April 22, 2009
Orlando, Florida, U.S.A.
INTRODUCTION
Facing the prospect of a 3-day meeting
filled with 2,000 oral and poster presentations may approximate the feeling of a
child entering a theme park full of all kinds of attractions, and choosing which
attractions to try, or which presentations to attend and to report on, is not an
easy task. So many attractive shapes, noises and colors competing for one’s attention!
However, theme parks are one of the local specialties in Orlando, as well as what
first comes to mind when this city in Florida is mentioned. This reporter, not unfamiliar
with Orlando and large medical meetings, has done his best to select topics of interest.
He would also like to remind readers that the following report will certainly reflect
a selection bias, and that it is intended to guide readers through the main ideas
discussed. The panic of the aforementioned child facing so many colorful attractions
may be comparable to that of a reporter facing so much news with limited time and
space available. The aim of this report is therefore not to enter into detail but
to present the main ideas that can be further explored in the abstracts of this
year’s ACC congress available on the society’s website.
INTERVENTIONAL VERSUS NONINTERVENTIONAL APPROACHES TO THERAPY
Judging from the number of presentations, especially but not restricted to the I2 summit, the main areas of interest for cardiologists actively contributing their research to this year’s meeting were drug-eluting stents and antiplatelet/anticoagulant therapy during percutaneous coronary interventions, which may reflect an overall preference for interventional approaches over noninterventional therapies. However, according to the results of the COURAGE trial, adding percutaneous coronary interventions to optimal medical therapy did not reduce long-term cardiac events in patients with silent myocardial infarction [Boden, W.E. et al., Abst 0918-4], while the results of the DANAMI-2 trial, the longest follow-up from the largest randomized study comparing primary angioplasty versus medical fibrinolysis, demonstrated no differences in total and cardiac mortality [Nielsen, P.H. et al., Abst 1001-292] (Fig. 1), two votes for medical-only or medical-mostly therapy. On the other end of the scale, according to other patient registries, early, facilitated or nonfacilitated revascularization was more effective than medical therapy in high- or even standard-risk patients [Bugiardini, R. et al., Abst 0918-5; Zhang, Y. et al., Abst 0918-6], and specifically in patients with acute coronary syndromes [Kolm, P. et al., Abst 0919-3], calling for interventional approaches at least in high-risk situations. In any case, drug-eluting stents and antiplatelet/anticoagulant agents are both drugs, and this report focuses mainly on drugs and pharmacotherapy. It includes short mention of most new research contributions having drug therapy as main subject of study.
Fig. 1. Overall and cardiac death rates over a median follow-up of 7.8 years among 1,572 patients undergoing primary percutaneous angioplasty or fibrinolysis for ST segment-elevated myocardial infarction [Nielsen, P.H. et al., Abst 1001-292].
HEART FAILURE
The usefulness of beta-blockers in the treatment of chronic heart failure is well recognized, with a direct, independent relationship between optimal beta-blocker therapy (and lower achieved heart rate) and survival [Cullington, D. et al., Abst 1024-201]. Novel data disclosed during the ACC meeting in Orlando confirmed the benefits of carvedilol in improving left ventricular ejection fraction [Masukata, Y. et al., Abst 1024-193], shortening hospitalization in case of decompensated acute heart failure [Chiong, J.R. et al., Abst 1024-198] and improving outcomes in children with heart failure [Auerbach, S.R. et al., Abst 1017-220], as well as its tolerability in patients with comorbid chronic obstructive pulmonary disease [Harris, M.M. et al., Abst 1024-197]. Favorable outcomes were also reported with low-dose landiolol in patients with acute heart failure or undergoing percutaneous coronary interventions [Kobayshi, S. et al., Abst 1015-203; Morita, H. et al., Abst 1041-157] and for bucindolol in increasing survival and attenuating progression of heart failure [Bristow, M. et al., Abst 1024-184]. On the other hand, use of nebivolol combined with sildenafil was shown to reverse diabetes-induced erectile dysfunction in experimental animals [Angulo, J. et al., Abst 1040-110].
Continuous furosemide infusion with low-dose dopamine was another approach reported effective and safe in the treatment of acute decompensated heart failure, with less nephrotoxicity than intermittent bolus treatment [Aziz, E.F. et al., Abst 1033-166]. With their activity in counteracting angiotensin II, suppressing activated sympathetic nerve and improving left ventricular function, atrial natriuretic peptide analogs have been developed as a treatment for chronic heart failure, and novel experimental studies revealed additional benefits on cardiorenal status [Lisy, O.J. et al., Abst 1015-191] as well as the feasibility of intranasal administration [Kono, T. et al., Abst 1015-187].
Regarding additional issues, the results of the Pre-RELAX-AHF study evidenced the benefits of intravenous relaxin on dyspnea and other symptoms of acute heart failure, although without an effect on hypotension or renal impairment [Teerlink, J.R. et al., Abst 402-12]. New experimental studies with eplerenone demonstrated an effect in attenuating atrial remodeling and preventing vulnerability to induced atrial fibrillation [Moe, G.W. et al., Abst 1015-196]. In the experimental arena, the cholinesterase inhibitor donepezil prevented remodeling and improved survival in experimental models of heart failure secondary to volume overload [Handa, T. et al., Abst 1015-194], while phenylephrine increased myocardial distensibility through activation of protein kinase C [Fontes-Sousa, A.P. et al., Abst 1015-195].
Among nonpharmacological approaches, alcohol septal ablation provided functional benefits to patients with hypertrophic cardiomyopathy [Pelliccia, F. et al., Abst 2509-625] and improved longitudinal and radial strains without affecting left ventricular twist in patients with left ventricular deformations [Wang, J. et al., Abst 1036-240].
Stem cell therapy has been gaining popularity in the treatment of heart failure, and randomized controlled trial data confirmed the functional benefits of transendocardially or intracoronary injected bone marrow mononuclear cells [Perin, E.C. et al., Abst 1051-191; Lipiec, P. et al., Abst 1032-142; van Ramshorst, J. et al., Abst 1041-145] and the feasibility of percutaneous intramyocardial stem cell injection [Krause, K.T. et al., Abst 1032-130] and intracoronary autologous bone marrow CD34-positive cell infusion [Quyyumi, A.A. et al., Abst 1032-139; Losordo, D.W. et al., Abst 2404-12]. Experimental data reported this year further confirmed the feasibility and benefits of bone marrow-derived mesenchymal stem cells [Umar, S. et al., Abst 1015-172; Chen, G. et al., Abst 1015-197], umbilical cord blood stem cells [Henning, R.J. et al., Abst 1024-185], human embryonic mesenchymal stem cells [Cervio, E. et al., Abst 1014-126] and human CD34-positive cells [Kumar, A. et al., Abst 2509-630]. Turning to a novel chapter, direct intramyocardial grafting of bone marrow-derived stem cells did not result in cardiac nerve sprouting in models of chronic myocardial ischemia [Liu, Y. et al., Abst 1011-37].
Miscellaneous additional information on therapeutic issues in heart failure included descriptions of the benefit of granulocyte colony-stimulating factor in improving Chagas’ chronic heart failure [Carvalho, V.B. et al., Abst 1015-200] and ischemic heart failure in patients not eligible for revascularization [Leone, A.M. et al., Abst 1024-182], a report on the detrimental effects of a high-fat diet, which reduced the benefits of omega 3-polyunsaturated fatty acids on ventricular hypertrophy [Shah, K.B. et al., Abst 1015-190] and a description of the antiinflammatory effect of intermediate-dose pentaglobin in patients with parvovirus B19- and adenovirus-positive myocarditis [Maisch, B. et al., Abst 1015-170].
Regarding anemia in heart failure, a common occurrence, a meta-analysis of clinical trials confirmed the benefits of erythropoiesis-stimulating agents in increasing hemoglobin and reducing heart failure-related hospitalizations without a negative impact on mortality, thrombosis or myocardial infarction [Gorodeski, E.Z. et al., Abst 1024-169], but according to a comparative trial, iron supplementation alone was as effective as darbepoetin alfa in advanced heart failure patients with anemia and iron deficiency [Kaldara, E. et al., Abst 1024-166], while in the REVIVAL-3 study use of high-dose erythropoietin was not associated with benefits in patients with an acute myocardial infarction [Ott, M. et al., Abst 411-8].
CARDIAC ARRHYTHMIA
Supraventricular arrhythmias
Isoproterenol was suggested beneficial in controlling patients with long-standing permanent atrial fibrillation [Di Biase, L. et al., Abst 1011-53], as was dofetilide combined with intravenous magnesium sulfate [Chawla, O. et al., Abst 1020-32], spironolactone-containing regimens with beta-blockers with or without angiotensin-converting enzyme inhibitors [Dabrowski, R. et al., Abst 1020-48] and renin-angiotensin system blockers [Ishikawa, K. et al., Abst 0903-6]. Ranolazine was also reported an effective drug for reducing ventricular arrhythmias after coronary reperfusion [Dow, J. et al., Abst 1012-69]. Regarding mechanistic data, D,L-sotalol was shown to reverse atrial electrical remodeling and prevent atrial fibrillation perpetuation without an effect on L-type calcium channel expression and activity [Tamotsu, S. et al., Abst 1011-34]. On the other hand, the sodium/potassium channel blocker AZD-1305 was shown to prolong QT interval without increasing repolarization instability in experimental animals, suggesting no liability to induce torsades de pointes, but was able to suppress dofetilide-induced torsades de pointes and attenuate the proarrhythmic activity of the potassium I-Kr blocker E-4031 [Carlsson, L. et al., Abst 1011-35; Carlsson, L. et al., Abst 1011-36].
New results disclosed during the meeting regarding cardiovascular outcomes in patients with atrial fibrillation or flutter treated with dronedarone deserve special mention. A meta-analysis of the DAFNE, EURIDIS, ERATO and ATHENA trials, with an overall population of 6,157 patients, confirmed individual trial results suggesting marked improvements compared to placebo on death and cardiovascular hospitalization across a wide range of patients [Hohnloser, S.H. et al., Abst 1020-54] (Fig. 2).
Fig. 2. Death/cardiovascular hospitalization rates in patients treated with dronedarone or placebo across 5 randomized trials and the pooled analysis [Hohnloser, S.H. et al., Abst 1020-54].
Surgical and invasive options for the control of supraventricular arrhythmias were also described as effective in trials presented and discussed in the Orange County Convention Center this year, including notably pulmonary vein isolation/ablation [Gabriel, R.S. et al., Abst 1011-56; Wong, C.X. et al., Abst 1011-58; Hussain, S.K. et al., Abst 1011-63; Patel, D. et al., Abst 1020-35; Santinelli, V. et al., Abst 1020-38; Patel, D. et al., Abst 1020-39; Molaee, P. et al., Abst 1020-50; Shah, A.J. et al., Abst 1020-53; Arua, A. et al., Abst 1020-64; Vogt, J. et al., Abst 0903-3], radiofrequency/catheter ablation [Lam, B.K. et al., Abst 1020-36; Banchs, J.E. et al., Abst 1020-46; Burgon, N.S. et al., Abst 1020-47; Wijnmaalen, A.P. et al., Abst 1029-34], cavotricuspid isthmus ablation [Navarrete, A.J. et al., Abst 1020-42; Kim, J.B. et al., Abst 1029-32] and the maze procedure [Das, M.K. et al., Abst 1011-57; Kong, M.H. et al., Abst 1029-33], while noninvasive electrical cardioversion [Baman, T.S. et al., Abst 1020-37; Dukes, J. et al., Abst 0903-4] and atrial resynchronization [Lee, K.T. et al., Abst 1020-58] were also among the useful approaches to the treatment of supraventricular tachyarrhythmia.
Ventricular arrhythmias
Among scarce news disclosed during this year’s meeting related directly to the treatment of ventricular arrhythmias, significant reduction in the frequency of reentry during ventricular fibrillation was noted upon treatment with verapamil in experimental animals [Jim, Q. et al., Abst 1029-50]. Regarding interventional approaches, cardiac resynchronization therapy continued to be reported feasible and effective [Ajijola, O.A. et al., Abst 1029-66; Hara, H. et al., Abst 1038-32; Ginks, M. et al., Abst 1038-37; Shen, X. et al., Abst 1038-42; Stellbrink, C. et al., Abst 1038-55; Tanaka, H. et al., Abst 0909-3; Gold, M.R. et al., Abst 0909-4; Rickard, J. et al., Abst 0909-5; Lin, G. et al., Abst 1024-191; Sutton, M.G.S.J. et al., Abst 1051-167; Linde, C. et al., Abst 1051-169; Chandra, R. et al., Abst 1051-177; Sutton, M.G.S.J. et al., Abst 1051-189; Avari, J.N. et al., Abst 1026-228], with improvements in cardiac but also endothelial function [Arao, K. et al., Abst 1029-65]. In addition to pacing device implantation (which as resynchronization therapy also improved cardiac remodeling in patients with heart failure) [Manne, M. et al., Abst 1038-36; Zhang, J. et al., Abst 1038-39; Abe, H. et al., Abst 1038-40; Gademan, M.G.J. et al., Abst 1038-43; Refaat, M. et al., Abst 1038-44; Rossi, L. et al., Abst 1038-46; Wang, Y.C. et al., Abst 1051-176; Tse, H.F. et al., Abst 1051-190] and implantable cardioverter-defibrillators [Mattlock, D.D. et al., Abst 1038-47; Lakshmanadoss, U. et al., Abst 1038-48; Saliaris, A.P. et al., Abst 1038-49; Aggarwal, A. et al., Abst 1038-51; Badheka, A. et al., Abst 1038-52; Sakhuja, R. et al., Abst 1038-53; Borleffs, C.J.W. et al., Abst 1038-56; Bardy, G.H. et al., Abst 1038-57; Mohn, J.N. et al., Abst 1038-60; Tanawuttiwat, T. et al., Abst 1038-61; Natan, S.R. et al., Abst 1038-62; Ayyad, A.M. et al., Abst 1038-63; Hager, C.S. et al., Abst 1038-64; Russo, A.M. et al., Abst 1038-66; McLaughlin, C. et al., Abst 0909-7; Caliskan, K. et al., Abst 1047-32; Brady, P.A. et al., Abst 1047-44; Feingold, B.D. et al., Abst 1017-229], other techniques reported effective included alcohol septal ablation [Rajendra, A. et al., Abst 1038-31].
Anticoagulation in cardiac arrhythmia
Anticoagulation is required in patients with atrial fibrillation, with a significant favorable impact on mortality [Fauchier, L. et al., Abst 1002-308], and undertreatment, but not overtreatment, was noted to result in increased risk of death [Fauchier, L. et al., Abst 1011-47], while use of warfarin was identified as an independent predictor of lower six-month mortality/reinfarction in patients with atrial fibrillation suffering an acute coronary syndrome [Lopes, R.D. et al., Abst 0923-6], although evidence of under- or suboptimal use of the agent was reported [Nieuwlaat, R. et al., Abst 1010-08; Ogilvie, I.M. et al., Abst 1019-12; Baker, W.L. et al., Abst 1028-15; Sander, S.D. et al., Abst 0915-5]. However, oral anticoagulation may carry a risk for patients requiring surgery, but bridge therapy with enoxaparin offered a suitable alternative while interrupting use of oral agents, according to the BRAVE registry [Hammerstingl, C. et al., Abst 1039-75]. Clinical data was reported on a novel direct thrombin inhibitor, AZD-0837, results of a randomized trial suggesting it suppressed thrombogenesis as effective as vitamin K antagonists, with good tolerability and a similar or lower risk of bleeding [Lip, G.Y. et al., Abst 1022-110]. Results with a further agent, the oral factor Xa inhibitor edoxaban, also tested in patients with atrial fibrillation, suggested good tolerability and efficacy in patients naïve to warfarin [Koretsune, Y. et al., Abst 1022-114]. In addition, the protease-activated receptor-1 antagonist F-16618 was confirmed active in reducing thrombus formation in ex vivo experimental studies [Chelliah, R.K. et al., Abst 1013-116].
An important contribution to this year’s meeting were the results of the ACTIVE A trial, according to which the combination of clopidogrel and aspirin reduced major vascular events, especially stroke, with an acceptable increase in the risk of major bleeding in patients with high-risk atrial fibrillation unsuitable for vitamin K antagonist therapy [Connolly, S.J. et al., Abst 416-6] (Fig. 3).
Fig. 3. Stroke, myocardial infarction, vascular death, non-central nervous system embolism and combined endpoint rates in patients receiving aspirin alone or combined with clopidogrel in the ACTIVE A trial [Connolly, S.J. et al., Abst 416-6].
CORONARY ARTERY DISEASE
Fibrinolytic therapy is essential in the acute treatment of many patients with acute coronary syndromes, although its use has been decreasing steadily in recent years with a concomitant increase in use of antiplatelet agents, as well as an increase in the use of prehospital fibrin-specific fibrinolytic drugs that, according to the SWEDEHEART registry, has been associated with an increase in the incidence of major bleeding [Oldgren, J. et al., Abst 1032-125]. In that context, the fibrin peptide FX-06 used as an adjunct to primary percutaneous coronary intervention in patients with ST segment-elevated myocardial infarction was associated with significant reductions in infarct size in the FIRE trial, but only in patients catheterized less than 3 hours after pain onset [Hallen, J. et al., Abst 1032-131] (Fig. 4).
Fig. 4. Infarct size at 4 months as assessed by gadolinium-enhanced cardiac magnetic resonance imaging in patients treated with FX-06 or placebo undergoing percutaneous coronary intervention earlier or later than 3 hours after pain onset [Hallen, J. et al., Abst 1032-131].
News continued to be reported during this year’s ACC Scientific Sessions on the usefulness of aspirin and clopidogrel as antiplatelet agents for the treatment and prevention of cardiovascular events, including aspects of efficacy, as well as regarding their underuse in the real-world setting [Sanchez, D.R. et al., Abst 1010-04; Maddox, T. et al., Abst 1019-02; Tamariz, L. et al., Abst 1037-29] and resistance to either of the agents or their combination [Waksman, R. et al., Abst 2510-643; Eshtehardi, P. et al., Abst 2515-758; Price, M.J. et al., Abst 2515-759; Rade, J.J. et al., Abst 0906-4; Lee, K. et al., Abst 1041-128; Saraf, S. et al., Abst 1013-108; Schäfer, A. et al., Abst 0403-7] and the risk for events in case of underresponse or lack of treatment [Sibbing, D. et al., Abst 2627-10], which may be the case in patients with resistance to antiplatelet therapy, which is not uncommon in diabetic individuals [Mangiacapra, F. et al., Abst 2505-659] and could be overcome by higher loading and/or maintenance doses, although with an increased risk for bleeding [Serebruany, V. et al., Abst 1041-126; Hobson, A. et al., Abst 1037-26; Huczek, Z. et al., Abst 1022-101]. While confirmation of the benefits of low-dose aspirin (81 mg) on the incidence of stent thrombosis after either bare metal or drug-eluting stent implantation was reported [Cui, J. et al., Abst 2515-746], specific data regarding clopidogrel confirmed its significant, dose-dependent inhibitory effect on platelet aggregation and induction of disaggregation [Cushing, D. et al., Abst 2515-749; Capranzano, P. et al., Abst 2515-752; Angiolillo, D.J. et al., Abst 2515-757], establishing an effect in improving endothelial function [Luu, L.J. et al., Abst 1013-106], enhancing platelet-derived nitric oxide bioavailability (at least in experimental animals) [Mason, R.P. et al., Abst 1022-120; Mason, R.P. et al., Abst 1031-95] and protecting against diabetes-induced vascular damage [McChung, J.A. e tal., Abst 1013-119]. Further results corroborated its beneficial impact on patency and clinical outcomes after percutaneous coronary intervention for ST segment-elevated myocardial infarction [Vlaar, P.J. et al., Abst 1032-135] (Fig. 5) and demonstrated an association between high use of clopidogrel during 12 months after drug-eluting stent implantation and higher risk for bleeding, whilst low use of clopidogrel was associated with a greater risk for death or nonfatal myocardial infarction [Petersen J.L. et al., Abst 2501-522]. Cessation of clopidogrel within 90 days was related to high risk of recurrent coronary syndromes [Wygant, G.D. et al., Abst 0919-7], within 6 months was strongly associated with a rebound effect, which was not observed when cessation of the drug was later after percutaneous coronary interventions [Lemesle, G. et al., Abst 2903-6] and discontinuation prior to a full year of therapy after stent implantation for acute myocardial infarction resulted in significantly increased risk of death, acute myocardial infarction-related hospitalization or acute coronary syndrome-related procedure [Wiederkehr, D. et al., Abst 1032-41] although discontinuation for up to 10 days was deemed safe in additional studies [Filion, K.B. et al., Abst 1037-28]; platelet transfusion without interrupting clopidogrel therapy could be another option in case of surgery [Sharma, S. et al., Abst 1046-13]. On the other hand, extending treatment with clopidogrel beyond 12 months after coronary stent implantation did not further reduce the risk of stent thrombosis, death or myocardial infarction [Seo, J.S. et al., Abst 2501-527; Harjai, K.J. et al., Abst 2515-741]. Furthermore, pretreatment with clopidogrel plus aspirin and heparin prior to percutaneous intervention in patients with ST segment-elevated myocardial infarction brought about significant reductions in ischemic complications and improvements in patency without excess risk of bleeding [Larson, D.M. et al., Abst 2512-697]. Regarding additional issues, no pharmacokinetic or pharmacodynamic interaction was noted between clopidogrel and proton pump inhibitors, concomitant therapy resulting in no adverse clinical outcomes [Tsiajousis, G.Z. et al., Abst 1041-125], except for a reduced response to clopidogrel when omeprazole was used [Ramirez, J.F. et al., Abst 2903-7; Sibbing, D. et al., Abst 2515-736], although reduced response to clopidogrel was noted in carriers of the CYP2C19*2 allele [Anderson, J.L. et al., Abst 2903-8; Gurbel, P.A. et al., Abst 2404-14; Collet, J.P. et al., Abst 2404-16]. On the other hand, the CATER study ruled out a direct antiinflammatory effect of clopidogrel on C-reactive protein levels [Muhlestein, J.B. et al., Abst 1022-108]. Finally, while hypersensitivity to clopidogrel has been described, characterized by pruritic erythematous rash [Cheema, A.N. & Mohammad, A., Abst 2515-751], desensitization after a percutaneous coronary intervention was deemed feasible with corticosteroid/antihistamine combinations, without compromising short- and long-term outcomes [Jilaihawi, H. et al., Abst 2903-9; Campbell, K.L. et al., Abst 2515-739]. An additional issue was the suggestion and evidence of improved outcomes with higher loading and/or maintenance doses of clopidogrel in patients with or at risk for resistance/underresponsiveness. According to some studies, higher maintenance doses of clopidogrel did not prolong platelet aggregation time [Tsagalou, E. et al., Abst 1041-137], while high loading doses were unable to sufficiently inhibit platelet reactivity in patients with the PIA2 variant of the glycoprotein IIIa gene [Motovska, Z. et al., Abst 1041-158].
Fig. 5. Multivariate-adjusted relative risk of TIMI grade 2-3 flow, mortality and death/reinfarction in patients treated or not with clopidogrel [Vlaar, P.J. et al., Abst 1032-135].
A more recent thienopyridine, prasugrel, has been previously reported more effective than clopidogrel at inhibiting platelet aggregation, and was also found superior to clopidogrel in preventing cardiovascular death, reinfarction and stroke after percutaneous coronary intervention [O’Donoghue, M.L. et al., Abst 1001-293]; new research has identified its lack of interaction with drugs metabolized by the P450 cytochrome enzyme system [O’Donoghue, M. et al., Abst 1032-143], although polymorphisms of P450 2C19 do have an impact on the response to and risk in patients treated with clopidogrel [Collet, J.P. et al., Abst 0912-6]. However, new results from the TRITON-TIMI 38 study, presented as a poster in Orlando, suggested no superiority over prasugrel regarding clinical outcomes, but a trend towards higher risk for bleeding in patients with a history of transient ischemic attack or cerebrovascular accidents undergoing percutaneous coronary intervention [Desai, N.R. et al., Abst 2514-718] (Fig. 6). A further novel antiplatelet agent, the oral reversible P2Y12 receptor blocker ticagrelor, was shown to enable sustained coronary artery recanalization with recovery of myocardial perfusion after myocardial infarction when combined with alteplase, an effect that was not attained with clopidogrel in the same experimental model [Wang, K. et al., Abst 1014-133] (Fig. 7).
Fig. 6. Rates of death/myocardial infarction/stroke/major non-coronary artery bypass-related bleeding in patients receiving prasugrel or clopidogrel combined with aspirin, depending on prior history or not of transient ischemic attack/cerebrovascular accident [Desai, N.R. et al., Abst 2514-718].
Fig. 7. Infarct size after treatment with ticagrelor or clopidogrel after experimental myocardial infarction [Wang, K. et al., Abst 1014-133].
Besides the widely accepted dual antiplatelet therapy, usually consisting of aspirin and clopidogrel, triple therapies have been tested for efficacy, in some cases showing improved cardiovascular outcomes without increasing the risk of bleeding. That was the case in a trial in diabetic patients with acute myocardial infarction undergoing drug-eluting stent implantation with triple therapy containing cilostazol compared to dual therapy alone [Chen, K.Y. et al., Abst 2505-661] (Fig. 8), results that were corroborated in additional studies in other high- or standard-risk patient populations [Ueda, H. et al., Abst 2508-616; Chen, K.Y. et al., Abst 2512-705; Chen, K.Y. et al., Abst 2515-747; Park, K.H. et al., Abst 2515-754], but apparently not, or at least not significantly, in an overall cohort of patients with acute non-ST segment-elevated myocardial infarction without high-risk characteristics undergoing percutaneous interventions [Chen, K.Y. et al., Abst 2512-692] (Fig. 9). Furthermore, addition of cilostazol was deemed superior to increasing the dose of clopidogrel to improve antiplatelet responsiveness after drug-eluting stent implantation [Joo-Yong, H. et al., Abst 2515-738]. On the contrary, no evidence of benefit, but rather nonconclusive harm (significant increase in 1-year mortality partially explainable by baseline differences), was noted in a registry when assessing addition of warfarin to dual antiplatelet therapy with aspirin and clopidogrel [Plessa, A.M. et al., Abst 2515-745], although diagnostic and interventional procedures during uninterrupted combined oral anticoagulation and antiplatelet therapy was considered feasible and safe in additional studies [Tizon-Marcos, H. et al., Abst 2520-785] and according to a meta-analysis, triple therapy may be superior to standard dual therapy despite the higher risk for major bleeding complications [Singh, P.P. et al., Abst 1028-08].
Fig. 8. Major adverse cardiovascular event rates over 8 months in diabetic patients receiving dual (aspirin plus clopidogrel) or triple (the same plus cilostazol) antiplatelet therapy after drug-eluting stent implantation [Chen, K.Y. et al., Abst 2505-661].
Fig. 9. Major adverse cardiovascular event rates over 8 months in patients receiving dual (aspirin plus clopidogrel) or triple (the same plus cilostazol) antiplatelet therapy after percutaneous coronary interventions [Chen, K.Y. et al., Abst 2512-692].
In addition to antiplatelet therapies, antithrombotic regimens are also crucial in the acute management of acute coronary syndromes. In that respect, heparin dose requirements were reported to be reduced in obese compared to nonobese patients undergoing coronary interventions [Shimada, Y.J. & Kanei, Y., Abst 2515-737], while in patients not undergoing reperfusion, the relative risk reduction for in-hospital death was lower when using enoxaparin compared to heparin [Tatu-Chitoiu, G. et al., Abst 1032-144]. To note, the anticoagulant effect of enoxaparin could be effectively monitored immediately before catheterization to allow for safe percutaneous coronary interventions [Silvain, J. et al., Abst 2515-755]. Further observations were reported with fondaparinux, which according to a two-year routine experience in almost 3,000 patients with acute coronary syndromes was extensively and effectively used for medium-risk patients, although high-risk patients were still mainly receiving unfractionated heparin [Schiele, F. et al., Abst 1023-147]; according to the ACTION registry, unfractionated heparin continues to be the most commonly used antithrombin drug for myocardial infarction [Kadakla, M.B. et al., Abst 1032-129].
Although abciximab did not offer clear additional benefits when added to clopidogrel in patients with acute myocardial infarction, as demonstrated in the BRAVE-3 trial [Birkmeier, K.A. et al., Abst 2907-8], and offered no advantages over tirofiban regarding postinfarction left ventricular function in patients undergoing primary angioplasty in the FATA trial [Tagliery, N. et al., Abst 1032-137], the agent has been effectively and safely used in a number of studies in patients undergoing primary percutaneous interventions [Bertrand, O.F. et al., Abst 2907-9]. Tirofiban was also reported effective, with benefits on ST segment resolution and reduced infarct size when administered as high-dose bolus prior to percutaneous reperfusion [Heestermans, A.A.C.M. et al., Abst 1032-153], but according to the AGIR2 trial, prehospital administration of high-dose tirofiban did not offer advantages over cath-lab administration [Bonnefoy, E. et al., Abst 2406-13] (although benefits were derived from early tirofiban in the ON-TIME-2 trial, creating discussion and discrepancy [Hamm, C.W. et al., Abst 2406-16]). Similarly, early administration of eptifibatide offered no advantage in the EARLY-ACS trial [Newby, L.K. et al., Abst 411-10]. The safety and efficacy of the small-molecular-weight glycoprotein IIb/IIIa blockers tirofiban and eptifibatide combined with abciximab in patients undergoing primary percutaneous coronary interventions was demonstrated in a pooled analysis of five randomized trials [Tamhane, U.U. et al., Abst 2514-731], although intracoronary administration resulted in adverse cardiac events compared to intravenous administration [Bahekar, A.A. et al., Abst 2514-733]. Furthermore, comparisons between bivalirudin and heparin with glycoprotein IIb/IIIa inhibitors or protamine revealed equiefficacy, but a lower risk of bleeding in elderly and nonelderly subjects undergoing percutaneous interventions when using bivalirudin [Nikolsky, E. et al., Abst 2903-5; Mehran, R. et al., Abst 2507-665; Mehilli, J. et al., Abst 2514-729; Goto, K. et al., Abst 2514-730; Iqbal, S.N. et al., Abst 2514-732; Singh, S. et al., Abst 2514-735; Parodi, G. et al., Abst 1050-152] (Fig. 10); the safety of bivalirudin compared to heparin with glycoprotein IIb/IIIa inhibitors was also confirmed in an analysis of results in diabetic populations [Feit, F. et al., Abst 2505-653], although some studies found no superiority of bivalirudin over heparin alone regarding safety, bleeding risk or clinical outcomes after low-risk percutaneous coronary intervention for ST segment-elevated myocardial infarction [Kaul, S. et al., Abs 2512-684; Kaul, S. et al., Abst 1041-160] and at least one study suggested better outcomes with bivalirudin than heparin in the very elderly [Lemesle, G. et al., Abst 2514-726] (additional data supporting the use of bivalirudin in nonagenarian, mostly female patients, was also presented [Lemesle, G. et al., Abst 2520-786]). In addition, while wire perforation is a risk inherent to percutaneous coronary interventions, it could normally be managed by discontinuing anticoagulation when bivalirudin was used, but often needed aggressive treatment when heparin was used, pointing to a further advantage of bivalirudin over heparin [Kini, A.S. et al., Abst 2515-743]. Furthermore, the safety of add-on bivalirudin regarding bleeding was independent of clopidogrel loading dose, and was maintained in patients receiving 600 mg of the thienopiridine [Dangas, G.D. et al., Abst 2512-691]. Nevertheless, although bivalirudin was effective in both men and women, women had consistently poorer outcomes [Grinfeld, L. et al., Abst 2512-702], whilst the higher risk of adverse events in women treated with bivalirudin resulted in superior overall outcomes with heparin plus glycoprotein IIb/IIIa blockers in the female gender [Lansky, A.J. et al., Abst 2514-719].
Fig. 10. Ischemic event rates and major/minor bleeding rates in patients receiving bivalirudin or heparin plus glycoprotein IIb/IIIa inhibitors [Mehran, R. et al., Abst 2507-665].
Antianginal therapies may also have a role, not only in chronic stable angina, but also in acute syndromes. As an example, intracoronary administration of nicorandil prior to reperfusion for acute ST segment-elevated myocardial infarction was noted to reduce no- and slow reflow phenomena, prevent reperfusion arrhythmia and improve myocardial blood flow during percutaneous interventions [Lee, H.C. et al., Abst 2512-679] (Fig. 11). On the contrary, intracoronary administration of adenosine before and after stenting of the infarct artery did not improve myocardial perfusion in the ADAPT trial [Fokkema, M.L. et al., Abst 2514-727].
Fig. 11. Reperfusion arrhythmia or no-/slow reflow rates in patients receiving or not intracoronary nicorandil [Lee, H.C. et al., Abst 2512-679].
Miscellaneous additional topics discussed in relation to treatment of myocardial infarction included the benefits brought about by anakinra in preventing adverse cardiac remodeling after experimental acute myocardial infarctions [Salloum, F.N. et al., Abst 1015-184; Salloum, F.N. et al., Abst 1012-68], the effect of tadalafil in limiting experimental myocardial ischemia/reperfusion injury and preserving left ventricular function [Salloum, F.N. et al., Abst 1014-151], the favorable impact of indapamide in patients with in-stent restenosis [Deftereos, S. et al., Abst 1037-27] and the feasibility of the BL-1040 myocardial implant for preventing deterioration of the myocardium after acute infarction [Tuvia, S. et al., Abst 407-10]. Also in the experimental setting, cotreatment with adenovirus-associated vascular endothelial growth factor and angiopoietin-1 enhanced collateral vascularization and attenuated ventricular remodeling after a myocardial infarction [Samuel, S.M. et al., Abst 0921-6].
Interest in the topic of drug-eluting stents remains high, as reflected by the important number of presentations on this topic at the meeting, including the benefits of sirolimus- and paclitaxel-eluting stents in diabetic individuals and other high-risk patients and lesions [Caixeta, A. et al., Abst 2901-5; Lemesle, G. et al., Abst 2505-655; Nasu, K. et al., Abst 2505-656; Kataoka, Y. et al., Abst 2505-658; Kataoka, Y. et al., Abst 2505-663; Sabate, M. et al., Abst 2515-744; Lee, J.Y. et al., Abst 2909-5; Chieffo, A. et al., Abst 2909-6; Nakamura, S. et al., Abst 2909-7; Mendiz, O.A. et al., Abst 2909-8; Nakamura, S. et al., Abst 2519-779; de Ribamar Costa, J. et al., Abst 2519-780; Harjai, K.J. et al., Abst 2519-781; Kleiman, N.S. et al., Abst 2519-782; Naidu, S.S. et al., Abst 2520-791; Kyono, H. et al., Abst 2520-794; Moreira, A. et al., Abst 2520-795; Zhao, M. et al., Abst 2522-809; Girasis, C. et al., Abst 2522-810; Hayes, K.R. et al., Abst 1023-140; Cruden, N. et al., Abst 2901-6; Ohno, Y. et al., Abst 2901-7; Kadota, K. et al., Abst 2901-8; Byrne, R.A. et al., Abst 2901-9; de Ribamar Costa, J. et al., Abst 2901-10; Lansky, A.J. et al., Abst 2604-7; Thayssen, P. et al., Abst 2501-502; Collins, S.D. et al., Abst 2501-503; Nakazawa, G. et al., Abst 2501-504; Tellez, A. et al., Abst 2501-505; Pengyala, L.K. et al., Abst 2501-506; Oposlki, M.P. et al., Abst 2501-511; Han, Y. et al., Abst 2501-512; Waseda, K. et al., Abst 2501-513; Aboodi, M.S. et al., Abst 2501-516; Miyamoto, M. et al., Abst 2501-517; Costa, R.A. et al., Abst 2501-519; Shiode, N. et al., Abst 2501-523; Kelbæk, H. et al., Abst 2501-524; Endo, M. et al., Abst 2501-528; Kawaguchi, R. et al., Abst 2501-531; Ellis, S.G. et al., Abst 2501-534; Kimura, M. et al., Abst 2501-535; Costa, R.A. et al., Abst 2501-537; Kim, U. et al., Abst 2501-538; Kimura, M. et al., Abst 2501-539; Kim, B.K. et al., Abst 2501-541; Tsai, T.T. et al., Abst 2501-542; Gioia, G. et al., Abst 2501-544; Matsumoto, D. et al., Abst 2502-546; Jabara, R. et al., Abst 2502-547; Chamié, D. et al., Abst 2502-554; Matsumoto, D. et al., Abst 2502-555; de Ribamar, Costa, J. et al., Abst 2502-558; Toutouzas, K. et al., Abst 2502-561; Jensen, L.O. et al., Abst 2505-654; Chakravarty, T. et al., Abst 2506-608; Nakamura, S. et al., Abst 2506-611; Nakamura, S. et al., Abst 2506-612; Kang, S.H. et al., Abst 2506-613; Soingh, T. et al., Abst 2507-669; Hussain, S.A. et al., Abst 2507-672; Syed, A. et al., Abst 2507-674; Stolker, J.M. et al., Abst 2508-617; Habara, S. et al., Abst 2508-618; Novack, V. et al., Abst 2508-619; de Ribamar Costa, J. et al., Abst 2508-621; Yeo, W.T. et al., Abst 2510-631; Yano, M. et al., Abst 2510-632; Lasala, J.M. et al., Abst 2510-633; Kozuki, A. et al., Abst 2510-634; Nasu, K. et al., Abst 2510-635; Lasala, J.M. et al., Abst 2510-636; Maluenda, G. et al., Abst 2510-637; Gandhi, N.K. et al., Abst 2510-638; Kaodta, K. et al., Abst 2510-639; Mahajan, N. et al., Abst 2510-640; Ito, H. et al., Abst 2510-642; Lee, J.Y et al., Abst 2510-645; Nakagawa, Y. et al., Abst 2510-647; Mavromatis, K. et al., Abst 2510-648; Beach, S. et al., Abst 2511-589; Nakao, K. et al., Abst 2511-598; Tamura, T. et al., Abst 2906-6; Han, Y. et al., Abst 2906-8; Ahn, Y. et al., Abst 2512-706; Price, G.S. et al., Abst 2516-762; Ormiston, J. et al., Abst 2517-769; Nakamura, S. et al., Abst 2518-774; Nakamura, S. et al., Abst 2518-775; Fujita, H. et al., Abst 2518-776; Nakamura, S. et al., Abst 2519-777; Higo, T. et al., Abst 1041-144; Higo, T. et al., Abst 1041-149; Noda, K. et al., Abst 1041-150; Hu, S. et al., Abst 1050-150; Tamura, H. et al., Abst 1050-153; Applegate, R.J. et al., Abst 0918-7; Jurkovitz, C.T. et al., Abst 1028-04; Brennan, J.M. et al., Abst 1028-25; Serikawa, T. et al., Abst 1037-19; Kiukreja, N. et al., Abst 1037-20; Tiwari, D. et al., Abst 1037-22; Santos, R.M. et al., Abst 1037-24; Schneider, H. et al., Abst 1046-01; Hawi, R. et al., Abst 1046-04; Douglas, P.S. et al., Abst 0919-4], and confirmation of the effectiveness of newer drug-eluting stents, including those releasing zotarolimus [de la Torre Hernández, J.M. et al., Abst 2501-508; Dibra, A. et al., Abst 2501-518; Lotan, C. et al., Abst 2501-521; Waseda, K. et al., Abst 2501-525; Park, S.M. et al., Abst 2501-532; Lotan, C. et al., Abst 2501-533; Nakatani, D. et al., Abst 2501-536; Kim, J.W. et al., Abst 2501-543; Williams, M.L. et al., Abst 2510-641; Rothman, M.T. et al., Abst 2510-644; Nakatani, D. et al., Abst 2523-834], everolimus [Onuma, Y. et al., Abst 2501-510; Onuma, Y. et al., Abst 2501-514; Serruys, P.W. et al., Abst 2501-520; Trabattoni, D. e tal., Abst 2517-768; Kukreja, N. et al., Abst 1037-25], biolimus A9 [Kaluza, G.L. et al., Abst 2516-761; Katuza, G.L. et al., Abst 2516-763; Hasegawa, T. et al., Abst 2517-764; Tada, N. et al., Abst 1037-21], myolimus [Rutsch, W. et al., Abst 2510-646] and bevacizumab [Toutouzas, K. et al., Abst 2521-797; Toutouzas, K. et al., Abst 1031-101] (some of them only in experimental animal models), without marked differences in outcomes between all currently available stents, although with lower restenosis rates for sirolimus- and everolimus-eluting stents [Nakamura, S. et al., Abst 2506-609; Nakamura, S. et al., Abst 2506-610; Nakamura, S. et al., Abst 2519-778] (Figs. 12 and 13); however, according to some data, sirolimus- and paclitaxel-, but not novel stents may be associated with impaired endothelium-dependent vasomotion [Shin, D.I. et al., Abst 1022-100]. However, results from the SYNTAX registry suggested reduced need for revascularization after coronary artery bypass graft surgery compared to paclitaxel-eluting stents, although with no differences in major adverse cardiovascular event rates [Banning, A.P. et al., Abst 2901-12] (Fig. 14) (although other reviews suggested equiefficacy or even superiority, but lower revascularization rates with drug-eluting stents [Roukoz, H. et al., Abst 2501-509; Parikh, S.V. et al., Abst 2501-530]), while a review at autopsy from the CVPath registry suggested higher rates of stent-related death among patients implanted with drug-eluting compared to bare metal stents [Vorpahl, M. et al., Abst 2501-507].
Fig. 12. Target lesion revascularization rates at 9 months and major adverse cardiovascular event rates at 2 years in patients receiving sirolimus-, paclitaxel-, zotarolimus- or everolimus-eluting stents as a treatment for left main coronary artery disease [Nakamura, S. et al., Abst 2506-609].
Fig. 13. Target lesion revascularization, restenosis and major adverse cardiovascular event rates at 9 months in patients receiving sirolimus-, paclitaxel-, zotarolimus- or everolimus-eluting stents as a treatment for small coronary artery disease [Nakamura, S. et al., Abst 2519-778].
Fig. 14. Revascularization rates in patients undergoing coronary artery bypass graft surgery or paclitaxel-eluting stent implantation according to background disease state [Banning, A.P. et al., Abst 2901-12].
CARDIOVASCULAR RISK FACTORS
Hypertension
New observations with beta-blockers reported during this year’s meeting included data to suggest an effect not only in reducing blood pressure, but at least in the case of atenolol, also in reducing arterial stiffness and increasing arterial wave reflection, while metoprolol increased arterial stiffness and reduced arterial wave reflection [Hefferman, K.S. et al., Abst 0904-6]. Differences were also apparent comparing extended-release formulations of carvedilol and metoprolol, the former significantly lowering triglyceride, fasting insulin and C-peptide levels [Lukas, M.A.E. et al., Abst 0910-5]. Propranolol, which is still used frequently in primary care for hypertension, was reported to increase the risk of severe myopathy in elderly subjects [Setoguchi, S. et al., Abst 1021-72].
Dihydropyridine-type calcium channel blockers offer also a valid option for the treatment of hypertension, with activity reducing the risk of all-cause death compared to placebo or alternative drugs, according to a meta-analysis [Costanzo, P. et al., Abst 0910-6].
Regarding angiotensin-converting enzyme inhibitors, their activity was documented to depend on genetic polymorphisms of the renin-angiotensin system and bradykinin pathway genes, indicating the feasibility of pharmacogenetic profiling to identify patients most likely to benefit from such agents in the treatment of hypertension [Brugts, J.J. et al., Abst 1048-74]. Nevertheless, according to a retrospective observational registry of more than 10,000 patients, use of angiotensin-converting enzyme inhibitors prior to coronary artery bypass graft surgery was associated with increased risk for death, postoperative renal dysfunction, atrial fibrillation and need for inotropic support [Miceli, A. et al., Abst 0906-3]. Specific data was reported with perindopril, which in the ADVANCE, EUROPA and PROGRESS trials offered consistent cardioprotective effects across the full range of blood pressure strata [Brugts, J.J. et al., Abst 1048-87]. On the other hand, a general effect of renin-angiotensin system blockers in preventing left atrial remodeling in patients with chronic atrial fibrillation was reported in a long-term echocardiographic study [Fukuda, Y. et al., Abst 1018-242].
According to the JIKEI Heart Study, valsartan was both effective in the management of hypertension in diabetic individuals, and effective in preventing new-onset diabetes in nondiabetic hypertensive patients, and in both populations was superior to non-angiotensin receptor blocker-based therapy in preventing cardiovascular outcomes [Ikewaki, K. et al., Abst 1030-72]. Besides blood pressure-lowering activity, telmisartan brought about increases in adiponectin levels [Kawagoe, J. et al., Abst 1031-118] and improvements in endothelial function and nitrate tolerance [Watanabe, H. et al., Abst 1031-112] (Fig. 15), and a new mechanistic study revealed inhibitory activity on the ATP-binding cassette transporters P-glycoprotein, breast cancer resistance protein (BCRP) and multidrug resistance-related protein-2 (MRP2) [Benndorf, R.A. et al., Abst 1039-69]. On the other hand, candesartan, like omapatrilat, modulated matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinases-3 levels in the reperfused myocardium, limiting remodeling during healing after ischemia [Jungdutt, B.I. et al., Abst 1014-159].
Fig. 15. Flow-mediated vasodilatation during 8 weeks of treatment with telmisartan compared to control subjects with coronary artery disease and metabolic syndrome [Watanabe, H. et al., Abst 1031-112].
With additional peroxisome modulator-activated receptor-gamma-modulating activity, the angiotensin receptor blocker irbesartan improved insulin sensitivity in nondiabetic patients with chronic heart failure, offering additional benefits [Doehner, W. et al., Abst 1024-206].
Use of aliskiren alone or combined with losartan did not result in excess rates of hyperpotassemia in the ALLAY trial [Desai, A.S. et al., Abst 0910-3], although surveillance for hyperpotassemia remains important when using renin-angiotensin inhibitors in the treatment of hypertension in patients with diabetes or renal impairment [Desai, A.S. et al., Abst 0910-3].
Dyslipidemia and hypercholesterolemia
Statins have become the mainstay in the treatment of hypercholesterolemia, with an effect in inhibiting atheroma progression and/or inducing regression [Kokubu. N. et al., Abst 1012-88; Komura, N. et al., Abst 1021-68; Arai, H. et al., Abst 1032-152; Ozaki, Y. et al., Abst 1041-138], preventing cardiovascular events [Stein, E.A. et al., Abst 1048-89] including stroke [Alsheikh-Ali, A.A. et al., Abst 1012-90; Chen, P.S. et al., Abst 1021-73], and benefits directly correlated to their effect in lowering LDL-cholesterol [Alsheikh-Ali, A.A. et al., Abst 1012-84], although the benefits of statin therapy seem to be reduced in patients with diabetes [Hiro, T. et al., Abst 1021-69]. Furthermore, a meta-analysis confirmed an effect of statin therapy in lowering all-cause mortality in patients without coronary artery disease [Ray, K.K. et al., Abst 1021-88]. Interestingly, with rosuvastatin and simvastatin, but not with atorvastatin, a correlation was noted between increases in HDL-cholesterol and dose of the statin, independently of the effect on LDL-cholesterol levels [Barter, P.J. et al., Abst 1021-87].
Results with specific statins were discussed during the meeting, including a trial suggesting that switch from atorvastatin to simvastatin resulted in significantly lower likelihood of meeting LDL-cholesterol treatment goals compared to continuing atorvastatin in a secondary prevention setting [Aronow, H.D. et al., Abst 1021-78], while compared to lower doses, high-dose atorvastatin offered sustained benefits in cardiovascular prevention in elderly patients with stable coronary artery disease [Wenger, N.K. et al., Abst 1039-87]. Atorvastatin was also reported to protect against periprocedural non-Q-wave myocardial infarction and improve clinical outcomes in patients undergoing percutaneous coronary interventions [Briguori, C. et al., Abst 2412-7; DiSciascio, G. et al., Abst 2412-10], prevent progression of aortic valve calcification [Goldman, M.J. et al., Abst 1043-214] and attenuate severe myxomatous mitral regurgitation in experimental animals through an effect on the Sox9 pathway controlling chondrocyte formation [Rajamannan, N.M. et al., Abst 1034-227], and when combined with metformin reduced post-glucose loading E-selectin and tumor necrosis factor-alpha levels [Konniari, A. et al., Abst 1040-99]. However, simvastatin remains an effective statin, and evidence of blockade of LDL-cholesterol-mediated monocyte adhesion molecule overexpression was obtained [Serrano, C.V. et al., Abst 1039-76].
Rosuvastatin was also corroborated as an effective statin for the management of hypercholesterolemia, as further confirmed during this year’s meeting by the presentation of the PLUTO trial in children with familiar hypercholesterolemia [Avis, H.J. et al., Abst 1021-83] (Fig. 16). Furthermore, the CORONA trial confirmed the benefits of rosuvastatin in prevention of hospitalization in patients with advanced systolic heart failure [Waagstein, F. et al., Abst 1015-205] (Fig. 17), while the JUPITER study evidenced the benefits of early rosuvastatin administration in healthy men and women and its preventive effect against venous thromboembolism in normocholesterolemic individuals [Glynn, R.J. et al., Abst 404-6; Ridker, P.M. et al., Abst 413-6] (Fig. 18). On the contrary, in the AURORA trial rosuvastatin did not offer apparent cardiovascular protection in patients with end-stage renal disease [Fellstrom, B. et al., Abst 413-12].
Fig. 16. Percent of children treated with increasing doses of rosuvastatin achieving LDL-cholesterol levels <110 mg/dl during 12 weeks of treatment [Avis, H.J. et al., Abst 1021-83].
Fig. 17. Cardiovascular hospitalization and hospitalization for worsening heart failure in patients treated with rosuvastatin or placebo during the 24-month CORONA trial [Waagstein, F. et al., Abst 1015-205].
Fig. 18. Venous thromboembolism rates in patients treated with rosuvastatin or placebo in the JUPITER trial [Glynn, R.J. et al., Abst 404-6].
Many, if not all statins have been shown to possess additional beneficial activities on the cardiovascular system, named "pleiotropic effects," which may be one of the mechanisms by which statin therapy reduces mortality in a number of settings independent of atherosclerosis disease status [Shah, A.I. et al., Abst 1012-87]. New pleiotropic effects of statins were reported during this year’s ACC meeting, as described here. First, pretreatment with high-dose atorvastatin before percutaneous coronary intervention significantly prevented periprocedural myocardial damage, but no benefit was obtained in patients on chronic statin therapy [Carla, A. et al., Abst 2515-756]. In the case of rosuvastatin, studies in patients with stable systolic heart failure demonstrated an effect in increasing endothelial progenitor cell counts [Tousoulis, D. et al., Abst 1033-169], while studies in patients with familial dyslipidemia confirmed a role in improving aortic stiffness [Masoura, C. et al., Abst 1013-118]. Regarding pravastatin, an effect was noted in increasing adiponectin levels without modifying insulin levels, whereas simvastatin significantly increased insulin levels and decreased plasma adiponectin [Koh, K.K. et al., Abst 1022-102] (Fig. 19). Turning to related experimental findings, pravastatin synergistically amplified endogenous cardiac repair in the hibernating myocardium when administered prior to intracoronary fibroblast growth factor-5 [Szuki, G. et al., Abst 0913-3]. Drawbacks of statin use include the increased risk of tendon rupture confirmed in women during treatment [Beri, A. et al., Abst 1030-68].
Fig. 19. Comparative extralipidic metabolic effects of simvastatin and pravastatin [Koh, K.K. et al., Abst 1022-102].
Statins are remarkably effective, but not all patients reach target lipid levels with these agents alone. Their efficacy could be complemented by concomitant administration of drugs with different mechanisms of action. One such approach is the addition of the cholesterol absorption inhibitor ezetimibe, which coadministered with simvastatin improved apolipoprotein A1 and LDL- and HDL-cholesterol levels as well as platelet aggregation, but resulted in dysfunctional HDL particles that inhibited reverse cholesterol transport [Laaksonen, R. et al., Abst 1021-81; Pesaro, A.E.P. et al., Abst 1041-162] (Fig. 20). On the other hand, addition of fenofibric acid to statins improved lipid profiles in women with mixed dyslipidemia, according to trials discussed during this year’s meting [Goldberg, A.C. et al., Abst 1012-85] (Fig. 21), and addition to rosuvastatin was well tolerated and improved triglyceride and LDL- and HDL-cholesterol levels in patients with atherogenic dyslipidemia compared to either monotherapy [Roth, E.M. et al., Abst 1021-85]. In a similar fashion, addition of eprotirome to statin therapy improved lipid control, especially in patients inadequately controlled with or intolerant to statins [Kristensen, J. et al., Abst 404-8] (Fig. 22).
Fig. 20. Change in platelet aggregation time (as assessed by platelet function analyzer) after 6 weeks of treatment with high-dose simvastatin (80 mg) or low-dose simvastatin (20 mg) combined with ezetimibe (10 mg) [Pesaro, A.E.P. et al., Abst 1041-162].
Fig. 21. Percent change in lipid levels after treatment with low- or moderate-dose statin, fenofibric acid or their combination [Goldberg, A.C. et al., Abst 1012-85].
Fig. 22. Percent change in lipid levels after 12 weeks of adding increasing doses of eprotirome or placebo to statin [Kristensen, J. et al., Abst 404-8].
A further addition to the management of atherosclerosis, the selective secretory phospholipase A2 inhibitor varespladib was confirmed effective in decreasing atherogenic lipoprotein levels, with similar efficacy in patients with diabetes and normoglycemic individuals [Rosenson, R.S. et al., Abst 1021-70] (Fig. 23).
Fig. 23. Percent change in non-HDL-cholesterol levels in diabetic and nondiabetic subjects treated with varespladib or placebo [Rosenson, R.S. et al., Abst 1021-70].
Considering alternative antiatherosclerosis approaches, activity on lipid levels was also demonstrated with the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar, which showed favorable cardiovascular safety while significantly improving glycemic and lipidic profiles compared to maximum doses of pioglitazone [Lincoff, A.M. et al., Abst 1021-82] (Fig. 24).
Fig. 24. Change in glycemic and lipidic parameters after treatment with increasing doses of aleglitazar, pioglitazone 45 mg or placebo [Lincoff, A.M. et al., Abst 1021-82].
In patients with dyslipidemia and high C-reactive protein levels refractory to statin therapy, purified eicosapentaenoic acid exhibited favorable complementary antiinflammatory activity [Matsuo, Y. et al., Abst 1012-86]. Interestingly, omega 3 fatty acids also lowered C-reactive protein levels compared to placebo in a randomized trial [Muhammad, K.I. et al., Abst 1021-79] and enhanced responses to aspirin in patients with hyporesponsiveness [Lev, E.I. et al., Abst 1021-67], and in the OMEGA trial was associated with reduced mortality within one year after an acute myocardial infarction [Senges, J. et al., Abst 411-6]. Red yeast rice is an alternative approach to the treatment of dyslipidemia, as it contains monacolins that inhibit hydroxymethylglutaryl-coenzyme A reductase activity and reduce LDL-cholesterol and cardiac events [Gordon, R.Y. et al., Abst 1021-75], but high variability in the content of different products was detected [Gordon, R.Y. et al., Abst 1012-67]. Red yeast rice offered a useful approach to the control of cholesterol levels in patients with statin-associated myalgia [Becker, D.J. et al., Abst 1021-90].
Novel therapeutic options may include the small-molecular-weight apolipoprotein A1 production enhancer RVS-208, which effectively increased apolipoprotein A1 and HDL-cholesterol levels in clinical trials [Gordon, A. et al., Abst 1021-74], and the short-chain polysaccharide HEP-40, which given thrice daily to patients with high LDL-cholesterol levels effectively improved lipid profiles compared to placebo, both added to a prior statin to which the patients did not respond adequately [Sampalis, J.S. et al., Abst 1021-71] (Fig. 25). Direct antiatherosclerosis effect with inhibition of plaque progression in animals was demonstrated with the apolipoprotein A1 mimetic peptide ETC-642 [Iwata, A. et al., Abst 1013-98].
Fig. 25. Percent change in lipid levels after 12 weeks of adding HEP-40 or placebo to statin therapy [Sampalis, J.S. et al., Abst 1021-71].
Diabetes
Besides improving insulin resistance and adiponectin levels, use of pioglitazone brought about increases in arterial baroreflex sensitivity and decreases in sympathetic nerve trafficking [Yokoe, H. et al., Abst 1024-181] and, in zotarolimus-eluting stent recipients, was associated with decreased total neointima and plaque volume in diabetic patients undergoing percutaneous coronary interventions [Hong, S.J. et al., Abst 2505-650]. Treatment with pioglitazone also improved the efficacy of bone marrow-derived mesenchymal stem cell transplantation in in vivo studies [Raichlin, E. et al., Abst 1042-201]. Discordant effects of rosiglitazone compared to placebo were noted on novel biomarkers of atherosclerosis, with seemingly unfavorable effects on lymphotoin beta-receptor, peptidoglycan recognition protein-1 and macrophage inflammatory protein-3 levels despite favorable effects on advanced glycation endproducts and lipid and classic biomarker levels [Owens, A.W. et al., Abst 1021-80]. However, both pioglitazone and rosiglitazone were associated with an increased risk of edema related to adenosine signaling and vascular permeability [Ruano, G. et al., Abst 1024-187], although data from a large cohort of high-risk patients with diabetes in the real world practice demonstrated no increase in the risk of cardiovascular events with either drug compared to other diabetes medications [Naderi, N. et al., Abst 1019-16].
Smoking
Smoking is another significant cardiovascular risk factor, and exposure to environmental tobacco smoke resulted in a risk for developing left ventricular systolic dysfunction in inpatients with acute coronary syndrome, an effect mediated by exaggerated inflammatory responses [Chrysohoou, C. et al., Abst 1048-84]. In patients with coronary artery disease the effectiveness of varenicline for smoking cessation was demonstrated in a 12-week trial with a 52-week post-study follow-up [Rigotti, N.A. et al., Abst 1048-67] (Fig. 26). On the other hand, short-term (3-day) treatment with oral L-arginine in smokers improved arterial performance, prevented acute downregulation of the fibrinolytic pathway and attenuated vascular inflammation during smoking [Siasos, G. et al., Abst 1040-118].
Fig. 26. Smoking abstinence rates after 12 weeks of treatment with varenicline or placebo [Rigotti, N.A. et al., Abst 1048-67].
Additional risk factors
Diet is a recognized cardiovascular risk factor modifier, an extend that was further corroborated by a four-year follow-up of the ATTICA study confirming that adherence to a traditional Mediterranean diet is associated with improved endothelial function and lower risk for cardiovascular events and left ventricular systolic dysfunction [Panagiotakos, D.B. et al., Abst 1048-75; Panagiotakos, D.B. et al., Abst 1032-159; Rallidis, L.S. et al., Abst 1022-116]; in a related fashion, the DASH diet was associated with improved blood pressure profiles in the ENCORE trial [Blumenthal, J.A. et al., Abst 413-10]. Wine is a historical component of the Mediterranean diet, and on top of known benefits of wine in moderate amounts on endothelial function, new data revealed also an association between moderate wine consumption and low glycosylated hemoglobin levels [Sicard, P. et al., Abst 1031-116]. Additionally, the results of a retrospective evaluation indicated that moderate consumption of coffee was associated with a lower risk for developing left ventricular dysfunction after an acute coronary event in normotensive, but not hypertensive individuals [Chrysohoou, C. et al., Abst 1039-86].
VALVULAR HEART DISEASE
Besides pathophysiological and surgical aspects of valvular heart disease, a single presentation describing the results of a retrospective study suggested promise for bisphosphonates in slowing progression of degenerative aortic stenosis [Innasimuthu, A.L. et al., Abst 1043-213], although nitrogen-containing bisphosphonates were also associated with increased risk for aortic valve calcification [Elmariah, S. et al., Abst 1001-299], while analyses of the SEAS study did not establish a relationship between lipid-lowering treatment and aortic valve-related events in patients with aortic valve stenosis [Gerdis, E. et al., Abst 1043-224]. Regarding mitral regurgitation, early treatment with carvedilol was associated with worsened left ventricular remodeling and function and increased mortality [Pu, M. et al., Abst 1001-298].
HEART TRANSPLANTATION
Scarce specific news on pharmacotherapeutic support for heart transplantation were discussed during the ACC meeting in Orlando, although a poster describing an effect of sirolimus-based immunosuppression in improving coronary endothelial and vasomotor function compared to ciclosporin-based immunosuppression in stable heart transplant recipients suggested an important mechanism for prevention of allograft vasculopathy [Raichlin, E. et al., Abst 1042-187]. Also to note, sirolimus decreased, while paclitaxel increased, the expression of vascular endothelial growth factor in coronary artery smooth muscle cells [Katsaros, K.M. et al., Abst 1013-93]. On the other hand, use of bosentan and sildenafil allowed for heart transplantation with favorable outcomes in patients ineligible for transplantation because of pulmonary hypertension [Farrero, M. et al., Abst 1042-191]. In the experimental arena, combined use of nitroglycerin, cariporide and human neuregulin-1 peptide to activate prosurvival pathways during storage of donor hearts improved preservation and post-transplant function [Jabbour, A. et al., Abst 1042-194].
PULMONARY HYPERTENSION
Scarce news was reported on pulmonary hypertension during the meeting at Disney World, but a couple of presentations are worth comment. Besides improving lung function and exercise capacity, treatment with sildenafil in patients with chronic lung disease and secondary pulmonary hypertension improved hemodynamic parameters [Seo, H.S. et al., Abst 1024-190]. According to another report, inhaled iloprost improved gas exchange and pulmonary hemodynamics after acute meconium aspiration-induced lung injury, reducing pulmonary artery pressure and increasing cardiac output [Becker, E.M. et al., Abst 1049-112]. A third presentation evidenced the favorable antiinflammatory effects (decrease in intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and interleukin-6 levels) of bosentan, added to the known hemodynamic and clinical benefits in patients with severe pulmonary hypertension [Karavolias, G.K. et al., Abst 1049-119].
PERIPHERAL VASCULAR DISEASE
A late-breaking trial describing the lack of benefit of hypoxia-inducible factor-1alpha gene therapy in patients with peripheral arterial disease and intermittent claudication deserves mention [Creager, M.A. et al., Abst 404-12], although no other remarkable new data on that topic was presented during the meeting.
MISCELLANEOUS
Iodixanol was not associated with reduced nephrotoxicity compared to iomeprol when used as contrast agents in patients with renal failure undergoing coronary angiography [Koppara, T. et al., Abst 2507-664]; additional data suggested no differences between iodixanol and ioxilan, provided a renal protection strategy was utilized [Malins, T. et al., Abst 1019-19].
A phase I study confirmed the safety and feasibility of [18F]-BMS-747158 for rest/stress myocardial imaging [Maddahi, J. et al., Abst 1034-263].
Stem cell therapy was reported feasible, safe and effective in the treatment of severe limb ischemia in a phase I trial in 10 patients [Lasala, G.P. et al., Abst 2509-626].
As opposed to naproxen, use of naproxcinod in the treatment of osteoarthritis induced no meaningful changes in blood pressure [White, W.B. et al., Abst 0910-4]. On the other hand, the proatherogenic profile of celecoxib was confirmed in in vitro studies [Reiss, A.B. et al., Abst 1022-93], while a large case-crossover study confirmed the increased risk of sudden cardiac arrest during treatment with diclofenac, rofecoxib and celecoxib but not during treatment with ibuprofen or naproxen [Folke, F. et al., Abst 1001-291]. In a similar way, use of bevacizumab for cancer therapy brought about significant increases in the risk for high-grade hypertension [Pullpati, B.C. et al., Abst 1001-303].
Twice- and once-daily gentamicin were equieffective and associated with similar nephrotoxicity in the treatment of infective endocarditis [Buchholtz, K. et al., Abst 1034-212].
Use of abacavir in the treatment of HIV infection was associated with impairments in endothelial function [Hsue, P.Y. et al., Abst 1022-115].