As jazz and indeed most music has rhythm at its very core, so does life with the heart steadily pumping blood to the body. But as in jazz rhythm, irregular rhythm is paired with changes in pitch and velocity making melody and harmony, so it is to a large extent in heart disease, with irregular rhythm, irregular pumping effectiveness, arterial stiffness and so many diverse alterations completely changing the melody of life. And pairing music with the heart makes New Orleans a very reasonable place for the ACC's scientific session to be held. To keep pace with the rhythm and the music, the following report will complement the meeting by briefly reviewing news reported during the oral and poster sessions that have a direct impact on treatments for cardiovascular diseases and risk factors.
Although digitalic glycosides have been extensively used in cardiovascular pharmacotherapy, secondary analyses of the AFFIRM trial indicated an increased risk of overall and cardiovascular death in patients receiving digoxin irrespective of the presence of congestive heart failure or low left ventricular ejection fraction [Whitbeck, M.G. et al., Abst 906-6].
Diuretics are extensively used in the management of heart failure, with higher doses upon admission for acute heart failure associated with worse severity and renal function and more prolonged hospitalization [Shah, R.V. et al., Abst 1017-25]. Comparing individual strategies, furosemide/metolazone and continuous infusional bumetanide offered greater efficacy than continuous infusional furosemide in patients not responding to furosemide bolus therapy [Ng, T.M. et al., Abst 1017-24]. However, in the experimental laboratory hydralazine significantly increased cardiac hypertrophy and myocyte size in models of established diabetic cardiomyopathy, whereas the use of enalapril significantly attenuated myocardial inflammation [O'Brien, K.D. et al., Abst 914-5].
beta-Adrenoceptor blockers have a well-established role in the management of heart failure, although a study with the nonselective, mild vasodilating agent bucindolol revealed reductions in all-cause death only in patients with relatively preserved right ventricular ejection fraction [Ahmed, A. et al., Abst 1085-41] (Fig. 1). Metoprolol and carvedilol have also both been effectively used in the management of heart failure, although metoprolol was associated with greater improvements in left ventricular ejection fraction in a comparative trial, without such benefit translating into better survival [Shore, S. et al., Abst 1085-27] (Fig. 2). However, real-world data from an observational study appreciated underdosing with once-daily-only metoprolol (tartrate salt) in over two-thirds of patients from a cardiology clinic [Kerwin, T.C. et al., Abst 1150-276]. As opposed to metoprolol, beta-blockade with nebivolol did not increase asymmetric dimethylarginine levels in hypertensive conditions [Giles, T.D. et al., Abst 1150-273] (it should should be noted that increased asymmetric dimethylarginine levels were associated with residual platelet activity after clopidogrel administration in patients undergoing percutaneous coronary interventions [Nusca, A. et al., Abst 2514-508]).
Fig. 1. Four-year all-cause death rates in patients with right ventricular ejection fraction (RVEF) over or under 35% receiving bucindolol or placebo [Ahmed, A. et al., Abst 1085-41].
Fig. 2. Change in the left ventricular ejection fraction during 5 years of treatment with metoprolol or carvedilol [Shore, S. et al., Abst 1085-27].
Aldosterone blockers also have an established role in the heart failure armamentarium. Compared to placebo, adding eplerenone to angiotensin-converting enzyme inhibitor- or angiotensin receptor blocker-based therapy in patients with suspected myocardial ischemia improved endothelial function [Bavry, A.A. et al., Abst 1074-359].
Similarly, natriuretic peptides have been developed as drugs for treating heart failure. While carperitide proved superior to nicorandil in improving renal function and preventing further damage in patients with acute heart failure and chronic kidney disease [Kawamura, A. et al., Abst 1052-43], two additional agents demonstrated putative therapeutic activity in new trials reported during ACC'11: cenderitide exerted aldosterone-suppressing, cardiac-unloading and renal-preserving activity in a placebo-controlled trial while maintaining blood pressure [Costello, E. et al., Abst 1118-20; Lieu, H.D. et al., Abst 1182-256], and add-on nesiritide offered renal-protective activity compared to furosemide alone in patients with acutely decompensated heart failure [Reddy, V.K. et al., Abst 1017-42; Kelesidis, I. et al., Abst 1052-28] (Fig. 3). Experimental studies with a novel cardiac-type natriuretic peptide, CBA-NP, indicated potential for attenuating left ventricular hypertrophy, reducing cardiac fibrosis and improving cardiac function in conditions of diabetic cardiomyopathy [Ameenuddin, S. et al., Abst 1055-10].
Fig. 3. Change in glomerular filtration rate 3 days after discharge in patients receiving furosemide alone or combined with nesiritide [Kelesidis, I. et al., Abst 1052-28].
Among additional putative therapies currently under investigation, maintenance of serum potassium levels and prevention of hyperpotassemic complications in patients with high-risk heart failure and chronic kidney disease were attained with the novel potassium binder RLY-5016 in patients on background beta-adrenoceptor, renin-angiotensin system and aldosterone blockade [Pitt, B. et al., Abst 1085-44]. A first-in-human study with the nitric oxide donor CLX-1020 indicated safety and tolerability in patients with congestive heart failure, with potential for improving lusitropy and inotropy in decompensated heart failure [Cowart, D. et al., Abst 1085-42]; similar activity was observed in experimental animal models [Del Rio, C.L. et al., Abst 1118-21]. In addition, testosterone supplementation was noted to improve exercise capacity in patients with heart failure, supporting its role as a new putative therapy for the disease [Toma, M. et al., Abst 1118-48]. On the contrary, idebenone offered no clinical benefits on cardiac function or left ventricular hypertrophy compared to placebo in patients with Friedreich's ataxia-related cardiomyopathy [Lagedrost, S.J. et al., Abst 1119-41].
Experimental findings were also disclosed during the meeting. While heart rated reduction with ivabradine reduced the hyperactivation of the renin-angiotensin-aldosterone system in animals with chronic heart failure [Sabbah, H.N. et al., Abst 921-4], tranilast prevented atrial fibrillation in animal models of pacing-induced cardiomyopathy [Nakatani, Y. et al., Abst 1055-401]. On the other hand, inhibition of mammalian target of rapamycin (mTOR) with sirolimus reversed left ventricular remodeling in animal models of compensated heart failure [Bishu, K. et al., Abst 1052-25]. In addition, exogenous administration of sepiapterin in conditions of left ventricular hypertrophy prevented dilatory remodeling and heart failure through inhibition of cardiomyocyte hypertrophy and increase in angiogenesis [Yoshioka, K. et al., Abst 1016-51].
Specifically in models of diabetic cardiomyopathy, tanshinone IIA offered cardioprotective activity via modulation of the bradykinin B2 receptor-Akt-glycogen synthase kinase-3beta pathway [Sun, D. et al., Abst 1053-36].
In addition to pharmacotherapy, favorable preclinical animal model results were reported using S100A1-based gene therapy [Pleger, S.T. et al., Abst 1019-5; Brinks, H.L. et al., Abst 911-5].
Among antiarrhythmic agents, amiodarone prevented hospitalization more effectively than sotalol, although cardiovascular adverse outcomes increased comparably with both agents and persistence was superior with sotalol [Kim, M.H. et al., Abst 1134-148]. On the contrary, used to prevent atrial fibrillation after coronary bypass graft surgery, ranolazine proved superior to amiodarone, without an increased adverse event load [Murdock, D.K. et al., Abst 1161-405] (Fig. 4). Furthermore, ranolazine was shown to reduce left ventricular dyssynchrony during stress myocardial perfusion imaging, suggesting anti-ischemic benefits [Venkataraman, R. et al., Abst 1027-183]. Data from a new meta-analysis confirmed the safety and efficacy of dronedarone as a treatment for atrial fibrillation, improving overall mortality and cardiovascular hospitalization rates [Lang, C. et al., Abst 1021-398]. At an experimental level, dronedarone dose-dependently increased aortic and glomerular nitric oxide release, supporting additional cardiovascular benefits [Mason, P. et al., Abst 1007-115].
Fig. 4. Post-coronary artery bypass graft surgery atrial fibrillation rates in patients receiving ranolazine or amiodarone [Murdock, D.K. et al., Abst 1161-405].
Anticoagulation is mandatory to prevent thromboembolic strokes in patients with atrial fibrillation, and while dabigatran proved superior to warfarin in preventing strokes and systemic embolism [Oldgren, J. et al., Abst 906-4; Flaker, G.C. et al., Abst 1056-398] (Fig. 5) (although according to other analyses using dabigatran would result in substantial increases in cost, not considering the savings for the potential decreases in strokes and bleeding [Atay, J. et al., Abst 1034-144]), the use of apixaban was associated with a lower incidence of strokes but no excess bleeding compared to aspirin, even combined with clopidogrel [Focks, J.J. et al., Abst 1056-397] (Fig. 6). It should be added that dabigatran did not prolong the QT interval even at supratherapeutic doses [Ring, A. et al., Abst 1055-413], and that an engineered anti-dabigatran antibody able to reverse the anticoagulant activity without affecting normal hemostasis was developed and tested in in vivo and in vitro models [van Ryn, J. et al., Abst 1142-367].
Fig. 5. Annualized stroke rates in patients with permanent, paroxysmal or persistent atrial fibrillation (AF) receiving dabigatran or warfarin [Flaker, G.C. et al., Abst 1056-398].
Fig. 6. Annualized stroke and bleeding rates in patients receiving apixaban or aspirin alone or combined with clopidogrel [Focks, J.J. et al., Abst 1056-397].
By prolonging coronary sinus refractoriness, reducing conduction anisotropy and decreasing inducibility, chronic omega 3-fatty acid supplementation offered protection against atrial fibrillation in subjects without structural heart disease or clinical supraventricular arrhythmia undergoing procedures for ventricular tachyarrhythmia [Kumar, S. et al., Abst 1088-402], although no antiarrhythmic protection compared to placebo was noted in coronary artery disease patients with an implantable cardioverter defibrillator [Weisman, D. et al., Abst 1124-388]. Moreover, chronic supplementation with omega 3-polyunsaturated fatty acids attenuated post-atrial fibrillation mechanical stunning [Kumar, S. et al., Abst 1088-403]. However, chronic supplementation with high-dose docosahexaenoic acid, but not low-dose supplementation or supplementation with eicosapentaenoic acid, prevented death in experimental animal models of cardiomyopathy by improving mitochondrial function [Galvao, T.F. et al., Abst 1016-48].
Besides pharmacotherapy, radiofrequency ablation has been successfully used as a treatment for atrial fibrillation [Deneke, T. et al., Abst 1020-412], resulting in improvements in the quality of life of the patients and their significant others [Vanga, S.R. et al., Abst 1223-399].
In the preclinical arena, the gap junction-enhancing antiarrhythmic peptide AAP10 prevented lysophosphatidic acid-induced ventricular arrhythmia [Wang, T. et al., Abst 1055-405]. Class III antiarrhythmic activity against torsades de pointes in the experimental laboratory was demonstrated with the ryanodine receptor modulator K-201 [Stams, T.R. et al., Abst 1055-415].
Aspirin is the most widely used antiplatelet therapy in the primary and secondary prevention of adverse cardiovascular events, although a large study in patients undergoing percutaneous stenting for stable or unstable coronary artery disease demonstrated similar efficacy for a lower dose of 81 mg/day compared to doses of 162-325 mg/day [Harjai, K.J. et al., Abst 2513-591] (Fig. 7). Although an increased risk for bleeding complications was apparent with a higher intensity of anticoagulant therapy using aspirin plus clopidogrel plus warfarin [Fosbøl, E.L. et al., Abst 1005-316], dual antiplatelet therapy has become standard in patients with acute coronary syndromes without the need for reloading, at least in the case of clopidogrel, in patients with acute coronary syndromes already receiving the agent [Syed, A.I. et al., Abst 1002-346]. However, dual therapy with clopidogrel and aspirin did not improve outcomes over aspirin alone in patients undergoing coronary artery bypass graft surgery [Banerjee, S. et al., Abst 2514-504]. Clopidogrel pretreatment before percutaneous angioplasty effectively inhibited platelet reactivity [Beigel, R. et al., Abst 1005-313], but shorter dual antiplatelet therapy offered similar outcomes compared to longer-duration therapy, at least after drug-eluting stent implantation (with variable results in different trials) [Gwon, H.C. et al., Abst 3015-14; Feres, F. et al., Abst 2503-505] (Fig. 8), whereas higher-dose clopidogrel loading (600 mg) was associated with reduced myocardial infarct size [Song, Y.B. et al., Abst 1005-319] (an intermediate loading dose of 450 mg was as safe and effective as the higher dose, at least in an Asian population [Poddar, K.L. et al., Abst 2513-592]), and the use of triple therapy with aspirin, clopidogrel or ticlopidine and warfarin proved effective in preventing ischemic strokes and stent thrombosis after percutaneous coronary interventions, but was associated with an increased risk of major bleeding with longer duration of therapy [Deshmukh, A. et al., Abst 1149-301]. However, under-responsiveness to aspirin and clopidogrel has been recognized and related to an increased risk for adverse outcomes [Varenhorst, C. et al., Abst 1005-317; Brar, S. et al., Abst 2903-6], especially in the case of aspirin in subjects with diabetes (who could benefit from twice-daily dosing [Capodanno, D. et al., Abst 2513-590]) and in the case of clopidogrel in patients carrying selected CYP2C19 mutations [Singh, M. et al., Abst 1182-272]. In diabetic conditions, increased serum cotidine levels (a marker of tobacco smoking) were associated with enhanced responsiveness to clopidogrel [Ueno, M. et al., Abst 2514-501]. On the other hand, underresponsiveness to clopidogrel had no influence on the risk of bleeding complications [Eng, M. et al., Abst 2903-9] and did not translate into an increased risk of stent thrombosis, according to an open-label study [Ann, S.G. et al., Abst 1002-335], whereas hyperresponsiveness resulting in increased bleeding was identified [Ricottini, E. et al., Abst 2903-5].
Fig. 7. Major adverse cardiovascular event (MACE; death, myocardial infarction, stent thrombosis or target vessel revascularization) and net adverse clinical event (NACE; the same plus major or minor bleeding) rates in patients receiving higher- or lower-dose aspirin [Harjai, K.J. et al., Abst 2513-591].
Fig. 8. Major adverse cardiovascular event (MACE; death, myocardial infarction, cerebrovascular accident or revascularization) and bleeding rates in patients receiving dual antiplatelet therapy for 6 or 12 months after drug-eluting stent implantation [Gwon, H.C. et al., Abst 3015-14].
According to a comparative crossover trial, levels of clopidogrel's active metabolite and platelet inhibition were not reduced by coadministration of dexlansoprazole or lansoprazole as much as by coadministration of omeprazole or esomeprazole [Frelinger, A.L. et al., Abst 1139-308], especially in patients with loss-of-function CYP2C19 mutations [Nadipalli, S. et al., Abst 1067-160], but variable inhibition was noted depending on CYP2C19 polymorphic variants [Nisho, R. et al., Abst 1178-68; Toma, Y. et al., Abst 1068-169], and wide variability in pharmacokinetics and pharmacodynamics was also noted independent of cytochrome polymorphisms [Frelinger, A.L. et al., Abst 1002-333]. Similarly, pantoprazole had no impact on the pharmacodynamics of clopidogrel [Ferreiro, J.L. et al., Abst 2513-529], and rosuvastatin and atorvastatin had no impact on dual antiplatelet therapy [Suh, J.W. et al., Abst 1045-277], whereas coad-ministration of pentoxifylline had no impact on the antiplatelet activity of dual aspirin/clopidogrel therapy in patients with type 2 diabetes [Ueno, M. et al., Abst 2514-502], and coadministration of proton pump inhibitors had no negative impact on thrombosis and cardiovascular outcomes during clopidogrel therapy [Nisho, R. et al., Abst 1068-170].
As an alternative to clopidogrel, prasugrel was a more potent antiplatelet agent, but high on-treatment platelet reactivity was also documented in patients undergoing percutaneous coronary interventions, which was related to an increased likelihood for adverse cardiovascular events [Bonello, L. et al., Abst 2133-6].
By activating AMP-dependent protein kinase, the use of cilostazol in experimental animal models of hyperglycemia resulted in improved glucose-induced endothelial dysfunction and angiogenic potential [Chao, T.H. et al., Abst 1076-95]. In the experimental arena, cilostazol was also shown to improve endothelial cell differentiation and angiogenesis in ischemic conditions [Chao, T.H. et al., Abst 1042-112].
Glycoprotein IIb/IIIa inhibitors have been extensively used as antiplatelet therapy for coronary artery disease, but although adjunctive eptifibatide reduced mortality without excess bleeding complications in patients with ST segment elevation myocardial infarction [Mahmoudi, M. et al., Abst 2506-567], a new meta-analysis identified no additional benefit in patients receiving thienopyridines [Zhang, F. et al., Abst 1005-321].
As alternative antiplatelet strategies, ticagrelor proved superior to clopidogrel in preventing ischemic events and death, without increasing bleeding complications, regardless of the patients' age [Husted, S. et al., Abst 1139-309] (Fig. 9), whereas cangrelor, which exhibited potent antiplatelet activity via blockade of P2Y12 receptors and other mechanisms [Ferreiro, J.L. et al., Abst 2514-530], has been extensively studied as antiplatelet therapy and, compared to clopidogrel in patients undergoing percutaneous coronary interventions, it was associated with a reduced risk for death/myocardial infarction/revascularization [White, H.D. et al., Abst 1139-307] (Fig. 10). The agent exerted dose-dependent antiplatelet activity in in vitro studies [Tomasello, S.D. et al., Abst 2903-8]. Ex vivo studies in healthy volunteers also revealed superiority for sarpogrelate over clopidogrel, aspirin and ticlopidine in inhibiting platelet aggregation [Yang, T.H. et al., Abst 2514-505].
Fig. 9. Death, myocardial infarction and/or stroke rates in patients aged over or under 75 years receiving ticagrelor or clopidogrel [Husted, S. et al., Abst 1139-309].
Fig. 10. Death, myocardial infarction (MI) and/or ischemia-driven revascularization rates in patients receiving cangrelor or clopidogrel [White, H.D. et al., Abst 1139-307].
While the lipolytic effects of heparin were confirmed in cardiac catheterization samples from treated subjects [Brunner, M.P. et al., Abst 1181-320], a study investigating standard and reduced dosing of heparin did not reveal differences in efficacy but a lower risk for major bleeding with reduced 50 IU/kg doses [Pasceri, V. et al., Abst 2131-12] (Fig. 11). Compared to unfractionated heparin, the use of enoxaparin in patients with high-risk ST segment elevation myocardial infarction undergoing fibrinolysis and/or percutaneous coronary intervention was associated with similar efficacy and overall bleeding risk, but a higher likelihood for access-site and mild bleeding in one study [Goodman, S.G. et al., Abst 1037-314; Montalescot, G. et al., Abst 2131-16] (Fig. 12).
Fig. 11. Major adverse cardiovascular event (left graph) and bleeding (right graph) rates in patients receiving 50 or 100 IU/kg heparin before clopidogrel/aspirin-loaded percutaneous coronary interventions. MI, myocardial infarction [Pasceri, V. et al., Abst 2131-12].
Fig. 12. Thirty-day death, reinfarction and combined death/reinfarction/recurrent ischemia/new or worsening heart failure/cardiogenic shock and in-hospital severe or mild bleeding rates in patients receiving enoxaparin or heparin [Goodman, S.G. et al., Abst 1037-314].
Favorable results were also reported with bivalirudin, which, according to some reg-istries, was as effective as and safer than heparin [Sardi, G. et al., Abst 2514-534; Patti, G. et al., Abst 2131-10], and according to other studies it was associated with a marked and sustained reduction in bleeding complications and also reinfarction and cardiac death rates compared to a heparin/glycoprotein IIb/IIIa inhibitor in patients undergoing percutaneous coronary interventions for acute myocardial infarction regardless of the presence of diabetes [Witzenbichler, B. et al., Abst 2506-558] (Fig. 13). Furthermore, bivalirudin prevented bleeding following percutaneous coronary intervention compared to heparin, regardless of the use of closure devices or manual compression [Vidi, V.D. et al., Abst 2518-542].
Fig. 13. Three-year death/reinfarction rates in diabetic and nondiabetic patients receiving bivalirudin or heparin/glycoprotein IIb/IIIa inhibitor (GPI) therapy during percutaneous coronary intervention for acute myocardial infarction [Witzenbichler, B. et al., Abst 2506-558].
As another alternative to heparin plus eptifibatide, otamixaban in elderly patients with ST segment elevation myocardial infarction was associated with lower death and repeated myocardial infarction rates at no excess risk of major or minor bleeding [Ruff, C.T. et al., Abst 927-6] (Fig. 14). Pharmacokinetic testing with a related agent, edoxaban, indicated increased exposure upon coadministration of quinidine, amiodarone or verapamil, but not atorvastatin or digoxin [Mendell, J. et al., Abst 1075-118].
Fig. 14. Death/myocardial infarction/urgent revascularization (MACE)/bailout glycoprotein IIb/IIIa inhibitor therapy and bleeding rates in patients receiving otamixaban or unfractionated heparin [Ruff, C.T. et al., Abst 927-6].
A novel anticoagulant, pegnivacogin, and its selective antagonist anivamersen, administered at the time of sheath removal, offered dose-dependent benefits compared to heparin in patients undergoing early cardiac catheterization, with rates of bleeding complications comparable to heparin but reduced major adverse cardiovascular event rates [Povsic, T.J. et al., Abst 2131-14] (Fig. 15).
Fig. 15. Major adverse cardiovascular event (MACE; death, myocardial infarction and/or target vessel revascularization) and bleeding rates in patients receiving pegnivacogin or heparin [Povsic, T.J. et al., Abst 2131-14].
With significant improvements in microvascular function during thrombectomy with distal protection [Kawai, Y. et al., Abst 1037-309], single-dose intracoronary nicorandil administered after successful primary percutaneous coronary intervention for ST segment elevation myocardial infarction improved microcirculatory resistance, contributing to a better left ventricular function over the long term [Doi, Y. et al., Abst 1037-316]; intravenous administration of the agent resulted in reductions in matrix metallopro-teinase-2 levels in patients with acute heart failure [Kunishige, M. et al., Abst 1052-27]. Compared to nitroglycerin, nitroprusside also showed benefits during percutaneous coronary interventions, safely preventing no or slow reflow and improving reperfusion of infracted myocardium, with better blush grade and similar TIMI flow grade [Sai, S. et al., Abst 1037-315] (Fig. 16). Antianginal efficacy was similarly reported with ranolazine, which improved angina class in a significant proportion of patients with refractory angina, although many patients had to discontinue treatment because of adverse events, cost, disease progression or suboptimal response [Bennett, N.M. et al., Abst 1074-362]. Potent endothelium-dependent vasodilation was also obtained with intracoronary salbutamol in patients with near-normal angiograms [Puri, R. et al., Abst 0410-08].
Fig. 16. No or slow reflow rates in patients receiving nitroprusside or nitroglycerin [Sai, S. et al., Abst 1037-315].
Pressor therapy with intracoronary phenylephrine bolus was as safe as but more effective than intravenous epinephrine in patients undergoing coronary stent implantation [Hassan, W.S.M. et al., Abst 2514-513]. Early blockade of aldosterone with spironolactone reliably prevented lethal arrhythmias and cardiac death for at least 6 months in patients undergoing percutaneous coronary interventions [Beygui, F. et al., Abst 1037-317]. Two interesting additional studies indicated benefits on arterial stiffness and coronary artery disease progression in at-risk firefighters receiving aged garlic extract and coenzyme Q10 supplements [Larijani, V.N. et al., Abst 1043-103], and corroborated the cardiovascular benefits of moderate alcohol consumption on cardiovascular event prevention in smokers, the effect being associated with increases in high-density lipopro-tein cholesterol levels [Kondo, T. et al., Abst 1149-305].
On the contrary, the results of the PROTECTION AMI study did not demonstrate benefits for protein kinase C delta inhibition with delcasertib, which, administered prior to a percutaneous coronary intervention for ST segment elevation myocardial infarction, did not reduce infarct size, affect biomarker levels, EGC markers or left ventricular function, and did not improve clinical outcomes [Lincoff, A.M. et al., Abst 3015-12].
Miscellaneous experimental findings
Low-dose insulin-like growth factor I administered during the reperfusion phase after experimental coronary artery balloon occlusion exerted favorable effects on survival and long-term functional and remodeling outcomes [O'Sullivan, J.F. et al., Abst 0410-06].
Without increasing the risk for complications or all-cause death, the use of drug-eluting stents was associated with lower rates of major adverse cardiovascular events and the need for revascularization, as well as superior cost-effectiveness, compared to bare metal stents in large patient registries and individual trials [Tolerico, P.H. et al., Abst 2504-594; Sethi, A. et al., Abst 1072-315; Turco, M.A. et al., Abst 1034-141; Witzenbichler, B. et al., Abst 2906-7; Schafer, P. et al., Abst 1034-140; Park, S.J. et al., Abst 2132-14; Schneider, H. et al., Abst 1072-317; Mehili, J. et al., Abst 3914-6], although conflicting data from some individual trials indicated no difference, or a trend towards higher rates of hard cardiac events, in patients receiving sirolimus-eluting compared to bare metal stents [Rodriguez, A.E. et al., Abst 2904-5], and a particular study in large coronary arteries did not find major benefits of drug-eluting over bare metal stents [Gordon, P.C. et al., Abst 2501-600]. Besides sirolimus- and paclitaxel-eluting stents, which were confirmed to be effective in new studies and observations reported during the meeting, favorable clinical outcomes were reported with everolimus-eluting stents even in high-risk patient populations [Gruberg, L. et al., Abst 2512-536; Rutledge, D.R. et al., Abst 2501-522; Onuma, Y. et al., Abst 2508-511; Costa, M.A. et al., Abst 2501-512]. Large real-world comparative registries, studies and meta-analyses suggested similar low rates of major adverse cardiovascular events in patients receiving everolimus- and sirolimus-eluting stents (both along with biolimus-eluting stents faring better or slightly better than other drug-eluting stents, including paclitaxel- and zotarolimus-eluting stents) [Park, S.J. et al., Abst 2508-513; Park, D.W. et al., Abst 2508-512; Lee, K. et al., Abst 2506-545; Kedhi, E. et al., Abst 2508-507; Planer, D. et al., Abst 904-6; Smits, P. et al., Abst 2504-597; Nakamura, S. et al., Abst 2507-511; Kereiakes, D.J. et al., Abst 2901-5; Park, S.J. et al., Abst 2132-10; Zhang, F. et al., Abst 2508-503; Amin, A.P. et al., Abst 2501-598; Sethi, A. et al., Abst 2503-501; Collet, C.A. et al., Abst 2504-592; Maeng, M. et al., Abst 2132-8; Yamawaki, M. et al., Abst 2502-559; Jang, J.S. et al., Abst 2501-595], although a polymer-based paclitaxel-eluting stent proved superior to a polymer-free sirolimus-eluting stent in a trial in patients with diabetes [Desch, S. et al., Abst 2508-535]. A novel bioresorbable everolimus-eluting scaffold tested positive in the first trial in patients with de novo coronary artery lesions [Serruys, P.W., Abst 2132-16; Serruys, P.W. et al., Abst 2901-6; Chevalier, B. et al., Abst 2905-5; Gomez-Lara, J. et al., Abst 2911-9; Diletti, R. et al., Abst 2503-504]. A novel platinum chromium everolimus-eluting stent also proved effective [Stone, G.W. et al., Abst 3014-12; James, S.K. et al., Abst 2508-533], and a polymer-free biolimus-eluting stent tested positive regarding 12-month outcomes [Costa, R.A. et al., Abst 2905-8; Collet, C.A. et al., Abst 2504-575], with earlier and greater neointimal coverage without encroaching compared to the biodegradable polymer-based stent [Sakata, K. et al., Abst 2504-574].
Stem cell therapy
The safety of intracoronary injection of autologous bone marrow-derived mesenchymal stem cells in patients with acute myocardial infarction was corroborated in a pivotal trial in which left ventricular ejection fraction improved to a greater extent than in patients undergoing percutaneous coronary intervention alone, without differences in cardiovascular event rates [Lee, J.W. et al., Abst 1037-308] (Fig. 17). In an analogous manner, bone marrow-derived mesenchymal stem cells improved perfusion in patients with end-stage peripheral arterial disease [Malyar, N.M. et al., Abst 1044-127].
Fig. 17. Change in the left ventricular ejection fraction at 6 months in patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction with the addition or not of intracoronary autologous bone marrow-derived human mesenchymal stem cell (hMSC) injection [Lee, J.W. et al., Abst 1037-308].
Use of angiotensin-converting enzyme inhibitors with aspirin significantly reduced all-cause death rates in high-risk patients according to a meta-analysis of randomized, controlled trials [Lather, N. et al., Abst 1052-26]. However, differences were identified, with zofenopril offering advantages over ramipril in post-myocardial infarction patients with left ventricular dysfunction [Borghi, C. et al., Abst 1085-43] (Fig. 18).
Fig. 18. Cardiovascular (CV) death/hospitalization rates in patients receiving zofenopril or ramipril [Borghi, C. et al., Abst 1085-43].
While compared to amlodipine-based therapy valsartan-based antihypertensive regimens resulted in comparable prevention of major cardiovascular events but better prevention of congestive heart failure [Murohara, T. et al., Abst 3015-10] (Fig. 19), the angiotensin receptor blocker was also associated with regression of atherosclerotic plaques, although without suppression of neointimal hyperplasia after drug-eluting stent implantation [Park, D.W. et al., Abst 2513-589]. Besides lowering blood pressure, candesartan offered additional cardiovascular benefits as well by limiting remodeling during myocardial reperfusion and attenuating age-related increases in angiotensin II, matricellular proteins, matrix metalloproteinases, myeloperoxidase and inflammatory cytokines [Jugdutt, B.I. et al., Abst 1035-346]. Pleiotropic effects of olmesartan beyond blood pressure reduction were also demonstrated in the OLIVUS trial, in which the drug reduced highly sensitive C-reactive protein and increased adiponectin levels compared to placebo, correlating with slowed progression of coronary atherosclerosis [Miyoshi, T. et al., Abst 1149-303] (Fig. 20). Combined with calcium channel blockers, olmesartan reduced blood pressure to a larger extent than high-dose olmesartan alone, although without benefits on cardiovascular endpoints, except for patients with diabetes, who showed better cardiovascular protection with high-dose olmesartan monotherapy [Ogawa, H. et al., Abst 3015-8]. Regarding novel angiotensin receptor blockers, fimasartan, showed protective activity against ischemia/reperfusion injury in experimental animals through direct antiapoptotic and antiinflammatory effects [Choi, D.J. et al., Abst 1035-336], whereas azilsartan suppressed plasminogen activator inhibitor 1 expression [French, C. et al., Abst 1075-89].
Fig. 19. Acute myocardial infarction (AMI), stroke, revascularization, congestive heart failure (CHF), sudden cardiac death (SCD) and composite endpoint rates in patients receiving valsartan- or amlodipine-based antihypertensive therapy for a median of 3.2 years [Murohara, T. et al., Abst 3015-10].
Fig. 20. Change in high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and adiponectin levels in patients treated or not with olmesartan [Miyoshi, T. et al., Abst 1149-303].
At similar levels of blood pressure reduction, the direct renin inhibitor aliskiren reduced left ventricular hypertrophy comparably to losartan in nondiabetic subjects, but more effectively than the angiotensin receptor blocker in patients with diabetes, the combination of both agents being effective regardless of the diabetic status [Vardeny, O. et al., Abst 1150-280]. Like the angiotensin receptor blocker valsartan, aliskiren effectively lowered blood pressure, but in experimental animals it also reduced myocardial infarct size, with the combination of both agents offering additive benefits [Ye, Y. et al., Abst 1070-334]. Furthermore, aliskiren reduced QT dispersion in diabetic individuals independently, at least in part, of the blood pressure-lowering activity, suggesting potential for preventing arrhythmias in hypertensive patients with diabetes [Fogari, R. et al., Abst 2514-533] (Fig. 21).
Fig. 21. Left: percent of patients with successful control of blood pressure after treatment with aliskiren or amlodipine; right: change in the corrected QTc interval dispersion after treatment with the two agents [Fogari, R. et al., Abst 2514-533].
A significant advance in anti-remodeling for hypertension may result from the discovery of the novel dual nitric oxide-releasing agents ST-071002 and ST-1003, which also showed affinity for matrix metalloproteinase-2 and -9. Besides hypertension, such agents may also offer potential as anti-remodeling therapy for heart failure with preserved ejection fraction [Ledwidge, M.T. et al., Abst 1150-274].
Dyslipidemia and atherosclerosis
Experimental findings with simvastatin indicated an effect in reducing myocardial edema, associated with suppression of aquaporin expression by modulation of protein kinase A [Li, X.D. et al., Abst 1035-334].
While intensive atorvastatin therapy reduced cardiovascular events in high-risk individuals with dyslipidemia, coronary artery disease and chronic kidney disease [Wilson, D.J. et al., Abst 1043-107], treatment with the statin improved arterial stiffness, endothelial function and glomerular filtration rate, especially in patients with heart failure [Oikonomou, E. et al., Abst 1110-103; Kean, A. et al., Abst 1085-45]. A clinically irrelevant drug-drug interaction was described with atorvastatin and colchicine coadministration in healthy volunteers, resulting in increased bioexposure to the latter without worsening the tolerability profile [Davis, M.W. et al., Abst 1113-284].
Besides improving lipid levels, but independently from the lipid benefits, rosuvastatin lowered C-reactive protein levels and reduced coronary fibrous cap thickness in patients with acute coronary syndrome [Kitabata, H. et al., Abst 2911-5]. Compared to standard atorvastatin therapy, weekly high-dose rosuvastatin similarly improved lipid levels without the need for daily dosing [Backes, J. et al., Abst 1011-303] (Fig. 22). Thrice-weekly reduced-dose rosuvastatin also maintained efficacy and was acceptably tolerated as an alternative to daily dosing in patients with statin intolerance [Achtchi, A.N. et al., Abst 1045-274].
Fig. 22. Change in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and C-reactive protein (CRP) levels during 8 weeks of treatment with weekly rosuvastatin 80 mg or daily atorvastatin 10 mg [Backes, J. et al., Abst 1011-303].
Pitavastatin was also reported to be effective as an low-density lipoprotein cholesterol (LDL-C)-lowering drug for dyslipidemia, with on-treatment high-density lipoprotein cholesterol (HDL-C) levels predicting residual cardiovascular risk [Urashima, M. et al., Abst 1045-273]. Furthermore, besides lowering cholesterol and C-reactive protein levels, but independently of changes in these cardiovascular risk markers, pitavastatin effectively lowered lectin-like oxidized LDL receptor 1 expression in patients with hypercholesterolemia, regardless of the presence of concomitant diabetes [Kume, N. et al., Abst 1115-290]. However, as opposed to atorvastatin, pitavastatin did not increase fasting plasma glucose levels in patients with dyslipidemic type 2 diabetes [Kryzhanovski, V. et al., Abst 1113-279].
The addition of ezetimibe to statin therapy resulted in greater reduction in LDL-C levels and sustained inhibition of cholesterol absorption, which, during double-dose statin monotherapy, increased over time [Okada, K. et al., Abst 1045-278]. However, double-dose statin, but not the addition of ezetimibe, improved endothelial function, despite the greater reduction in LDL-C levels with the addition of ezetimibe [Matsue, Y. et al., Abst 928-4] (although a comparative trial with rosuvastatin indicated a superior reduction in LDL-C with the statin, but improvements in flow-mediated dilation and malondialdehyde-LDL particles with both agents [Ikeda, N. et al., Abst 1007-117]). A triple combination of ezetimibe/simvastatin and niacin further improved lipid levels, resulting in an increased proportion of patients at goal regardless of background risk category [Fazio, S. et al., Abst 1011-298] (Fig. 23), and in fact, the addition of niacin to prior statin therapy significantly improved the lipid profile compared to placebo, while also improving endothelial function, the benefit being greater with older age [Kothawade, K. et al., Abst 1115-292] (Fig. 24).
Fig. 23. Proportion of patients at goal (LDL-C < 100 mg/dL, non-HDL-C < 130 mg/dL and apolipoprotein B < 90 mg/dL) after 24 weeks of treatment with ezetimibe/simvastatin, niacin or the triple combination according to baseline risk profile. MS, metabolic syndrome [Fazio, S. et al., Abst 1011-298].
Fig. 24. Change in flow-mediated vasodilation in patients adding niacin or placebo to statin-based antihyperlipidemic therapy [Kothawade, K. et al., Abst 1115-292].
Fibrates are especially indicated for reducing triglycerides, which was confirmed in a new meta-analysis of studies using fenofibrate alone or combined with statins. However, the reductions in triglycerides were significantly greater in patients with higher very-low-density lipoprotein cholesterol (VLDL-C) levels [Voros, S. et al., Abst 1011-300]. Moreover, fenofibrate also improved adipocytokine levels and insulin sensitivity in patients with hypertriglyceridemia, with beneficial effects on endothelial and metabolic function [Koh, K.K. et al., Abst 1182-248].
Added to maximally tolerated lipid-lowering therapy, mipomersen was safe and effective in patients with hypercholesterolemia at high cardiovascular risk, effectively inhibiting apolipoprotein B synthesis and reducing LDL-C levels [Tardif, J.C. et al., Abst 920-3; Cromwell, W.C. et al., Abst 1011-304] (Fig. 25).
Fig. 25. Change in total cholesterol (TC)2, LDL-C1 and HDL-C1, triglycerides (TG)1, apolipoprotein B (Apo B)1 and lipoprotein(a) (Lp[a])1 levels after 28 weeks of adding mipomersen or placebo to maximally tolerated lipid-lowering therapy [1Tardif, J.C. et al., Abst 920-3; 2Cromwell, W.C. et al., Abst 1011-304].
Currently under clinical research, the anti-proprotein convertase subtilisin/kexin-type I (PCSK9) antibody REGN-727 dose-dependently lowered LDL-C levels with good tolerability in healthy volunteers [Swergold, G. et al., Abst 1182-247]. Also in initial clinical trials, the apolipoprotein A-I expression enhancer RVX-208 proved to be dose-dependently active in increasing HDL-C levels, while exhibiting antiatherosclerotic activity in experimental animal models [Wong, N.C. et al., Abst 1008-93].
In the experimental arena, and as a putative antiatherosclerotic/antiangiogenic therapy, a phosphatidylcholine-coupled fumagillin prodrug with improved chemical and circulatory stability was described, with effective inhibition of cell proliferation in an in vitro angiogenesis assay [Pan, D. et al., Abst 1145-123].
In addition to pharmacotherapy, prescription omega 3-fatty acids were shown to improve lipoprotein class distribution in patients with dyslipidemia already receiving statin therapy [Maki, K.C. et al., Abst 1045-276]. In fact, omega 3-fatty acid supplementation also improved arterial function and fibrinolysis in smokers [Zaromitidou, M. et al, Abst 928-7], while eicosapentaenoic acid improved hypertensive diastolic dysfunction and suppressed the negative impact of C-reactive protein on pressure overload-induced cardiac remodeling by attenuating oxidative stress [Nagai, T. et al., Abst 1016-49; Ito, H. et al., Abst 1118-19].
Hyperglycemia, insulin resistance and diabetes
In the experimental arena, insulin glargine increased nitric oxide bioavailability in diabetic animals, reversing and restoring endothelial nitro-oxidative stress [Mason, P. et al., Abst 1007-118].
The cardiovascular safety of thiazolidinediones is controversial, although novel meta-analysis of trials with rosiglitazone could not incriminate or exonerate the drug as a cause for increasing the risk of myocardial infarction [Kaul, S. et al., Abst 1079-302]. However, prescription of thiazolidinediones at discharge after drug-eluting stent implantation was associated with a decreased risk for death, without impacting on the likeli-hood for myocardial infarction or target vessel revascularization [Patel, D.B. et al., Abst 2508-510]. A novel agent in the group, ciglitazone, exerted pleiotropic effects by inhibiting smooth muscle cell proliferation, at least in the in vitro setting [Poerner, T.C. et al., Abst 1108-86].
Obesity and diet
Significant weight loss with an associated reduction in cardiovascular risk factors was demonstrated in obese individuals with significant morbidities treated with phentermine/topiramate compared to placebo [Davidson, M. et al., Abst 1048-293] (Fig. 26). The fixed-drug combination of naltrexone/bupropion also resulted in cardiovascular benefits in patients with obesity, inducing significant decreases in body weight accompanied by improvements in blood pressure and heart rate [Plutzky, J. et al., Abst 1013-286] (Fig. 26). On the other hand, the valvulopathic effect of fenfluramine/phentermine was attributed to a demonstrated in vivo and ex vivo proliferative effect on valve inter-stitial cells [Rajamannan, N.M. et al., Abst 1182-253].
Fig. 26. Left: change in body weight after 108 weeks of treatment with phentermine/topiramate or placebo [Davidson, M. et al., Abst 1048-293]; Right: change in body weight after 108 weeks of treatment with naltrexone/bupropion or placebo [Plutzky, J. et al., Abst 1013-286].
Contrary to other nuts, chronic chewing of areca nuts was identified as an independent risk factor for coronary artery disease additive to smoking, hypertension and dys-lipidemia [Tsai, W.C. et al., Abst 1043-102].
A nutraceutical product containing berberine, red yeast rice and policosanol offered broad benefits on cardiovascular risk factors, including LDL-C levels, insulin sensitivity, endothelial function and blood pressure, compared to placebo in patients with metabolic syndrome [Carlomagno, G. et al., Abst 1048-294].
Improved patency of femoropopliteal stents resulted from coadministration of cilostazol [Soga, Y. et al., Abst 925-6]. Sildenafil improved perfusion and vascularization and downregulated adhesion molecule expression in experimental models of limb ischemia [Valatsou, A. et al., Abst 1149-300]. At least in experimental animals, sildenafil also prevented left ventricular dysfunction and preserved the contractile reserve after exposure to radiation [Mezzaroma, E. et al., Abst 911-7].
Bosentan exerted prolonged benefits on exercise capacity in patients with pulmonary hypertension secondary to congenital heart disease, although 4-year mortality remained higher than desired [Schuuring, M.J. et al., Abst 1065-436].
Enoxaparin, and especially fondaparinux, showed optimal protection against in-hospital death, recurrent pulmonary embolism and major bleeding in patients with pulmonary embolism also receiving thrombolysis [Meneveau, N.F. et al., Abst 1078-124] (Fig. 27); both low-molecular-weight heparins proved to be comparably interchangeable in patients with recent pulmonary embolism, without excess bleeding risk [Meneveau, N.F. et al., Abst 1078-133].
Fig. 27. In-hospital death/recurrent pulmonary embolism (PE)/major bleeding and composite endpoint rates in patients receiving enoxaparin, fondaparinux or unfractionated heparin [Meneveau, N.F. et al., Abst 1078-124].
Compared to enoxaparin, rivaroxaban was noninferior regarding the prevention of pulmonary embolism in inpatients with acute medical illnesses resulting in reduced mobility, but extended prophylaxis with rivaroxaban offered greater preventive effectiveness [Cohen, A. et al., Abst 3015-6] (Fig. 28).
Fig. 28. Deep vein thrombosis and/or pulmonary thromboembolism rates after 10 days of prophylaxis with rivaroxaban or enoxaparin or a further 25 days of extended prophylaxis with rivaroxaban or placebo [Cohen, A. et al., Abst 3015-6].
With favorable safety and tolerability even in patients with advanced- or end-stage chronic kidney disease [Ananthasubramaniam, K. et al., Abst 926-3], regadenoson after symptom-limited exercise offered a well-tolerated protocol for stress testing [Parker, M.W. et al., Abst 1096-226] and assessment of fractional flow reserve [Nair, P.K. et al., Abst 2509-564], although heart rate and blood pressure changes after regadenoson administration did not predict ischemia on single photon emission computed tomography [Ananthasubramaniam, K. et al., Abst 1096-232].
Propofol was safely administered during defibrillator threshold testing for cardioverter-defibrillator implantation under anesthesiologist or electrophysiologist surveillance, although procedures were significantly longer when the supervisor was an anesthesiologist [Wase, A. et al., Abst 1164-389].
Improved myocardial remodeling and reduced oxidative stress were demonstrated in patients with rheumatoid arthritis receiving the anti-interleukin-1 agent anakinra [Ikonomidis, I. et al., Abst 1052-24].
Acetylcysteine and ascorbate were not superior to placebo in preventing contrast-induced nephropathy during cardiac catheterization [Brueck, M. et al., Abst 1115-293]. However, a meta-analysis of clinical trials identified a comparative study in which acetylcysteine was superior to bicarbonate in the prevention of contrast-induced nephropathy [Brar, S. et al., Abst 2514-511]. On the other hand, statin pretreatment reduced the risk of contrast-induced nephropathy in patients undergoing coronary angiography according to a meta-analysis of randomized trials [Pappy, R.M. et al., Abst 1113-283].
Safe coadministration of low-dose aspirin and naproxen/esomeprazole was reported in patients with arthritic conditions and increased cardiovascular risk, without loss of the antiplatelet effects of aspirin [Angiolillo, D.J. et al., Abst 2514-506].
Use of bisphosphonates for idiopathic osteoporosis in men was associated with an increased likelihood for atrial fibrillation that needs to be further investigated [Thadani, S.R. et al., Abst 1088-416].
No clear benefit could be demonstrated for glutamate infusion during surgery for acute coronary syndromes in a controlled trial [Svedjeholm, R. et al., Abst 1003-373].
The glutathione synthesis inhibitor buthionine sulfoximine induced left ventricular diastolic dysfunction in experimental animals by preventing phospholamban phosphorylation, an effect that was reverted by the Rac1 GTPase inhibitor NSC-23766 [Wang, H. et al., Abst 1084-21].
Intravenous immunoglobulin was effective in the treatment of Kawasaki's disease regardless of administration within 9 days or after 10 days of illness onset [Muta, H. et al., Abst 1097-426].
Treatment of chronic obstructive pulmonary disease with roflumilast was associated with a significant reduction in cardiovascular event rates compared to placebo [White, W.B. et al., Abst 1149-302].