, J.R. et al., Abst 2926; Nasu, K. et al., Abst 2925; Fajadet, J. et al., Abst 2923; Toutouzas, K. et al., Abst P2955; Schmidt Pedersen, S. et al., Abst P3169; Sato, T. et al., Abst P3188; Toutouzas, K. et al., Abst P3204; Sorop, O. et al., Abst P3205; Van Der Heuvel, M. et al., Abst P3210; Bergheanu, S.C. et al., Abst P3224; Nasu, K. et al., Abst 3562; Miyoshi, N. et al., Abst 3563, Gyoengyoesi, M. et al., Abst P4032; Gyongyosi, M. et al., Abst P4039; Tonino, P.A.L. et al., Abst P4040; Addad, F. et al., Abst P4042; Nakamura, S. et al., Abst P4043; Katritsis, D. et al., Abst P4044; Testa, L. et al., Abst P4047; Alahmar, A.E. et al., Abst P4041; Saitou, N. et al., Abst P4038; Schiele, F. et al., Abst P4037; Ribera, A. et al., Abst P4036; Zimarino, M. et al., Abst P4050; Guerin, P. et al., Abst P4056; Lu, C. et al., Abst P4055; Ferenc, M. et al., Abst P4053; Liu, Y. et al., Abst P4052; Atary, J.Z. et al., Abst P4082; Dibra, A. et al., Abst P4705; Dibra, A. et al., Abst P4711; Testa, L. et al., Abst P4710; Kim, U. et al., Abst P4709; Palmerini, T. et al., Abst P4723; Rubartelli, P. et al., Abst 5195, Jo, S.H. et al., Abst P5266; Leibungdut, G. et al., Abst P5289] (Fig. 7). Novel stents for which favorable clinical results were described during this year’s European Society of Cardiology meeting in Barcelona included tacrolimus- [Van Beusekom, H.M.M. et al., Abst P3211], everolimus- [Onuma, Y. et al., Abst P4030], zotarolimus- [Kim, J.S. et al., Abst P1511; Cremers, B. et al., Abst P3206], bevacizumab- [Toutouzas, K. et al., Abst P647] and biolimus A9-eluting stents [Chevalier, B. et al., Abst P671; Fath-Ordoubadi, F. et al., Abst P2115; Wykrykowska, J.J. et al., Abst P4045; Danzi, G.B. et al., Abst P4735; Patsa, C. et al., Abst P4730; Dupouy, P. et al., Abst P4729; Kim, K.H. et al., Abst P4728; Nakamura, S. et al., Abst P4726; Bernardo Garcia, E. et al., Abst 4958; Wakatsuki, T. et al., Abst 4957; Hong, Y.J. et al., Abst 4988]. In four comparative studies in patients with left main coronary artery disease, very long coronary artery stenosis, small coronary artery lesions and chronic total occlusion, respectively, sirolimus-, paclitaxel-, zotarolimus- and everolimus-eluting stents were equieffective regarding procedural success and major adverse cardiovascular event rates at 30 days, but target lesion revascularization rates at nine months and major adverse cardiovascular event rates at two months were lower with the sirolimus- and everolimus-eluting stents, and restenosis rates at nine months in one study and target vessel revascularization in the other were lower with everolimus-eluting stent in two of the studies [Nakamura, S. et al., Abst P4048; Nakamura, S. et al., Abst P4708; Nakamura, S. et al., Abst P4713; Nakamura, S. et al., Abst P4712] (Fig. 8). An additional study also suggested superiority for sirolimus- compared to zotarolimus-eluting stent [Jensen, L.O. et al., Abst P4720] and other studies were unable to demonstrate differences comparing sirolimus-, paclitaxel- and zotarolimus-eluting stents [Tonino, P.A.L. et al., Abst P4040]. Add to this that in the in vitro setting, everolimus was devoid of any impact on cardiomyocyte apoptosis during hypoxia, suggesting no contribution to reperfusion injury [Hynes, B. et al., Abst P5265], whereas sirolimus decreased and paclitaxel increased vascular endothelial growth factor expression in coronary artery smooth muscle cells, suggesting opposed effects on re-endothelization [Katsaros, K. et al., Abst P5376]; according to additional studies, sirolimus may induce tissue factor and promote arterial thrombosis at clinically relevant concentrations [Camici, G.G. et al., Abst P5385], but the negative effect of the agent on endothelial progenitor cells was counteracted by silymarin, a flavonolignan complex from milk thistle [Naruszewicz, M. et al., Abst P5723]. As an additional alternative, nonstent paclitaxel-eluting balloon catheters [Cremers, B. et al., Abst P1516], an antiplatelet polymer stent containing triflusal and eluting simvastatin [Casani, L. et al., Abst P3207] and a paclitaxel-eluting balloon aortic valve tested positive in experimental models of valve replacement for aortic stenosis [Gyoengyoesi, M. et al., Abst P3791].
Fig. 7. Death and major adverse cardiovascular event rates over a mean period of 41.9 months in patients receiving drug-eluting or bare metal stents [Balakrishnan Nair, S. et al., Abst P1554].
Fig. 8. Comparative outcomes of sirolimus-, paclitaxel-, zotarolimus- and everolimus-eluting stent implantation in patients with left main coronary artery disease. TLR, target lesion revascularization; MACE, major adverse cardiovascular events [Nakamura, S. et al., Abst P4048].
STROKE
Tirofiban did not fare superior to aspirin in improving the National Institutes of Health Stroke Scale or the Rankin’s Scale scores in patients with ischemic stroke in a randomized trial that concluded on the safety and efficacy of antiplatelet therapy started within hours of cerebral ischemia [Torgano, G. et al., Abst 151].
PULMONARY HYPERTENSION
According to clinical data discussed in the Fira Gran Via 2, where this year’s meeting was held, the usefulness of sildenafil against pulmonary hypertension extended to operable and inoperable chronic thromboembolic pulmonary hypertension, with benefits on exercise capacity and hemodynamic parameters [Leci, E. et al., Abst P722], and also to subgroups of patients with porto-pulmonary hypertension or pulmonary hypertension associated with HIV infection [Negro, L. et al., Abst P1598]. In children with acquired pulmonary hypertension, the agent improved hemodynamics as well as endothelial injuries and P-selectin levels [Kotby, A.A. et al., Abst P1601]. From a mechanistic point of view, experimental models of pulmonary hypertension were used to demonstrate the endothelial cell protection offered by sildenafil [Yip, H.K. et al., Abst P3100]. A related drug, tadalafil, was also shown to improve exercise performance and quality of life and to prevent deterioration in patients with pulmonary hypertension [Pepke-Zaba, J. et al., Abst 2672; Oudiz, R. et al., Abst 5173], while mechanistic data on a third compound, vardenafil, demonstrated improvements in arterial stiffness and wave reflection in patients with erectile dysfunction, confirming a favorable impact on the cardiovascular tree [Terentes-Printzios, D. et al., Abst P5721].
Novel findings with bosentan confirmed its efficacy in the treatment of Eisenmenger’s syndrome [Kaya, M.G. et al., Abst P4808] and revealed an effect of the agent in improving pulmonary microvascular endothelial function [Ilsar, R. et al., Abst P726] and prolonging survival, though the effect was more marked in patients with congenital heart disease-associated or chronic thromboembolic pulmonary hypertension than in patients with disease secondary to collagen vasculopathy or idiopathic pulmonary hypertension, even if survival benefits were also demonstrated in these cases [Vis, J.C. et al., Abst 5174; Beghetti, M. et al., Abst 5176]. Furthermore, a combination of bosentan and sildenafil was described as safe and well tolerated and was reported to significantly improve exercise tolerance and clinical status in a further study [Romeo, E. et al., Abst 5181]. The effectiveness of sitaxsentan was corroborated in novel analyses of the STRIDE-1 and -2 studies, which demonstrated a correlation between hemodynamic improvements and changes in patients’ functional class, indicating potential for early therapy aimed at preventing/delaying deterioration [Galie, N. et al., Abst P1579]. Further studies confirmed the long-term survival benefit of sitaxsentan, with 77.5% of 145 patients treated with doses of 100 mg surviving for at least three years, a rate that was numerically higher for patients with idiopathic pulmonary hypertension (82%) than for those with connective tissue disease-associated pulmonary hypertension (67%) [Galie, N. et al., Abst P1589].
Data from clinical studies corroborating the benefits of treprostinil on functional class, exercise performance and hemodynamics in patients with pulmonary hypertension were also presented at the meeting [Sadushi, R. et al., Abst 5177], whereas results with iloprost showed proangiogenic effects and exerted favorable effects on endothelial progenitor cell survival and cytokine release, at least in the in vitro laboratory [Di Stefano, R. et al., Abst P5512; Di Stefano, R. et al., Abst P5514].
As an additional issue related to pulmonary hypertension, as well as other conditions in which anticoagulation is indicated, the involvement of CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) gene polymorphisms on the metabolism and maintenance dose adjustments of warfarin in the management of pulmonary hypertension, atrial fibrillation or other conditions requiring chronic anticoagulation was confirmed in novel investigations [Baptista, R. et al., Abst P734; Mikheeva, Y.A. et al., Abst P2439; Azenha Balhau Jorge, E. et al., Abst 2677]. Polymorphisms of both genes had also a marked impact on acenocoumarol dose requirements, which also depended upon the CYP4F2 genotype [Perez-Andreu, V. et al., Abst 1953].
CARDIOVASCULAR RISK FACTORS
Hypertension
Although the diuretics were recently “rescued” because of their favorable clinical effectiveness in the management of hypertension, not all drugs within this group fare equally well. For example, combinations of angiotensin receptor blockers with chlorthalidone resulted in lowered rates of hospitalization and emergency care utilization than similar combinations with hydrochlorothiazide, as validated by a registry of 17,775 patients [Sun, S. et al., Abst P1738] (Fig. 9). As a note worth mentioning, also related to diuretic therapies, the potential of prolonged-release torasemide against myocardial fibrosis in patients with hypertensive chronic heart failure is being analyzed in the TORAFIC study, as announced in a poster presentation during the meeting [Gonzalez Juanatey, J.R. et al., Abst P4254].
Fig. 9. Hospitalization and urgent care rates within two years of treatment with chlorthalidone or hydrochlorothiazide combined with angiotensin receptor blockers [Sun, S. et al., Abst P1738].
Neither metoprolol nor propranolol affected fractional flow reserve or the microvascular resistance index in patients with normal left ventricle but intermediate coronary artery stenosis [Sarno, G. et al., Abst P1535], although pretreatment with metoprolol reduced infarct size in experimental models by decreasing reperfusion injury [Ibanez, B. et al., Abst P2113]. Also among beta-blockers, use of nebivolol combined with trimetazidine offered clinical efficacy and prevented or attenuated left ventricular hypertrophy in patients with isolated systolic hypertension, stable effort angina and documented coronary artery disease [Vatinian, S. et al., Abst P1726].
Surprisingly, few major findings related to calcium channel blockers in the management of hypertension were discussed during ESC 2009, although the drugs are still under very active research according to recent meetings on hypertension (American Society of Hypertension; European Meeting on Hypertension). However, a trial confirming the benefits of nifedipine-GITS alone or combined with renin-angiotensin system blockers in reducing cardiovascular morbidity in hypertensive patients [Meredith, P. et al., Abst P4509], a trial revealing therapeutic potential for combinations of azelnidipine with angiotensin receptor blockers in the hypertensive elderly [Doi, M. et al., Abst 5005] and a study on the fixed combination of amlodipine and atorvastatin, which confirmed benefits on endothelial function, adiponectin levels and insulin sensitivity larger than those obtained with either monotherapy [Koh, K. et al., Abst P4263], were discussed.
Both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were confirmed to prevent new-onset diabetes compared to alternative antihypertensive agents in a pooled analysis of data from 100,850 patients from 18 randomized, controlled trials [Al-Mallah, M. et al., Abst 1822], and both drug families, at least in the case of quinapril and losartan, improved coronary flow reserve in patients with new-onset hypertension [Stamatelopoulos, K. et al., Abst P2534]. In addition, imidapril but not candesartan improved insulin sensitivity and the fibrinolytic balance in patients with moderate hypertension, both agents showing comparable blood pressure-lowering activity [Fogari, R. et al., Abst P1737], whereas high-dose perindopril improved left ventricular diastolic function in patients with heart failure and reduced compliance [Adamyan, K.G. et al., Abst 5048].
Attenuation of cardiac fibrosis resulted from treatment with losartan in experimental animals submitted to chronic endurance training [Gay-Jordi, G. et al., Abst P557]. In the case of valsartan, the Jikei Heart Study confirmed the significant prevention of cardiovascular events regardless of gender [Yoshida, H. et al., Abst P5479], a study in diabetic subjects undergoing percutaneous interventions for coronary artery disease demonstrated improvements in hyperglycemia and hyperinsulinemia after an oral glucose tolerance test, suggesting benefits in the overall treatment results in the presence of impaired glucose tolerance [Koga, S. et al., Abst P1452], while a second study revealed equiefficacy compared to amlodipine regarding blood pressure and cardiovascular events, but superiority of valsartan regarding urinary albumin:creatinine ratio and cardiac sympathetic activity, suggesting higher cardionephroprotective potential for the angiotensin receptor blocker [Narumi, H. et al., Abst 5001]. While confirmed to attenuate the increase in blood pressure upon acute exposure to high altitude [Bilo, G. et al., Abst P3807], telmisartan inhibited renal collecting duct protein content in experimental high angiotensin II states more effectively than ramipril [Toma, I. et al., Abst P1431]. Furthermore, preliminary data suggesting potential for telmisartan in preventing epirubicin cardiotoxicity in cancer patients was presented from a placebo-controlled study [Piras, A. et al., Abst P2507]. Turning to irbesartan, the only new information reported this year was the confirmation of its superior blood pressure-lowering activity at rest and during exercise compared to diltiazem [Liakos, C. et al., Abst P5711] and the conclusion of a mechanistic case-control study that revealed a preventive effect against prothrombotic activation of monocytes during atrial fibrillation [Hammwoehner, M. et al., Abst P4186], whereas observations from the I-Preserve study suggested no impact of the agent on overall or mode-specific mortality in patients with heart failure, in spite of preserved ejection fraction [Zile, M.R. et al., Abst 5049]. In the in vitro laboratory, irbesartan, like enalapril and angiotensin1-7 showed anti-ionic remodeling activity during rapid atrial pacing, although through different mechanisms of action [Liu, E. et al., Abst 5105]. In the case of olmesartan, a study revealed that switching from candesartan or valsartan in patients with hypertension resulted in decreased left ventricular mass index and reduced angiotensin II levels [Tsutamoto, T. et al., Abst P4262].
Add-on aliskiren did not result in tolerability concerns in elderly and very elderly patients with heart failure receiving optimized therapy [Solomon, S.D. et al., Abst 1105].
In addition to the prior findings, a mechanistic study addressing the role of the fermented milk polypeptides Val-Pro-Pro and Ile-Pro-Pro in the management of hypertension found no evidence of inhibition of the renin-angiotensin system in humans, although inhibition of sympathetic activity was accompanied by modest blood pressure reduction [Usinger, L. et al., Abst P3800].
Glucose intolerance and diabetes
Although tighter glycemic control did not translate into lower mortality or major adverse cardiovascular event rates, according to a meta-analysis of five randomized trials including 27,082 patients [Ooi, K.Y. et al., Abst 1824], diabetes and glucose intolerance are independent cardiovascular risk factors that need to be addressed in the context of all additional modifiable risk factors for managing the risk of micro- and macrovascular disease. In this respect, data from alternative analyses was presented offering robust indication that lowering hemoglobin A1c by 1% over a five-year period significantly reduced coronary events [Ray, K.K. et al., Abst 1823].
Among the sulfonylureas, glibenclamide and tolbutamide were associated with increased risk of cardiovascular death or repeated myocardial infarction compared to metformin in diabetic patients undergoing early percutaneous coronary interventions [Joergensen, C.H. et al., Abst P1439]. However, poorer outcomes in terms of revascularization and disease progression in patients undergoing percutaneous coronary procedures were also demonstrated in diabetic individuals on insulin therapy [Castro, R. et al., Abst P1456].
The alpha-glucosidase inhibitor voglibose was discussed in a poster presentation summarizing an experimental study in which the agent improved left ventricular function and reduced the size of the ischemic injury after a myocardial infarction. The effect was related to activation of the glucagon-like polypeptide-1 receptor and the phosphatidyl triphosphate kinase pathway [Iwasa, M. et al., Abst P2478]. An alternative alpha-glucosidase inhibitor, miglitol showed potential for attenuating myocardial ischemia in diabetic patients with coronary artery disease [Kawamura, I. et al., Abst P4572].
Edema-free weight gain during pioglitazone therapy was identified as an independent predictor of improved survival according to novel post-hoc analyses of the PROactive study [Doehner, W. et al., Abst P1441], while mechanistic observations with the agent revealed an effect in significantly reducing biomarkers of monocyte activation in patients with acute coronary syndrome [Zhang, W.P. et al., Abst P2123] and, as a result of improved insulin sensitivity, in increasing arterial baroreflex sensitivity and decreasing sympathetic drive during a myocardial infarction in patients with type 2 diabetes [Yokoe, H. et al., Abst P2127]. In relation with that, a study in patients undergoing percutaneous coronary interventions revealed a lower incidence of creatine kinase-MB and cardiac troponin I elevation in patients treated with pioglitazone than in control patients not treated with the thiazolidinedione, despite similar glycemic control in both groups [Okawa, K. et al., Abst P4520]. New observations with rosiglitazone demonstrated a favorable impact on atheroma volume compared to glipizide in patients with type 2 diabetes [Garcia-Garcia, H.M. et al., Abst P1735] (Fig. 10). Furthermore, local delivery of rosiglitazone in experimental models of in-stent stenosis resulted in changes in gene expression toward a profile suggesting reduced intracoronary cell invasion and proliferation [Pels, K. et al., Abst P3212].
Fig. 10. Change in atheroma volume during 18 months of treatment with rosiglitazone or glipizide [Garcia-Garcia, H.M. et al., Abst P1735].
Among incretin-based therapies, liraglutide was shown to improve the cardiovascular risk profile in patients with type 2 diabetes by improving lipid, brain natriuretic peptide and C-reactive protein levels [Plutzky, J. et al., Abst P5247] (Fig. 11). Add-on or initial treatment with saxagliptin combined with metformin significantly lowered hemoglobin A1c levels and improved glycemic control with good tolerability in patients with type 2 diabetes [Gurieva, I. et al., Abst P1444] (Fig. 12), whereas inhibition of dipeptidyl peptidase-4 with sitagliptin improved global and regional left ventricular wall responses to dobutamine stress in patients with coronary artery disease [Read, P.A. et al., Abst P4506].
Fig. 11. Percent change in brain natriuretic peptide, highly sensitive C-reactive protein and apolipoprotein B levels after treatment with liraglutide, comparative antidiabetic therapies and placebo in a meta-analysis of 3 major trials [Plutzky, J. et al., Abst P5247].
Fig. 12. Change in hemoglobin A1c levels after 24 weeks of treatment in patients receiving metformin plus saxagliptin or placebo [Gurieva, I. et al., Abst P1444].
Dyslipidemia
Although still largely underused, at least in high-risk populations such as patients with diabetes [Dominguez, H. et al., Abst P1440; Korsgaard Thomsen, K. et al., Abst P3136], use of statins has been associated with primary and secondary cardiovascular prevention [Koval, O. et al., Abst P2988; Brugts, J.J. et al., Abst P3122], with novel data demonstrating a favorable impact on troponin I levels after a percutaneous coronary intervention that was more marked in patients with elevated C-reactive protein levels [Auguadro, C. et al., Abst P655]. Furthermore, rosuvastatin, which combined with plasmapheresis showed remarkable effect on total and LDL-cholesterol and lipoprotein(a) [Salchenko, V. et al., Abst P4511] and combined with ramipril showed synergistic atheroma volume-reducing activity [Han, S.H. et al., Abst P4535], was able to prevent endothelial dysfunction secondary to ischemia/reperfusion injuries independent of any effect on lipids [Liuni, A. et al., Abst P1731] and, as opposed to allopurinol, improved endothelial progenitor cell counts in patients with failing hearts [Andreou, I. et al., Abst 5044], whereas discontinuation of the statin in patients with heart failure resulted in rapid deterioration of endothelial function, the regenerative capacity of which was reduced in these patients but markedly improved during treatment [Beck, E.B. et al., Abst P2480]. In the case of simvastatin, pretreatment was associated with reduced thrombin generation and platelet aggregation in subjects suffering from an acute ST segment-elevated myocardial infarction [Undas, A. et al., Abst P5303], and experimental observations revealed an effect in attenuating cardiomyocyte hypertrophy through a beneficial impact on the S6 kinase-dependent pathway [Guzun, L. et al., Abst P1409]. On the contrary, although atorvastatin lowered oxidized LDL, adrenaline and blood pressure in normolipidemic hypertensive subjects [Kuklinska, A. et al., Abst P5712], improved inflammation and function of the left ventricule in patients with dilated cardiomyopathy [Bielecka-Dabrowa, A. et al., Abst P2505] as well as metabolic syndrome-associated cardiovascular risk factors, at least when administered at high (80-mg) doses [Deedwania, P. et al., Abst P3970], boosted myocardial perfusion in hypercholesterolemic conditions [Lario, F.C. et al., Abst P4748], increased endothelial progenitor cell counts and decreased microRNA-221/222 levels [Minami, Y. et al., Abst 2817], especially when reloaded prior to a percutaneous coronary intervention [De Caterina, R. et al., Abst P3175], reduced the risk of atrial fibrillation in patients with ischemic heart failure [Lopatin, Y.M. et al., Abst 2783], prevented periprocedural myocardial infarction during percutaneous coronary interventions [Veselka, J. et al., Abst P3219; Gatto, L. et al., Abst P4534] and inhibited transforming growth factor-beta1-induced endoglin expression in cardiac fibroblasts [Shyu, K.G. et al., Abst P3379], atorvastatin did not reduce the risk of atrial fibrillation during coronary artery bypass graft surgery [Melina, G. et al., Abst P407] and pretreatment with the statin did not result in improved cardiac function or microvascular perfusion, nor did it reduce infarct size upon subsequent myocardial infarction [Post, S. et al., Abst P2136], although patients with the -786TT variant of the endothelial nitric oxide synthase gene may derive additional benefit from early treatment, at least with atorvastatin and simvastatin [Lutay, Y.A. et al., Abst P2135]. Interestingly, low-dose atorvastatin did not protect, and in fact further deteriorated systolic performance in animal models of doxorubicin-induced cardiotoxicity [Kilter, H. et al., Abst 244], but was associated with reduced expression of L-type calcium and sodium channels in the atria, without any impact on potassium channels [Eick, C. et al., Abst P574]. Nonetheless, intensive, high-dose therapy with atorvastatin in patients with myocardial infarction was associated with a net gain in life years and quality-adjusted life years that was superior to that resulting from standard simvastatin therapy [Rublee, D. et al., Abst 4978] (Fig. 13) and in models of septic cardiomyopathy prevented systolic dysfunction [Robati, R. et al., Abst 5054]. The agent also improved severe myxomatous mitral regurgitation in rabbits [Rajamannan, R. et al., Abst P5563], induced regression of bicuspid aortic stenosis in ex vivo studies [Rajamannan, R. et al., Abst P5566] and improved coxsackievirus B3-induced myocarditis [Wang, G.G. et al., Abst P5596]. Turning to novel statins, the noninferiority of pitavastatin compared to simvastatin and atorvastatin in hypercholesterolemic or dyslipidemic patients was demonstrated in a 52-week study, which underlined the beneficial impact of the novel statin on LDL-cholesterol and other atherogenic markers [Hounslow, N. & Budinski, D., Abst P4624] (Fig. 14); pitavastatin was also demonstrated to stabilize vulnerable coronary plaques independent of effect on lipids in the TOGETHAR trial [Hirayama, A. et al., Abst P4060], while additional studies ruled out a pharmacokinetic interaction with CYP3A4 inhibitors [Nakagawa, S. et al., Abst P5413]. Also in relation to statin therapy, coenzyme Q10 supplementation was noted to improve left ventricular dysfunction during due to decreased cholesterol and coenzyme Q10 by these agents [Fedacko, J. et al., Abst P2255]; this could be one of the mechanisms explaining the beneficial increase in heart rate variability noted in studies with rosuvastatin [Zacharis, E.A. et al., Abst P2257; Zacharis, E.A. et al., Abst P2259].
Fig. 13. Incidence of cardiovascular events in the 5-year IDEAL study in patients treated with atorvastatin 40-80 mg or simvastatin 20-40 mg after a myocardial infarction [Rublee, D. et al., Abst 4978].
Fig. 14. Percent of patients at NCEP target after treatment with pitavastatin or control statins (simvastatin, atorvastatin) in two independent comparisons [Hounslow, N. & Budinski, D., Abst P4624].
In case of failure, add-on ezetimibe has improved the antihypercholesterolemic effect of statins, with ezetimibe/simvastatin proving superior to high-dose atorvastatin or rosuvastatin in a trial summarized as a poster presentation during the meeting [Robinson, P.J. et al., Abst P1734] (Fig. 15). Ezetimibe/atorvastatin proved more effective than uptitrated atorvastatin in lowering atherosclerotic lipid and C-reactive protein levels [Leiter, L. et al., Abst P2254], while addition of colesevelam to an ezetimibe/statin combination further improved the lipid profile in patients not at goal [Huijgen, R. et al., Abst P2244] (Fig. 16). In addition, although ezetimibe/simvastatin was superior to atorvastatin monotherapy in improving lipid levels, only atorvastatin showed a favorable effect on central pulse wave velocity [Lee, Y.S. et al., Abst P5410]. Besides statins, other therapeutic alternatives have become available for the management of dyslipidemia, including niacin, a drug usually not used over the long term and not uptitrated to recommended maintenance doses in the real-world setting [Krobot, K.J. et al., Abst 3541], the efficacy of which was not impaired by concomitant aspirin [Thakkar, R. et al., Abst P2287] but that proved effective in preventing proatherogenic marker expression [Stach, K. et al., Abst P4636]; niacin/laropiprant effectively managed dyslipidemia in diabetic and other high-risk patients [Ambegaonkar, B. et al., Abst P2250], although most patients required antidiabetic intensification due to manageable but untoward glycemic effects [Maclean, A. et al., Abst P1733] (Fig. 17), while niacin/simvastatin lowered atherogenic lipids more effectively than atorvastatin monotherapy [Insull, W. et al., Abst P2246], reduced cardiovascular risk more effectively than statin monotherapy in dyslipidemic patients [Simko, R. et al., Abst P2249] and proved superior to ezetimibe/simvastatin in preventing cardiovascular events, while incurring lower costs [Simko, R. et al., Abst P2247]. A different approach is the use of darapladib, a direct lipoprotein-associated phospholipase A2 inhibitor, which in the IBIS-2 study prevented necrotic core expansion and reduced necrotic core volume in patients with coronary plaques compared to placebo [Serruys, P.W. et al., Abst P1742]. Recombinant HDL-Milano, which showed similar effects on reverse cholesterol transport but higher antiinflammatory activity than native HDL particles [Ibanez, B. et al., Abst 892], is another potential option for the management of lipid abnormalities. In that context, the apolipoprotein A1 expression enhancer RVX-208 increased HDL while attenuating inflammation in experimental animal models [Wong, N.C.W. et al., Abst P5422] and the apolipoprotein A1 mimetic L-4F was able to revert structural and functional abnormalities of diabetic cardiomyopathy through upregulation of heme oxygenase-1 [Vecoli, C. et al., Abst P2475], opening additional research possibilities into novel therapeutic targets.
Fig. 15. Percent of patients at LDL-cholesterol goal after treatment with ezetimibe 10 mg/simvastatin 40 mg, atorvastatin 40 mg or rosuvastatin 5-10 mg for 6 weeks [Robinson, P.J. et al., Abst P1734].
Fig. 16. Percent of patients with 15% drop in LDL-cholesterol levels upon addition of colesevelam or placebo to maximal doses of ezetimibe/statins [Huijgen, R. et al., Abst P2244].
Fig. 17A. Change in lipid levels in patients receiving niacin/laropiprant or placebo for 12 weeks [Maclean, A. et al., Abst P1733].
Fig. 17B. Change in hemoglobin A1c in patients receiving niacin/laropiprant or placebo for 12 weeks [Maclean, A. et al., Abst P1733].
DIET AND DIETARY SUPPLEMENTS AND CARDIOVASCULAR RISK
Further data from the GISSI-Heart Failure study corroborated the preventive effect of omega 3 polyunsaturated fatty acids against heart failure-related morbidity and mortality, including notably arrhythmia [Marchioli, R. et al., Abst 1104; Finzi, A. et al., Abst P1660; Marchioli, R. et al., Abst P2495; Marchioli, R. et al., Abst P2518; Marchioli, R. et al., Abst P4206] and additional studies confirmed the benefits of early treatment with the supplement [Haberka, M. et al., Abst P2239], which also resulted in a favorable impact on diastolic function [Metallinos, G. et al., Abst P4919] and coronary plaque remodeling [Domei, T. et al., Abst 2642] and improvements in insulin resistance and systemic inflammation [Kim, J.Y. et al., Abst 2673], although without noticeable effects on soluble cell adhesion molecules and C-reactive protein levels, albeit improving P-selectin levels [Eschen, O. et al., Abst P5702]. Note that mechanistic experimental studies revealed the potential of omega 3 fatty acids for inhibiting inward-rectifying currents in atrial myocytes [Borchard, R. et al., Abst P4197], which could be related to the antiarrhythmic potential seen in clinical trials. The cytochrome P450-dependent metabolites of eicosapentaenoate and docosahexaenoate, 17,18-epoxyeicosatetraenoate and 19,20-epoxydocosapentaenoate showed cardioprotective activity contributing to the overall antiarrhythmic effects of these compounds [Fischer, R. et al., Abst P406]. In addition, docosahexaenoate attenuated insulin-induced long-chain fatty acid transporter (CD36) expression in endothelial cells, suggesting benefits in the treatment of diabetic microvascular disease [Madonna, R. et al., Abst P464]. Other fatty acids may also have a role in cardiovascular prevention, as exemplified by the attenuated atherothrombosis demonstrated after administering alpha-linolenic acid in experimental animal models [Lohmann, C. et al., Abst P4593].
Another natural compound commonly used as a spice in many cultures, curcumin was shown to prevent post-myocardial infarction heart failure in experimental animal models, with benefits on left ventricular structure and function [Morimoto, T. et al., Abst P2487], whereas the lipoxygenase-inhibiting quercetin improved renal function and long-term prognosis after ST segment-elevated myocardial infarction [Kozhukhov, S. et al., Abst P2959]. A further natural compound, resveratrol improved survival in models of heart failure through activation of the histone/protein deacetylase SIRT1 and upregulation of manganese-dependent superoxide dismutase [Kuno, A. et al., Abst P2476]. The olive oil component oleuropein was also shown beneficial, by preventing doxorubicin-induced heart failure in additional experimental studies [Andreadou, I. et al., Abst P2492], an effect that was also obtained by administration of brain-derived natriuretic peptide [Di Marco, A.P. et al., Abst P3392]. On the contrary, supplementation with folate and cyanocobalamin in two large trials in patients with coronary artery disease did not prevent cardiovascular events or cardiovascular death [Ebbing, M. et al., Abst P1274], and in fact a meta-analysis “provided reliable evidence to refute” a role of homocysteine on the risk of coronary artery disease or stroke, and explained the lack of efficacy of supplementation with folate and vitamins B [Clarke, R., Abst 3534]. However, riboflavin showed a beneficial effect by lowering blood pressure in patients with the C677T polymorphism of the methylenetetrahydrofolate reductase gene [Purvis, J.A. et al., Abst P3804].
Also in the setting of dietary approaches to cardiovascular risk management, data was presented revealing significant improvements in glycemic control with legume intake [Kendall, C.W. et al., Abst 3529], while chronic, moderate consumption of coffee was related to a lower likelihood for developing diabetes [Tyrovolas, S. et al., Abst 3539], neither coffee not caffeine being related to arrhythmia, according to an outpatient survey and a study in healthy women [Yamada, A.T. et al., Abst P4172; Conen, D. et al., Abst P5445]. Moreover, to the known benefits of red wine, at least in moderate quantities, novel data revealed an effect of both red and white wine in increasing endothelial progenitor cell count and function in diabetic individuals [Seck, C. et al., Abst P5448], although not all alcoholic beverages may act in a similar way, and in fact an overall analysis of the impact of alcohol at large on cardiovascular health, performed in India and hence probably not related specifically to wine, suggested an increased risk for coronary artery disease [Roy, A. et al., Abst P5449]. On the contrary, high intake of cola beverages resulted in increased unstable atheroma and decreased endothelial progenitor cell numbers, hindering survival of experimental animals [De Nigris, F. et al., Abst P4598].
HEART TRANSPLANTATION
Used as immunosuppressants for heart transplantation, tacrolimus and ciclosporin showed no differential impact on subclinical inflammation and oxidative stress, which were shown to be elevated for up to one year after transplantation, reaching maximum levels within 2-4 weeks [White, M. et al., Abst P2523]. In additional studies, ciclosporin depressed muscular mitochondrial energetic pathways [Mettauer, B. et al., Abst P2328] and limited the favorable immunological activity of allogeneic perivascular endothelial cell implantation in experimental animals [Methe, H. et al., Abst P2323]. As alternative antirejection strategies, IBP, a synthetic peptide that disrupts the calcineurin nuclear factorAT cascade through inhibition of calcineurin nuclear import, was able to suppress T-cell activation in in vitro assays [Gebhardt, C. et al., Abst P3366].
MISCELLANEOUS
Although not the focus of this report, a number of observations on diagnostic tools reported during this year’s meeting included detection of large vessel inflammation with [11C]-PK-11195 [Pugliese, F. et al., Abst 390], evaluation of the anti-atherosclerosis activity of statins with [99mTc]-annexin A5 [Doue, T. et al., Abst 394] and characterization of the safety, tolerability and biodistribution of [18F]-labeled BMS-747158 [Maddahi, J. et al., Abst 398], while additional studies corroborated the potential for [99mTc]-tetrofosmin for detecting myocardial ischemia in hypertensive subjects with left ventricular hypertrophy [Kisko, A. et al., Abst P868].
Increased risk for myocardial infarction or death resulted from treatment with diclofenac in healthy young subjects, according to a nationwide registry [Fosbol, E. et al., Abst 882].
A randomized study in 75 patients could not detect any benefit of acetylcysteine in preventing contrast-induced nephropathy in patients with moderate renal failure undergoing cardiovascular imaging procedures [Alioglu, E. et al., Abst P1369], although other studies demonstrated preventive activity when used at high doses alone or combined with ascorbic acid [Marenzi, G. et al., Abst P1736; Grygier, M. et al., Abst P3196] and yet further studies demonstrated a favorable impact on oxidative stress without a meaningful effect on the risk of contrast-induced nephropathy [Thiele, H. et al., Abst P2956]. On an independent basis, furosemide-forced dieresis during contrast procedures was a safe and feasible option for preventing nephropathy [Marenzi, G. et al., Abst P3184].
Blockade of human epithelial growth factor receptor-2 by trastuzumab resulted in systolic alterations eventually leading to cardiotoxicity [Lange, S.A. et al., Abst P1704]. Imatinib also led to infrequent cardiotoxicity, as described in four out of 103 patients with chronic myeloid leukemia [Marcolino, M.S. et al., Abst P1695]. Other observations corroborated the cardiotoxic potential of doxorubicin and other anthracyclines [Lestuzzi, C. et al., Abst P1694; Nurzynska, D. et al., Abst P3065; Samet, H. et al., Abst P3353; Ustaoglu, M.A. et al., Abst P3357], and also that of clozapine for causing myocarditis [Mcneil, J.J. et al., Abst P5585], but at least in the experimental setting, doxorubicin-induced cardiotoxicity was prevented by the flavone chrysoeriol [Liu, Z. et al., Abst P1730].
Blockade of tumor necrosis factor-alpha with adalimumab, etanercept or infliximab in patients with rheumatoid arthritis brought about improvements in arterial stiffness [Angel, K. et al., Abst P1732]. In addition, both fasudil and Y-27632 inhibited the adverse effects of tumor necrosis factor-alpha on endothelial progenitor cells [Balestrieri, M.I. et al., Abst P3946].
Increased urinary 11-dehydro-thromboxane B2 excretion during pregnancy was shown to be a risk factor for pre-eclampsia, but responded to low-dose aspirin therapy, which was also clinically active against pre-eclampsia [Perneby, C. et al., Abst P1727].
Treatment of hypothyroidism with levothyroxine worsened endothelial function and increased carotid intima-media thickness, with a pro-atherosclerotic profile [Arcopinto, M. et al., Abst P2240], but in experimental myocardial infarction models improved left ventricular remodeling and cardiac function [Mourouzis, I. et al., Abst P5664].
Use of sertraline to treat depression brought about improvements in endothelial dysfunction and inflammation in patients with comorbid coronary artery disease [Pizzi, C. et al., Abst P3156], while in patients with concomitant heart failure it reduced oxidative stress marker levels [Nikolaou, M. et al., Abst P5668].
The proteasome inhibitor bortezomib showed antiatherosclerotic properties in experimental animal models [Wilck, N. et al., Abst P4599].
Activation of peroxisome proliferator-activated receptor-alpha and -beta/delta by GW-7642 and GW-0742, respectively, was associated with reduced responsiveness to insulin in isolated cardiomyocytes [Montessuit, C.H. et al., Abst P1398].
Poly(ADP-ribose) polymerase inhibition with L-2286 prevented left ventricular hypertrophy in young spontaneously hypertensive animal models [Bartha, E. et al., Abst P1418].
Sublingual isosorbide mononitrate challenge proved able to identify outflow obstructions in patients with hypertrophic cardiomyopathy [Zemanek, D. et al., Abst P3283].
Diosgenin was reported to suppress Fas- and mitochondria-dependent cardiomyocyte apoptosis after ovariectomy in female experimental animals, suggesting therapeutic potential for postmenopausal cardioprotection [Lee, S.D. et al., Abst P5594].
Favorable antiatherosclerosis effects were reported in experimental animals with a complex of methotrexate and cholesterol-rich nanoemulsion [Bulgarelli, A. et al., Abst P5720].