Once again, the European Congress of Cardiology gathered cardiologists and related healthcare professionals to discuss optimal approaches to the management of a broad range of diseases of the heart and vascular system, including strategies to improve cardiovascular risk profile in subjects at risk, including notably individuals with hypertension, dyslipidemia, diabetes, obesity and related disorders. This year the meeting in Älvsjö, where the Stockholm Fair is located, allowed ample time for discussions both in the convention center itself, and in the trains commuting to and from central Stockholm, and matter for discussion there was, with the over 4,000 oral and poster presentations made during the five-day meeting. Important news were discussed on pharmacotherapy for cardiovascular disorders, and this is the main focus of the following report, prepared to complement information available through other sites and offering a comprehensive overview of new clinical and experimental findings that offer improved approaches to the treatment of patients with severe disease conditions that limit not only their life expectancy, but also function and enjoyment. DiabetesPRO offeres this full report to registered users who could not attend the meeting but still require direct knowledge of what was discussed.
Diuretics
continue to be used extensively in the management of heart failure, although
data reported in Stockholm suggested a detrimental effect of furosemide, at
least at doses higher than 15 mg, on survival in patients with systolic failure
[Dini, F.L. et al., Abst P827]. However, high-dose furosemide combined with
fluid restriction but normal sodium intake improved outcomes in advanced heart
failure that paralleled decreases in cytokine and neurohormonal biomarker
levels [Torres, D. et al., Abst P4845]. On the other hand, use of acetazolamide
in patients with heart failure and concomitant obstructive sleep apnea improved
heart rate variability and the functional class without a negative impact on
sleep apnea [Belyavskiy, E. et al., Abst P4878].
b-Blockers have a well established
role in the management of heart failure, and new studies revealed a favorable
impact on remodeling and long-term outcomes when used as a treatment for left
ventricular dysfunction after percutaneous coronary interventions for stable
angina [Ashida, K. et al., Abst P3002]. Furthermore, b-blockade, at least with carvedilol, offered
substantial protection against adverse outcomes in patients with renal failure
suffering from a myocardial infarction resulting in significant left
ventricular systolic dysfunction [Castagno, D. et al., Abst P3310], and the
agent, as well as metoprolol, restored intra- and interventricular
synchronization while reversing left ventricular remodeling and reducing
tenascin C levels in patients with idiopathic dilated cardiomyopathy [Kaya, M.G.
et al., Abst P3325] (Fig. 1),
and, combined with ornithine supplementation, further improved the quality of
life, hemodynamics and liver function in patients with chronic heart failure
secondary to coronary artery disease and concomitant nonalcoholic liver disease
[Evdokimov, V. et al., Abst P4887]. Moreover, carvedilol, but not eprosartan,
reduced not only morbidity but also mortality even in older patients with heart
failure [Adamyan, K.G. & Tumasyan, L.R., Abst P4870]. Furthermore,
metoprolol brought about a decrease in b1 receptor glutathionylation at the
sodium/potassium pump in the failing heart, resulting in increased pump
activity and helping restore adrenergic dysregulation, which is a key
pathophysiological feature of heart failure [Karimi Galougahi, K. et al., Abst
P4074]. However
insight from the CIBIS-ELD trial using carvedilol and bisoprolol suggested
clinical and ventricular improvements in systolic but only modest clinical
improvements in diastolic heart failure [Edelmann, F. et al., Abst 2862],
although both nebivolol and bisoprolol improved hemodynamic parameters, N-terminal pro-brain-type natriuretic
peptide levels and oxidative stress in patients with acute decompensated
failure, with bisoprolol faring better regarding the six-minute walking distance
and left ventricular ejection fraction [Sujeebun, S. et al., Abst P4882]. Besides,
carvedilol demonstrated potential for preventing anthracycline-induced
cardiomyopathy in patients with malignancies [Samura, B. et al., Abst P418]. In
addition, propranolol was used to demonstrate the potential of prophylactic b-blockade against exercise-triggered
arrhythmia in models of arrhythmogenic right ventricular cardiomyopathy [Gomes,
J. et al., Abst P592].
Fig. 1. Change in left ventricular ejection fraction after
6 months of treatment with carvedilol or metoprolol [Kaya, M.G. et al., Abst
P3325].
Angiotensin-converting
enzyme inhibitors and angiotensin receptor blockers have shown benefits in the
treatment of heart failure, but the combination of ramipril and telmisartan did
not result in additional efficacy in experimental models of cardiac overload
[Mueller, P. et al., Abst 176], although a combination of telmisartan and
amlodipine preserved the beneficial renal effects of the angiotensin receptor
blocker while improving blood pressure control in experimental diabetic
nephropathy [Peti-Peterdi, J. et al., Abst P648]. A combination of ramipril and
valsartan did improve outcomes slightly more than either drug alone in patients
with chronic heart failure, although similar or better results were attained
with direct renin inhibition with aliskiren monotherapy [Tumasyan, L.R. et al.,
Abst 2864] (Fig. 2),
the agent also improving QT interval duration dispersion in hypertensive
patients with diabetes [Fogari, R. et al., Abst P4044] and increasing the
number and potentiating the function of endothelial progenitor cells in experimental
animals, suggesting antiatherogenic potential [Poess, J. et al., Abst P4773].
In the same animal model, prevention of systolic and diastolic dysfunction was
demonstrated with the selective AT1 receptor blocker ZD-7155 [Fontes Carvalho, R. et al., Abst
P475]. Additional mechanistic studies in human patients indicated potential for
angiotensin-converting enzyme inhibitors, at least enalapril, for lowering ρ kinase activity, elevated
in heart failure [Liu, P.Y. et al., Abst P3196].
Fig. 2. One-year death, hospitalization and combined
endpoint rates in patients treated with ramipril, valsartan, the combination of
both or aliskiren [Tumasyan, L.R. et al., Abst 2864].
Although
underused in the clinical practice [Turner, R.D. et al., Abst P4885], aldosterone
antagonism is another area of intense research as an approach to the treatment
of heart failure, and new insight into the EPHESUS study results indicated
additional benefits of eplerenone in transiently lowering plasma glucose in
diabetic patients with post-acute myocardial infarction heart failure
[Deedwania, P. et al., Abst P2456] (Fig. 3), although a combined analysis of eplerenone and
spironolactone from an open registry did not demonstrate an impact on survival
in patients with systolic heart failure [Lund, L.H. et al., Abst 2863]. While
additional observations from experimental studies indicated an inhibitory
effect of eplerenone of degeneration of calcified aortic stenosis [Gkizas, S.
et al., Abst P5307] and experimental studies demonstrated prevention of
hypertensive cardiac remodeling [Yasuoka, S. et al., Abst P5528], observational
registry data from the clinical practice documented the safety and tolerability
of a further agent, canrenone, which, according to analyses performed by the
authors, reduced the risk of death by 40% and that of sudden death by 78%
[Nassiacos, D. et al., Abst P4880]. On the other hand, treatment of
experimental hypertension with spironolactone before heart failure develops was
associated with reduced mortality without attenuating adverse cardiac
remodeling [Cezar, M.D.M. et al., Abst P4886].
Fig. 3. Mean change in hemoglobin A1c after 1 and 12 months
of treatment with eplerenone or placebo [Deedwania, P. et al., Abst P2456].
Two
additional drugs, levosimendan and milrinone, offered hemodynamic control of
heart failure with optimal safety upon prolonged infusion without a loading
dose, but milrinone showed faster activity on systemic and pulmonary vascular
resistance, whereas levosimendan better maintained neurohumoral control
resulting in optimized clinical outcomes and less likelihood for readmission
during a three-month follow-up [Aidonidis, G. et al., Abst P4172] (Fig. 4). According to
additional, independent evidence, levosimendan enhanced the likelihood of
uptitrating b-blockers to maximal doses in
chronic heart failure patients [Kanonidis, I.K. et al., Abst P4888], had an
immediate renal vasodilating activity resulting in nephroprotection and
decreased intact parathormone levels (a predictor of rehospitalization) in
patients with decompensated heart failure [Mancone, M. et al., Abst P4861;
Okutucu, S. et al., Abst P4857] and proved as effective as dobutamine in
preventing death and rehospitalization with similar potential risk for
arrhythmia [Sargento, L. et al., Abst P4876; Cavusoglu, Y. et al., Abst 5133] (Fig. 5). A further agent,
ivabradine, improved cardiac inflammation as effectively as metoprolol in
animal models of heart failure, but as opposed to the b-blocker also improved collagen accumulation
and diastolic function, suggesting potential for the management of heart
failure with preserved ejection fraction [Westermann, D. et al., Abst P4203].
As a result, while further animal studies confirmed a heart rate-lowering
activity resulting in improved biomarkers of heart failure [Gupta, R.C. et al.,
Abst P4848], in the clinical arena, adding ivabradine to bisoprolol further
improved diastolic function and exercise capacity [Adamyan, K.G. et al., Abst
P4849]. In addition, a placebo-controlled study demonstrated benefits of
allopurinol on diastolic function, associated with reductions in N-terminal pro-brain-type natriuretic
peptide levels [Bergamini, C. et al., Abst P4847], while the results of
open-label studies documented improvements in myocardial perfusion and
hemodynamic parameters in patients with heart failure treated with nicorandil
[Tokita, Y. et al., Abst P4859; Hattori, H. et al., Abst P4871] and benefits on
left ventricular function and functional class in patients with chronic heart
failure treated with trimetazidine [Salerno, A. et al., Abst P4854]. However,
concerning the former, a comparative study suggested better effect on renal
function in acute heart failure patients receiving carperitide [Watanabe, K. et
al., Abst P4869] (Fig. 6),
although a comparison with nitroglycerin documented similar benefits on
pulmonary capillary wedge pressure at reduced hemodynamic tolerance [Singh, V.
et al., Abst 5134], whereas additional data with trimetazidine combined with
glucose-insulin-potassium indicated improved myocardial salvage after
thrombolysis for infarction [Adamyan, K.G. et al., Abst P4875]. On the
contrary, use of intravenous morphine in patients with acute decompensated
heart failure was independently associated with increased in-hospital death
rates, calling for caution in the use of the agent [Iakobishvili, Z. et al., Abst
P4867].
Fig. 4. Three-month readmission rates in patients treated
with levosimendan or milrinone [Aidonidis, G. et al., Abst P4172].
Fig. 5. Death and rehospitalization rates during 24 months
of follow-up in patients treated with levosimendan or dobutamine [Sargento, L.
et al., Abst P4876].
Fig. 6. Percent of patients treated with carperitide or
nicorandil developing a ³2.5% increase in serum creatinine during
hospitalization for acute heart failure [Watanabe, K. et al., Abst P4869].
The ρ kinase inhibitor fasudil
attenuated left ventricular hypertrophy and fibrosis more effectively than
vardenafil in animal models of diabetic cardionephropathy, resulting in better
improvement in cardiac function, although vardenafil was more effective in improving
kidney medulla fibrosis and renal function [Huntley, B.K. et al., Abst P594].
Nitrates were also reported useful, especially in patients with systolic failure,
improving worsening-related hospitalization although without reducing mortality
[Yaymaci, M. et al., Abst P4890].
At an
experimental level, apelin improved left ventricular function in animal models
of chronic heart failure without causing hypotension or modifying cardiac beat,
although with an untoward effect of increasing myocardial oxygen consumption
[Sabbah, H.N. et al., Abst P2458]. Improvements in left ventricular function in
models of advanced heart failure were also demonstrated with the nitroxyl donor
CXL-1020 [Wang, M. et al., Abst P4841].
Interesting
news were reported on cardiac dysfunction in thalassemia major, the results of
a double-blind trial indicating improvements in right ventricular function upon
iron chelation with deferoxamine [Alpendurada, F. et al., Abst P451]. Also in
relation with iron, but in the contrary situation, intravenous carboxymaltose
significantly improved the health-related quality of life regardless of the
presence of anemia in patients with chronic heart failure and iron deficiency
[Comin-Colet, J. et al., Abst P1470].
Should
heart transplantation be required in patients with advanced heart failure, it
should be noted that cotreatment with proton pump inhibitors used for the
management of post-transplant gastrointestinal discomfort resulted in reduced
exposure to mycophenolic acid in cases in which mycophenolate mofetil or
enteric-coated mycophenolate were used for immunosuppression [Doesch, A. et
al., Abst P2463; Kofler, S. et al., Abst 5222].
In the
experimental arena, the antifibrotic agent FT-23 attenuated structural and
functional remodeling in models of diabetic diastolic dysfunction [Tan, S.M. et
al., Abst 175]. In addition, oleuropein, a natural constituent of olive oil,
demonstrated cardioprotective activity against nitrosative stress-related
doxorubicin-induced cardiotoxicity [Ioannidis, K. et al., Abst P419].
Besides
pharmacotherapy, news were discussed on stem cell therapy for cardiomyopathy,
including observations on the feasibility of autologous bone marrow-derived
mesenchymal stem cells in patients with ischemic cardiomyopathy [Chin, S.P. et
al., Abst P610; Romanov, A. et al., Abst 2024], without increasing the
likelihood for arrhythmogenicity [Krause, K. et al., Abst P3851], and, in
preclinical models, the potential of human embryonic stem cell-derived
cardiomyocytes [Van Laake, L.W. et al., Abst P609]. In that context, it should
be emphasized that one of the studies presented during the Hot Line sessions of
the meeting in Stockholm, the STAR-heart trial, concluded that when
administered as an alternative to or in addition to conventional therapy,
intracoronary bone marrow-derived stem cell therapy improved the quality of
life, increased ventricular performance and prolonged survival in patients with
chronic heart failure [Strauer, B.E., Presentation 381], although such
treatment had no effect on natriuretic peptide levels in patients with acute ST
segment-elevated myocardial infarction in other studies [Miettinen, J. et al., Abst
1860]. In the experimental arena, potential was also described for skeletal
muscle- and adipose tissue-derived mesenchymal stem cells, despite no
differentiation into cardiomyocytes [Beitnes, J.O. et al., Abst P2346], and a
first in-human experience with adipose tissue-derived cells indicated safety
and feasibility as intracoronary therapy for ST segment-elevated myocardial
infarction [Houtgraaf, H.J. et al., Abst P3004]. Note that synergistic activity
was described between sildenafil and adipose tissue-derived mesenchymal stem
cells in reversing left ventricular remodeling and improving cardiac function
in models of dilated cardiomyopathy [Yip, H.K. et al., Abst P595].
During the
same Hot Line session, the results of the PEARL-HF study demonstrated that the
novel potassium binder RLY-5016 significantly reduced the risk of
hyperpotassemia compared to placebo, increasing the likelihood of using
spironolactone without serious adverse events in patients with heart failure
and chronic kidney disease [Pitt, B., Presentation 383] (Fig. 7).
Fig. 7. Hyperpotassemia rates in patients with chronic
heart failure receiving RLY-5016 or placebo [Pitt, B., Presentation 383].
New studies
discussed in Stockholm corroborated the efficacy and safety of ivabradine in
patients with angina, the treatment resulting in improved diastolic function,
reduced heart rate, improved exercise capacity and increased coronary blood
flow reserve, while preventing reperfusion ventricular fibrillation and
decreasing the number of attacks and nitrate consumption [Koester, R. et al., Abst
354; Tardif, J. et al., Abst P1335; Skalidis, E.I. et al., Abst P4600; Ng, F.S.
et al., Abst P5634] (Fig. 8).
Furthermore, ivabradine offered an alternative to patients not eligible for
intravenous b-blockers, by safely, rapidly and
persistently lowering heart rate allowing for coronary computed tomographic
angiography [Bax, J. et al., Abst 950; Guaricci, A.I. et al., Abst P1694], and
added to the best available treatment, further reduced the risk of death and
hospitalization, as demonstrated in the SHIFT trial [Komajda, M., Presentation
385] (Fig. 9). In fact,
add-on ivabradine improved exercise capacity independently of heart rate in
patients on chronic b-blockade
[Tardif, J. et al., Abst P2987], while the addition of ivabradine to bisoprolol
therapy improved not just myocardial ischemia, but also the chronotropic
reserve to a larger extent than uptitration of bisoprolol doses [Amosova, E. et
al., Abst P2981]. In addition, ivabradine in healthy volunteers increased
subendocardial viability [Dobosiewicz, A. et al., Abst P2323], whereas in
experimental severely dyslipidemic animals it improved cerebral artery
compliance and endothelial function [Bolduc, V. et al., Abst P4770]. Therapeutic
antiischemic activity was similarly obtained in patients with
exercise-triggered myocardial ischemia receiving low-dose sodium nitrite
[Ingram, T.E. et al., Abst P518]. In addition, a comparative study indicated
benefits of pentaerythritol tetranitrate, but not isosorbide dinitrate, on
circulating angiogenic cells in patients with coronary artery disease [Thum, T.
et al., Abst P1324].
Fig. 8. Total exercise time and time to 1-mm ST segment
depression, angina onset and limiting angina in patients adding ivabradine or
placebo to maximal tolerated b-blocker doses [Tardif, J. et al., Abst P1335].
|
Fig. 9. Thirty-day cardiovascular death/heart failure hospitalization
rates in patients treated with ivabradine or placebo [Komajda, M.,
Presentation 385].
|
Although
costly [Dawkins, S. et al., Abst P1340] and, at least in the case of aspirin,
with a risk for upper gastrointestinal symptoms and peptic ulcer that could be
prevented by concomitant esomeprazole [Scheiman, J. et al., Abst P2258;
Scheiman, J. et al., Abst P3982], antiplatelet therapy, mostly with aspirin and
clopidogrel, is essential in the management and prevention of coronary artery
disease [Garcia-Rodriguez, L.A. et al., Abst P2270], without the addition of
anticoagulants impacting on one-year mortality after a percutaneous coronary
intervention for ST segment-elevated myocardial infarction [Hawranek, M. et
al., Abst P1341]. In fact, individual trial data demonstrated the protective
effect of clopidogrel against recurrent myocardial infarction and death after
revascularization with coronary artery bypass graft surgery for infarction
[Sorensen, R. et al., Abst P1350], although the drug lacked direct
antiinflammatory or antioxidant activity [Ostad, M.A. et al., Abst P3218].
Besides its primary and secondary preventive benefits, upstream clopidogrel was
also associated with reduced mortality in patients undergoing primary
percutaneous coronary interventions for ST segment-elevated myocardial
infarction [Koul, S. et al., Abst 888]. Furthermore, discontinuation of
clopidogrel resulted in rebound platelet aggregability [Diehl, P. et al., Abst
1199] and increased likelihood of death [Oemrawsingh, R.M. et al., Abst P1421],
whereas earlier suspension of dual antiplatelet therapy contributed to an
increased risk for myocardial infarction, death and late or very late stent
thrombosis after drug-eluting stent implantation [Lozano Martínez-Luengas, I. et al., Abst
1344; Sakamoto, Y. et al., Abst P1345], suggesting the need for continued
treatment after drug-eluting stent implantation. Indeed, that was the case in
patients with diabetes, in which dual antiplatelet therapy for five years after
sirolimus-eluting stent implantation translated into better clinical outcomes
and reduced risk of late stent thrombosis [Karyofillis, P. et al., Abst P1430],
an extent further confirmed in unselected patients included in a registry,
which demonstrated lower risk of death and major adverse cardiovascular events
without increasing risk for bleeding with a longer duration of dual
antiplatelet therapy [Zeymer, U. et al., Abst P1424]. News were also reported
on aspirin, which was shown to improve arterial stiffness in hypertensive
conditions [Pietri, P. et al., Abst P4043]. However, resistance to antiplatelet
therapy has been reported and associated with worse outcomes [Silvain, J. et
al., Abst P1359; Moynagh, A. et al., Abst P1414; Vauranakis, M. et al., Abst
P5341; Vojacek, J.F. et al., Abst P5364], and novel data established a
relationship between underresponsiveness to clopidogrel and polymorphic
variability of the CYP2C19 gene [Giusti, B. et al., Abst 1032; Sibbing, D. et
al., Abst 1033; Ishiguro, H. et al., Abst P5334; Sawada, T. et al., Abst P5335;
Tunthong, R. et al., Abst P5336; Pettersen, A.A. et al., Abst P5337; Tanboga,
I.H. et al., Abst P5533], elevated leptin [Gatto, L. et al., Abst 1035] and
asymmetric dimethylarginine [Nusca, A. et al., Abst P1356] levels and,
according to some evidence, cotreatment with proton pump inhibitors [Jo, S.H.
et al., Abst P3008], although cotreatment with pantoprazole or lansoprazole had
no impact on dual antiplatelet therapy or the pharmacokinetics of clopidogrel
[Mizia-Stec, K. et al., Abst P1331; Rossini, R. et al., Abst P1354; Angiolillo,
D.J. et al., Abst P5339]. However, omeprazole and esomeprazole were noted to
reduce levels and antiplatelet activity during the maintenance phase [Ferreiro,
J.L. et al., Abst P1357; Harmsze, A.M. et al., Abst P5332] (albeit an
independent study suggested no impact of esomeprazole alone or combined with
atorvastatin or the statin alone on the clinical effectiveness of clopidogrel
[Theodosis Georgilas, A. et al., Abst P2324] and a meta-analysis identified no
harm of concomitant proton pump inhibitors on major adverse cardiovascular
event rates in patients receiving clopidogrel [Siller-Matula, J.M. et al., Abst
3745], whereas a further analysis of real-world patients also concluded on an
increased risk for myocardial infarction after percutaneous coronary
intervention in patients receiving proton pump inhibitors [Burkard, T. et al., Abst
5066]). Similarly, underresponsiveness and resistance to aspirin have been
reported [Jariwala, P.V. et al., Abst P1432], and the lack of efficacy of the
agent for sustaining 24-hour antiplatelet protection was also documented in a
series of patients with established coronary artery disease [Henry, P. et al., Abst
P1346]. It should be noted, though, that mechanistic data analyzing thrombosis
and bleeding during clopidogrel therapy indicated a ceiling threshold at which
higher drug levels did not increase efficacy, but result in increased bleeding,
a concept that should be remembered in case of underresponsiveness and use of
higher doses [Sibbing, D. et al., Abst 886]. Indeed increased clopidogrel doses
were associated with an elevated risk of bleeding after coronary procedures in
at least one clinical study [Cruden, N. et al., Abst P1347], although high-dose
loading was considered both safe and effective in at least two studies [Zeymer,
U. et al., Abst 1342; Sim, D.S. et al., Abst P1343], and higher maintenance
doses were also safe and effective in some patients [Aradi, D. et al., Abst
P5340; Ryu, J. et al., Abst P5365], specifically in subjects underresponsive
because of heterozygous, not homozygous CYP2C19 polymorphisms [Collet, J.P. et
al., Abst P1358], and translated into reduced risk for stent thrombosis in
patients with resistance to the antiplatelet effects of clopidogrel [Pathak, A.
et al., Abst P2327]. Note, however, that reloading with aspirin plus
clopidogrel before percutaneous coronary interventions was safe, but did not
further inhibit platelet reactivity [Ntalianis, A. et al., Abst P1420], and
consider that, although at low frequency, hyperresponsiveness to clopidogrel
with increased risk for bleeding resulting in poor outcomes has also been
reported [Moynagh, A. et al., Abst P1419; Geisler, T. et al., Abst P2121].
Regarding aspirin resistance, at least in diabetic conditions, twice- rather
than once-daily administration significantly reduced biological
underresponsiveness [Drissa, A. et al., Abst 5038]. Alternatives may include
the addition of cilostazol, as triple antiplatelet therapy in patients already
on aspirin/clopidogrel further reduced platelet reactivity, especially in
diabetic individuals, without affecting thrombin-mediated hemostasis and
increasing the risk of bleeding [Capranzano, P. et al., Abst 1198; Ha, S.J. et
al., Abst P5361], although compared to dual aspirin/clopidogrel therapy, the
addition of cilostazol had no impact on clinical outcomes in a real-world
experience in high-risk patients undergoing drug-eluting stent implantation
[Poddar, K.L. et al., Abst P3005]. In that context, cilostazol was also shown
to prevent high glucose-induced endothelial dysfunction while potentiating
angiogenesis in hyperglycemic animal models [Chao, T.H. et al., Abst P2367].
Patients not responding to clopidogrel may also benefit from treatment with
prasugrel, which proved superior in lowering platelet aggregation in patients
undergoing percutaneous coronary interventions [Xanthopoulou, I. et al., Abst
1196] (Fig. 10). Note
in that regards that discontinuation of either prasugrel or clopidogrel in the
OPTIMUS-3 trial, which included patients with type 2 diabetes, did not result
in rebound platelet reactivity [Angiolillo, D.J. et al., Abst P2315]. Another
alternative could be ticagrelor, which was less commonly associated with high
on-treatment platelet reactivity compared to clopidogrel in patients with
coronary artery disease [Bliden, K.P. et al., Abst 1195] (Fig. 11), was
nonsignificantly superior to clopidogrel in patients with non-ST
segment-elevated acute coronary syndrome in the PLATO trial [James, S. et al., Abst
P1349; James, S. et al., Abst P1353] (Fig. 12) and was not affected by concomitant proton pump
inhibitors [Patil, S.B. et al., Abst 5067], although it resulted in an
increased incidence of dyspnea [Storey, R.F. et al., Abst P1352]. An additional
meta-analysis confirmed the superiority of both prasugrel and ticagrelor over
clopidogrel, with a greater protective effect of prasugrel against stent
thrombosis [Biondi-Zoccai, G. et al., Abst P1351]. Add that, pending results
validating its impact on outcomes, improved antiplatelet activity was
documented with intravenous and oral elinogrel compared to clopidogrel in the
INNOVATE study, which included patients undergoing nonurgent percutaneous
coronary interventions [Rao, S., Presentation 2036], whereas results from the
J-LANCELOT trials with the protease-activated receptor-1 inhibitor atopaxar
revealed potent antiplatelet activity resulting in reductions in major adverse
cardiovascular outcomes after an acute
coronary syndrome compared to placebo [Van de Werf, F., Presentation 2047] (Fig. 13). A further strategy
demonstrated potentially useful for improving responses to clopidogrel after a
percutaneous coronary intervention was coadministration of ω3-polyunsaturated
fatty acids [Gajos, G.P. et al., Abst P1348], such supplementation offering
also overall benefits on cardiovascular outcomes [Kromhout, D., Presentation
387]. On the contrary, exaggerated antiplatelet response to aspirin plus
clopidogrel is a possibility, and can lead to excessive bleeding [Colic, M. et
al., Abst P1355].
Fig. 10. Platelet reactivity after 30 days of treatment with
high-dose clopidogrel or standard-dose prasugrel in patients not responding to
standard-dose clopidogrel [Xanthopoulou, I. et al., Abst 1196].
Fig. 11. Percent of patients with high platelet reactivity
(ADP-induced aggregation measured by aggregometry) after two weeks of treatment
with ticagrelor or clopidogrel [Bliden, K.P. et al., Abst 1195].
Fig. 12. Major adverse cardiovascular event rates in
patients treated with ticagrelor or clopidogrel in the PLATO trial [James, S.
et al., Abst P1353].
|
Fig. 13.
Major adverse cardiovascular event rates in
patients with high-risk coronary artery disease (CAD) or acute coronary
syndrome (ACS) treated with atopaxar or placebo for 12 weeks [Van de Werf,
F., Presentation 2047].
|
Further
anticoagulant and antithrombotic therapies may be of use in patients with
coronary artery disease, including thrombolytics and antithrombotics during the
acute phase of a coronary syndrome in patients planning to undergo percutaneous
coronary interventions. In that context, although underused in the elderly
[Kong, P.K. et al., Abst P1363], upstream abciximab was associated with reduced
in-hospital mortality in patients with ST segment-elevated myocardial
infarction not pretreated with clopidogrel [Crimi, G. et al., Abst P1369], and,
in an independent study, was associated with improved coronary flow without a
reduction in cardiac events [Bastos Fernandez, G. et al., Abst P1368]. More favorable
outcomes resulted from intracoronary compared to intravenous abciximab [Piscione,
F. et al., Abst P1431], intracoronary administration being independently
related to reduced risk for major adverse cardiovascular events and improved
left ventricular ejection fraction after an acute ST segment-elevated
myocardial infarction [Fuernau, G. et al., Abst 5032] (Fig. 14). Tirofiban was as safe and effective
as abciximab, according to data from a comparative study in patients also
undergoing primary angioplasty [Colangelo, S. et al., Abst P1360] (Fig. 15). Besides lowering
endothelium- and platelet-derived procoagulant microparticles during
percutaneous coronary interventions [Min, P.K. et al., Abst P1364], improved
outcomes with the use of glycoprotein IIb/IIIa blockers were especially noted
in patients with diabetes [Ferrieres, J. et al., Abst P1366]. However,
enoxaparin fared better than unfractionated heparin in terms of ischemic
complications and major bleeding rates during percutaneous coronary interventions
for ST segment-elevated myocardial infarction [Brieger, D. et al., Abst P1365;
Montaleskot, G., Presentation 2042], although low-dose heparin proved safe and
effective during elective percutaneous interventions in the ISAR-REACT 3A
trial, comparing favorably with historical data from patients treated with
bivalirudin [Schulz, S., Presentation 2044]. Nevertheless, in patients
pretreated with heparin, switch to bivalirudin for primary angioplasty was
safer and resulted in better outcomes than adding a glycoprotein IIb/IIIa
blocker [Dangas, G. et al., Abst P1367], whereas an additional bolus of
unfractionated heparin in patients receiving bivalirudin during primary
percutaneous intervention also prevented deaths and target lesion thrombosis
[Koutouzis, M. et al., Abst P1362].
Fig. 14. Major adverse cardiovascular event rates in
patients receiving intracoronary or intravenous abciximab [Fuernau, G. et al., Abst
5032].
|
Fig. 15.
One-year death and major adverse cardiovascular
event rates in patients receiving tirofiban or abciximab during primary
angioplasty for acute myocardial infarction [Colangelo, S. et al., Abst
P1360].
|
Additional
studies discussed during oral and poster presentations at the meeting indicated
potential for exenatide for protecting the endothelium against ischemia/reperfusion
[Kim, W. et al., Abst 372], high-dose adenosine for improving myocardial
salvage after an acute ST segment-elevated myocardial infarction [Desmet, W. et
al., Abst P4519] and prednisone for preventing restenosis after percutaneous
coronary interventions [Ribichini, F.L. et al., Abst P2187]. Furthermore,
sapropterin supplementation elevated biopterin levels without positively
affecting the redox status or vascular function compared to placebo in patients
with coronary artery disease [Cunnington, C. et al., Abst P2319]. In addition,
an open-label study confirmed the feasibility, safety and efficacy of vascular
endothelial growth factor plasmid gene therapy, resulting in improved symptoms
and ventricular function and reduced myocardial ischemia [Favaloro, L. et al., Abst
P2982].
Further
experimental studies demonstrated the potential of the mitochondrial
permeability transition pore inhibitor TRO-40303 for improving postischemic
ventricular remodeling and function [Thibault, H.B. et al., Abst P462;
Schaller, S. et al., Abst P478]. Cardioprotective activity against ischemia was
also shown with fimasartan [Choi, D.J. et al., Abst P476], the glycogen
synthase kinase-3b inhibitor SB-216763 [Iraqi, W. et
al., Abst P643], 6-bromoindirubin [Andreadou, I. et al., Abst P457], curcumin
[Kim, Y.S. et al., Abst P650], 3’,4-dihydroxyflavonol [Teramoto, T. et al., Abst
P3003], the protein kinase C inhibitor chelerythrine [Wiedemann, S. et al., Abst
P3190] and the enkephalin analog EP-94 [Karlsson, L.O. et al., Abst P3194],
whereas the guanylate cyclase activator cinaciguat prevented injury-related
neointima hyperplasia through an effect on matrix metalloproteinase-9
expression [Hirschberg, K. et al., Abst P5541]. Further preclinical studies
pointed to the favorable effect of sildenafil on sympathetic reinnervation
after a myocardial infarction, the effect depending on activation of
mitochondrial ATP-dependent potassium channels [Lee, T.M. et al., Abst P644].
In addition, therapeutic potential through improvement of postischemic
myocardial function was reported for the cys-lekotriene receptor-1 blocker
montelukast [Becher, M.U. et al., Abst P640]. On the contrary, administration
of epoetin in patients undergoing primary percutaneous interventions did not
improve postinfarction cardiac function [Voors, A.A., Presentation 389] and resulted
in increased rates of microvascular obstruction, left ventricular dilatation
and myocardial hypertrophy [Ludman, A.J. et al., Abst 878], although treatment
with darbepoetin alfa resulted in improved endothelial function and circulating
endothelial progenitor cell counts in patients with stable coronary artery
disease [Mueller, C. et al., Abst P2298].
Drug-eluting stents
Drug-eluting stents continue to be an area of
very active research, although the results of the ERACI III study indicated
higher risk of death and combined death, myocardial infarction and stroke in patients
with multivessel disease receiving drug-eluting compared to bare metal stents
[Rodriguez, A. et al., Abst P1413], whereas in patients with proximal left
anterior descending artery disease or chronic total occlusion, use of
drug-eluting stents was associated with lower major adverse cardiovascular
event rates [Jones, D. et al., Abst P1402; Godino, C. et al., Abst 5166] and in
patients with vein grafts, drug-eluting and bare metal stents were associated
with comparable outcomes [Rathod, K.S. et al., Abst 5164]. However, a detailed
review of all new studies and observations with sirolimus-, paclitaxel- and
everolimus-eluting stents would not fit the constrains of this overall report,
and only results from selected studies will be reviewed, including registry
data indicating a trend towards better outcomes with the everolimus- compared
to the other two drug-eluting stents [Nakamura, S. et al., Abst P2210;
Piscione, F. et al., Abst P5442] (Fig. 16), although overall results from other studies indicated
similar results with sirolimus- and everolimus-eluting stents [Pan
Alvarez-Osorio, M. et al., Abst P5420], both being superior to
paclitaxel-eluting stents [Nakamura, S. et al., Abst 5403; Yamawaki, M. et al.,
Abst P5429; Dibra, A. et al., Abst P5435; Chen, K.Y. et al., Abst P5450]; some
additional comparative studies were not able to identify any difference between
sirolimus- and paclitaxel-eluting stents [Nasu, K. et al., Abst P5444]. In that
sense, despite the excess risk associated with diabetes, no differences in the
combined rate of all-cause death, myocardial infarction and stroke were
apparent comparing diabetic and nondiabetic patients with multivessel disease
receiving sirolimus-eluting stents [Tada, T. et al., Abst 294], although
sirolimus-eluting stents were not only effective but cost-effective compared to
bare metal stents in diabetic patients with multivessel disease
[Barone-Rochette, G. et al., Abst P1450]. On the contrary, it should be worth
mentioning that the use of overlapping drug-eluting stents for long lesions was
associated with increased risk of stent thrombosis, raising safety concerns
[Cale, R. et al., Abst P586], whereas overlapping sirolimus-, but not
zotarolimus-eluting stents induced adverse effects on microcirculatory
endothelial function in experimental animal studies, possibly because of the
antioxidative molecule-rising effect of zotarolimus [Nakamura, T. et al., Abst
P639; Nakamura, T. et al., Abst P680], although individual trials and a
meta-analysis suggested reduced clinical efficacy of zotarolimus- compared to sirolimus-
and other first-generation drug-eluting stents [Martin Reyes, R. et al., Abst
P5432; Kaltoft, A.K. et al., Abst P5433]. In that context, nicorandil was
reported to prevent paclitaxel-induced endothelial dysfunction in experimental
animals [Serizawa, K. et al., Abst P693]. A further study suggested blunted
coronary microcirculation vasodilatation after everolimus-eluting stent
implantation [Kiviniemi, T.O. et al., Abst P1374], whereas endothelial function
after sirolimus-eluting stent implantation was significantly improved by
treatment with pioglitazone [Kitahara, H. et al., Abst P1386]. News regarding
other novel drug-eluting stents confirmed the safety and overall effectiveness
of bevacizumab-eluting stents [Toutouzas, K. et al., Abst P1387; Synetos, A. et
al., Abst 2376], indicating an increased risk for reintervention but a lower
risk for myocardial infarction with zotarolimus- compared to sirolimus-eluting
stents [Dibra, A. et al., Abst P2184], accompanied by lower effectiveness of
zotarolimus-eluting stents in preventing adverse outcomes, especially in
high-risk patients with diabetes [Maeng, M. et al., Abst 5162] (Fig. 17). Additional
observations suggested improved outcomes in terms of restenosis with an
additional stent, biolimus A9-eluting stent [Mavronasiou, E. et al., Abst
P5439], which was comparable to everolimus- and superior to sirolimus-,
paclitaxel- and zotarolimus-eluting stents [Nakamura, S. et al., Abst P5418;
Nakamura, S. et al., Abst P5437]. Epidemiological data indicated an increased
use of percutaneous coronary interventions for restenosis paralleling the
decreased utilization of drug-eluting stents [Marcoff, L. et al., Abst P583].
Fig. 16. One-year major adverse cardiovascular event rates
in patients implanted with a sirolimus-, paclitaxel- or everolimus-eluting
stent [Nakamura, S. et al., Abst P2210].
|
Fig. 17.
Eighteen-month major adverse cardiovascular event
rates in patient with or without diabetes implanted with sirolimus- or
zotarolimus-eluting stents [Maeng, M. et al., Abst 5162].
|
In
reference to drug-eluting stents, it should be mentioned that a comparison
between sirolimus-eluting stent versus bare metal stent combined with oral
treatment with sirolimus suggested lower costs and improved outcomes with the
latter approach [Rodriguez-Granillo, A.M. et al., Abst P2189] (Fig. 18). Also in the
context of adjuvant pharmacotherapies for stenting, the chemokine CCR2 receptor blocker
CCX-140 [Teramoto, T. et al., Abst P2230] and the monocyte chemoattractive
protein production inhibitor bindarit [Colombo, A. et al., Abst P2236] were
shown to significantly inhibit neointimal proliferation and restenosis after
experimental bare metal stent implantation.
Fig. 18. Three-year major adverse cardiovascular event rates
in patients receiving a sirolimus-eluting stent or a bare metal stent combined
with oral sirolimus [Rodriguez-Granillo, A.M. et al., Abst P2189].
Hypertension
Diuretics have a major role in the treatment of hypertension, although usually in combination with other drugs. In that respect, the addition of hydrochlorothiazide to the angiotensin receptor blockers candesartan or olmesartan was demonstrated to effectively lower blood pressure, without a negative impact on glucose or lipid parameters, at least in the case of candesartan [Izawa, H. et al., Abst P3169; Rump, L.C. et al., Abst P4054] (Fig. 19). Regarding other agents, without actual new information on blood pressure effects, the diuretic indapamide was shown to attenuate in-stent restenosis in patients submitted to percutaneous coronary interventions [Deftereos, S. et al., Abst P2190].
|
Fig. 19. Percent of patients failing initial olmesartan that achieved 24-hour, daytime and nighttime blood pressure target goals after 8 weeks of treatment with olmesartan alone or combined with hydrochlorothiazide [Rump, L.C. et al., Abst P4054]. |
Because it improved endothelial as well as erectile function, nebivolol was considered a treatment candidate for hypertensive male patients with erectile dysfunction [Ozben Sadic, B. et al., Abst P704], but the agent was also reported to induce regression of left ventricular hypertension in postmenopausal women with hypertension and type 2 diabetes, without a negative impact on glucose or lipid metabolism [Nikoghosyan, K. et al., Abst P3173], and to prevent arrhythmias and control heart rate during an ST segment-elevated myocardial infarction [Faynyk, A. et al., Abst P4516]. Combined with hydrochlorothiazide, the b-blocker induced additional reductions in glucose and lipid parameters adding to the blood pressure-lowering effect in hypertension [Marazzi, G. et al., Abst P3157].
Among the calcium channel blockers, nifedipine-GITS offered cardiovascular benefits in terms of major outcomes to patients with stable coronary artery disease on background angiotensin-converting enzyme inhibitor therapy [Elliott, H.L. et al., Abst P1325]. In addition, a combination of nifedipine-GITS and telmisartan offered earlier control of blood pressure compared to the respective monotherapies when used as first-line therapy, although with similar results over time [Mancia, G. et al., Abst P3167] (Fig. 20), whereas lercanidipine combined with enalapril or, especially, ramipril, induced regression of hypertensive left ventricular hypertrophy and remodeling [Nikoghosyan, K. et al., Abst P3160].
|
Fig. 20. Blood pressure during 24 weeks of treatment with nifedipine-GITS, telmisartan or the combination [Mancia, G. et al., Abst P3167]. |
While the antihypertensive efficacy without cardiodepressing activity of ramipril brought about a favorable impact on left ventricular remodeling over the long term [Triantafyllidi, H. et al., Abst P3164; Nikoghosyan, K. et al., Abst P3165], the blood pressure-lowering activity of perindopril, a representative angiotensin-converting enzyme inhibitor, was independent of variability of the atrial natriuretic precursor A gene, despite the link between such variability and increased cardiovascular risk in hypertensive conditions [Van Vark, L.C. et al., Abst P3155]. Combined with indapamide, the drug was shown to reverse adverse coronary microvascular remodeling in hypertensive patients with left ventricular hypertrophy, resulting in improved coronary blood flow [Neglia, D. et al., Abst P4595].
Valsartan was noted to improve left ventricular adrenergic innervation abnormalities in type 2 diabetes patients with normal blood pressure [Zacharis, E.A. et al., Abst P3096], protected against cardiovascular events in high-risk hypertensive patients with type 2 diabetes [Kimura, S. et al., Abst P4650; Shiraishi, J. et al., Abst 5211], effectively prevented stroke in high-risk hypertensive populations [Matsubara, H., Presentation 5082], reduced angina attacks and the incidence of congestive heart failure in patients with coronary artery disease [Shimizu, M., Presentation 5084] and offered additional cardioprotection in hypertensive patients without prior cardiovascular disease [Yamada, H.Y. et al., Abst P3154]. The drug outranked non-angiotensin receptor blocker therapies in preventing cardiovascular events in high-risk hypertensive patients with or without metabolic syndrome [Kimura, S. et al., Abst P3104] (Fig. 21), and in such patients offered synergistic cardioprotection upon combination with calcium channel blockers [Sawada, T. et al., Abst P4038]. A related agent, olmesartan showed efficacy in preventing new-onset microalbuminuria in hypertensive patients [Haller, H. et al., Presentation 54; Haller, H. et al., Abst 2016; Haller, H. et al., Abst P4678] (Fig. 22), and combined with hydrochlorothiazide provided reliable dose-dependent reductions in blood pressure over the 24-hour dosing interval in patients not controlled with the angiotensin receptor blocker in monotherapy [Rump, L.C. et al., Abst P3159]. However, the results of the ANTIPAF trial did not demonstrate superiority over placebo regarding the burden of atrial fibrillation in patients with paroxysmal disease, although olmesartan prolonged the time to prescription of amiodarone [Goette, A., Presentation 3772]. A further angiotensin receptor blocker, candesartan proved superior to olmesartan in improving insulin sensitivity at equivalent blood pressure-lowering activity [Derosa, G. et al., Abst P3156] and an additional drug, irbesartan, improved both central and peripheral blood pressure and arterial elasticity more effectively than diltiazem [Liakos, C. et al., Abst P4052], resulting in favorable changes of left ventricular mass and microalbuminuria [Triantafyllidi, H. et al., Abst P4051] and offering additional benefits in patients with metabolic syndrome [Vyssoulis, G. et al., Abst P3209]. Mechanistic results from a randomized trial with an additional agent, eprosartan, indicated no inhibition of the sympathetic nervous system even during sodium restriction [Vase, H. et al., Abst P3170]. Experimental observations indicated that telmisartan, but not losartan or its active metabolite, inhibited advanced glycation endproduct- and tumor necrosis factor-a-induced inflammation, pointing towards antiatherosclerotic activity especially in diabetic conditions [Del Turco, S. et al., Abst P694], a finding that was complemented by demonstration of an direct effect of the angiotensin receptor blocker on peroxisome proliferator-activated receptor-γ-dependent gene expression, resulting in attenuated monocyte chemoattractive protein-1 expression [Marketou, M.E. et al., Abst P4039]. As a possible consequence, at doses lowering blood pressure to the same extent as losartan, telmisartan also significantly improved left ventricular mass index and the intima-media thickness in hypertensive individuals [Hasegawa, H. et al., Abst P4057]. Furthermore, combined with hydrochlorothiazide, it significantly improved insulin resistance, whereas combinations of atenolol or fosinopril with the diuretic worsened or had no impact on insulin resistance, respectively [Rekovets, O. et al., Abst P4056] (Fig. 23). To note, candesartan and amlodipine also decreased advanced glycation endproduct receptor expression in the aorta of diabetic animals, attenuating aortic wall oxidative stress [Ihm, S.H. et al., Abst P5561].
Fig. 21. Cardiovascular event rates in patients with or without metabolic syndrome (METS) receiving valsartan or non-angiotensin receptor blocker therapy [Kimura, S. et al., Abst P3104].
Fig. 22. Incidence of new-onset microalbuminuria during 48 months of treatment with olmesartan or placebo [Haller, H. et al., Abst P4678].
|
Fig. 23. Change in the insulin resistance index after six months of treatment with telmisartan, fosinopril or atenolol alone or combined with hydrochlorothiazide [Rekovets, O. et al., Abst P4056]. |
In addition to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, the direct renin inhibitor aliskiren also proved an effective agent for lowering blood pressure, and in combination with hydrochlorothiazide offered greater benefits on central blood pressure, augmentation pressure and brain natriuretic peptide levels than a similar combination of atenolol with the diuretic [Fogari, R. et al., Abst P5106] (Fig. 24).
|
Fig. 24. Change in brachial and central systolic and aorta augmentation pressure after 12 weeks of treatment with aliskiren or atenolol combined with hydrochlorothiazide [Fogari, R. et al., Abst P5106]. |
Improvements in vascular remodeling and endothelium- and smooth muscle-dependent vascular function in hypertensive animal models resulted from chronic treatment with the poly(ADP-ribose) polymerase inhibitor L-2286 [Magyar, K. et al., Abst P630].
Within the scope of hypertension, it should be stated that naproxcinod slightly decreased blood pressure and improved endothelial function, suggesting benefits that should be considered when treating hypertensive patients with osteoarthritis [Bolla, M. et al., Abst P2331].
Dyslipidemia
Without any adverse impact on the incidence of or mortality from cancer [Emberson, J., Abst 5035], statins have become the gold standard in the treatment of hypercholesterolemia, additional extralipid benefits translating into, for example, coronary plaque stabilization [Miyai, M. et al., Abst P4646], attenuated hypercoagulability after drug-eluting stent implantation [Niki, T. et al., Abst P2195], prevention of ventricular arrhythmia and death in failing heart or during an acute coronary syndrome [Apiyasawat, S. et al., Abst P1623; Azenha Balhau Jorge, E. et al., Abst P4873], improvements in ventricular remodeling and function during chronic heart failure [Zhang, S. et al., Abst P4183], improvements in outcomes in patients without coronary artery disease undergoing cardiac surgery [Angeloni, E. et al., Abst 3576] and long-lasting positive impact on cardiovascular complications in patients undergoing nonvascular surgery [Voute, M.T. et al., Abst 5213]. These benefits could be magnified in the future by novel developments in statin administration, as local delivery to the microcirculatory endothelium was feasible with simvastatin encapsulated in biodegradable poly(l,l-lactic acid) [Wacisnki, P. et al., Abst P3006].
With a greater plaque-stabilizing effect in more unstable coronary plaques [Hirayama, A. et al., Abst P4645], high-dose atorvastatin 80 mg proved superior to the 20-mg dose in improving LDL-cholesterol goal attainment and lowering C-reactive protein levels in previously untreated patients scheduled to undergo vascular surgery [Almeida, R.C. et al., Abst P547]. However, adding high-dose atorvastatin to chronic standard-dose statin therapy had no impact on perioperative myocardial injury in patients undergoing coronary artery bypass graft surgery [Ludman, A.J. et al., Abst P573], although at standard doses atorvastatin improved endothelial function in type 2 diabetes patients with coronary artery disease [Chumburidze, S.H. et al., Abst P698] and high doses improved left ventricular function and exercise capacity in patients with chronic heart failure [Correale, M. et al., Abst P2328]. Note that the effect of atorvastatin was not affected by the presence of genetic variants in the ABCG8 (ATP-binding cassette sub-family G member 8) gene [Garg, N. et al., Abst P713]. Besides lowering LDL-cholesterol and improving lipid levels, atorvastatin exhibited a number of favorable effects on cardiovascular structure and function, including improvement of myocardial remodeling and sympatho-vagal balance, reduction of oxidative stress in vein grafts and prevention of arrhythmias, although these effects were greater in patients with left ventricular systolic than diastolic dysfunction [Kozlova, E.S. et al., Abst P784; Tribulova, N. et al., Abst P3210; Bakogiannis, C. et al., Abst P5099; Kozlova, E.S. et al., Abst P5620], and reduction in graft redox state in patients with advanced atherosclerosis or undergoing coronary artery bypass graft surgery through inhibition of NADPH oxidase and improvement of endothelial nitric oxide synthase coupling [Antoniades, C. et al., Abst P1889; Demosthenous, M. et al., Abst P5557], whereas in the experimental setting treatment with the statin suppressed upregulation of connective tissue growth factor and reduced cardiac fibrosis in models of atrial fibrillation [Kiryu, M. et al., Abst P4108]. Add to the prior information that the current policy of switching from atorvastatin to generic simvastatin at nonequipotent doses has resulted in increased cardiovascular risk, maintenance of atorvastatin arising as cost-effective at least from a Dutch perspective [Liew, D. et al., Abst P1440; Liew, D. et al., Abst 3562]. As an additional finding, concomitant treatment with atorvastatin and lisinopril was noted to improve endothelial function in patients with Behçet’s disease [Kaya, M.G. et al., Abst P696].
Besides its known LDL-cholesterol-lowering effects, which were further confirmed in the studies commented below, treatment with rosuvastatin of patients with atherosclerosis induced regression of plaques and coronary remodeling [Takayama, T. et al., Abst P4619], whereas treatment of patients with metabolic syndrome resulted in decreased inflammation, although without a significant effect on C-reactive protein levels, at least over the short term [Yigit, Z. et al., Abst P711] and treatment of patients with hypertension and dyslipidemia brought about beneficial effects on arterial stiffness that were not obtained with bezafibrate [Hongo, M. et al., Abst P2325]. Similarly, rosuvastatin significantly decreased fasting and nonfasting lipid levels, without an effect on C-reactive protein levels in an independent study [Cakmak, A. et al., Abst P715], and attenuated postocclusive reactive hyperemia, an effect that was especially relevant in ischemic conditions [Wouters, C.W. et al., Abst P2322]. In fact, single-dose rosuvastatin was demonstrated to prevent periprocedural myocardial necrosis and infarction in patients undergoing percutaneous coronary interventions [Cay, S. et al., Abst 3577]. In addition, treatment of patients with heart failure with rosuvastatin, but not allopurinol, significantly increased circulating endothelial progenitor cell counts [Andreou, I. et al., Abst P4862]. Despite minimal differences, both rosuvastatin and atorvastatin also improved inflammation and the activity of enzymes involved in lipoprotein metabolism, the former more effectively lowering platelet-activating factor acyl hydrolase [Karalis, I. et al., Abst P716]. Overall, the results of the JUPITER trial suggested cost-effectiveness for rosuvastatin, especially in patients at higher cardiovascular risk [Ohsfeldt, R.L. et al., Abst P1436].
Phase III clinical trial data with a further novel statin, pitavastatin, indicated high goal attainment rates in elderly patients at risk for coronary artery disease, whereas even with uptitration to maximal doses, target attainment was suboptimal with simvastatin [Hounslow, N., Abst P1567]. In addition, pitavastatin was superior to pravastatin in lowering LDL-cholesterol levels [Ose, L. et al., Abst P4677] (Fig. 25), and at high doses was shown to improve intima-media thickness and carotid distensibility in patients with asymptomatic atherosclerosis [Lee, Y.S. et al., Abst P1566]. Note that although the risk of rhabdomyolysis/myopathy during pitavastatin therapy was higher in patients with renal impairment, use of the agent at therapeutic doses of up to 4 mg/day was not associated with such risk in real-life conditions [Hounslow, N. et al., Abst P5549].
|
Fig. 25. Percentage of patients at goal after 56 weeks of treatment with pitavastatin or simvastatin, both uptitrated as required to maximal doses of 4 and 80 mg/day [Hounslow, N., Abst P1567], or 12 weeks of treatment with fixed-dose pitavastatin or pravastatin [Ose, L. et al., Abst P4677]. |
Besides improving lipid levels, fenofibrate improved proinflammatory biomarker and adipocytokine levels and insulin resistance in patients with primary hypertriglyceridemia [Koh, K. et al., Abst 1221]. Fenofibrate was also effectively used in combination with pravastatin to improve lipid control and led patients to target after failing simvastatin [Farnier, M. et al., Abst P2317] (Fig. 26); the combination of fenofibrate and simvastatin was also superior to simvastatin monotherapy in patients not adequately controlled with the latter [Scott, R. et al., Abst P2318].
|
Fig. 26. LDL- and/or non-HDL-cholesterol target attainment rates after 12 weeks of treatment with simvastatin or fenofibrate/pravastatin in patients not responding to initial therapy with simvastatin [Farnier, M. et al., Abst P2317]. |
While directly increasing small, dense LDL particles in healthy volunteers regardless of concomitant statin use [Gouni-Berthold, I. et al., Abst 3578], combined use of ezetimibe and simvastatin was a further option, with superiority over other statins in monotherapy in the control of cholesterol levels, although without differences in their impact on C-reactive protein, adiponectin and oxidized LDL levels [Bae, J.W. et al., Abst P2330; Toth, P.P. et al., Abst P5554; Robinson, J.G. et al., Abst 5555]. Moreover, both ezetimibe/simvastatin and rosuvastatin improved reduction of apolipoprotein B compared to prior monotherapy with another statin in high-risk patients, the combination being more effective than rosuvastatin [Vaverkova, H. et al., Abst P4686] (Fig. 27), whereas compared to placebo, ezetimibe/simvastatin also prevented new-onset atrial fibrillation in patients with asymptomatic mild to moderate aortic stenosis, in direct relationship with decreases in LDL-cholesterol and C-reactive protein levels brought about by such treatment [Bang, C.A. et al., Abst P4146], whereas compared to simvastatin monotherapy, the combination with ezetimibe offered greater suppression of oxidative stress and improved antithrombotic/thrombolytic profile following an acute myocardial infarction [Undas, A. et al., Abst P4526]. Further improvements in lowering triglycerides and fibrinogen, but not LDL- and non-HDL-cholesterol, in patients with type 2 diabetes resulted from the combined use of ezetimibe/simvastatin and fenofibrate [Farnier, M. et al., Abst P5553] or fenofibrate/pravastatin and ezetimibe [Farnier, M. et al., Abst 3579] compared to ezetimibe/simvastatin (Figs. 28 and 29).
Fig. 27. Percentage of patients at LDL-cholesterol (<100 mg/dl), non-HDL-cholesterol (<130 mg/dl) or apolipoprotein B (<90 m/dl) target after treatment with ezetimibe/simvastatin or rosuvastatin [Vaverkova, H. et al., Abst P4686].
Fig. 28. Percentage of patients at LDL- and non-HDL-cholesterol goal (<100 mg/dl and <130 mg/dl, respectively) after 12 weeks of treatment with ezetimibe/simvastatin alone or combined with fenofibrate [Farnier, M. et al., Abst P5553].
|
Fig. 29. Percent change in lipid and fibrinogen levels after 12 weeks of treatment with ezetimibe/simvastatin or ezetimibe/pravastatin/fenofibrate [Farnier, M. et al., Abst 3579]. |
Although a fixed combination of niacin and laropiprant improved the overall lipid profile toward a less atherogenic pattern in patients with type 2 diabetes [Maclean, A. et al., Abst P5098], the benefits of niacin in patients with low HDL-cholesterol levels did not translate into improvements in endothelial function after a recent acute coronary syndrome, as endothelial function also recovered rapidly in patients receiving placebo [Lhermusier, T.H. et al., Abst P681], but a direct antiplatelet effect of niacin was suggested potentially useful, especially in patients with low HDL-cholesterol [Serebruany, V.L. et al., Abst P2277].
Concerning additional drugs and drug families, the apolipoprotein A1 expression enhancer RVX-208 proved safe and pharmacodynamically active in experimental animal models [Wong, N. et al., Abst P5097] and the soluble epoxide hydroxylase inhibitor BIX-01753 also prevented high-cholesterol diet-induced atherogenesis [Wolf, D. et al., Abst P5558], whereas, at least in the experimental setting, the cholesterol ester transfer protein inhibitor torcetrapib was shown to impair endothelial function in hypertensive conditions through activation of endothelin and aldosterone pathways [Simic, B. et al., Abst 3746]. By as-yet-unexplained mechanisms, the thrombin inhibitor dabigatran showed potential antioxidative and antiatherosclerotic activity in experimental animal models, expanding its use as an anticoagulant [Pingel, S. et al., Abst P5563]; atherosclerosis regression was similarly demonstrated in additional studies with the combined use of methotrexate and etoposide in lipidic nanoemulsion [Leite Junior, A.C. et al., Abst P5559].
Besides pharmacotherapy, gene therapy with mipomersen, an antisense apolipoprotein B synthesis inhibitor, effectively lowered LDL-cholesterol levels in patients with familial hypercholesterolemia and coronary artery disease on optimal background lipid-lowering therapy [Stein, E.A. et el., Abst 5036] (Fig. 30), whereas alipogene tiparvovec, a recombinant adeno-associated virus serotype 1 vector expressing the S447X variant of the human lipoprotein lipase gene, brought about long-term beneficial changes in lipoprotein characteristics in patients with lipoprotein lipase deficiency [Brisson, D. et al., Abst P5095]. In addition, ω3-polyunsaturated fatty acid supplementation improved endothelial function and vascular elasticity, even in smokers [Zaromitidou, M. et al., Abst P683], while supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, also improved lipid levels and attenuated overload-related cardiac dysfunction and hypertrophy [Duda, M.K. et al., Abst P598]. Supplementation with ω3-polyunsaturated fatty acids also improved left ventricular function and exercise capacity in patients with idiopathic dilated cardiomyopathy [Nodari, S. et al., Abst P4852], whereas pycnogenol from pine bark improved endothelial function in patients with coronary artery disease [Enseleit, F. et al., Abst P4045] (Fig. 31). On the other hand, by increasing free cholesterol transfer to HDL, orange juice improved LDL-cholesterol levels in normal and hypercholesterolemic individuals [Aptekmann, N.P. et al., Abst P717], whereas the whey fermentation product malleable protein matrix-SL0905 improved triglyceridemia and reduced LDL-cholesterol levels in patients with hypercholesterolemia [Berthold, H.K. et al., Abst P5517]. Still within the context of dietary components and supplements, a-linolenic acid exhibited antiatherogenic, antiplatelet and antithrombotic activity and attenuated T cell-mediated inflammation in models of hypercholesterolemic disease [Winnik, S. et al., Abst P1536; Holy, E.W. et al., Abst P5356], whereas by downregulating phosphatidylinositol 3-phosphate kinase expression and inhibiting the activation of the enzyme, the natural alkaloid berberine prevented Chlamydia pneumoniae-induced vascular endothelial cell migration [Zhang, L. et al., Abst P4768]. Antiatherosclerotic potential was similarly attributed to annexin A5, which attenuated systemic inflammation and vascular remodeling and improved vascular function in hypercholesterolemic animal models [Ewing, M. et al., Abst P4769].
Fig. 30. Change in lipid parameters during 26 weeks of treatment with mipomersen or placebo [Stein, E.A. et al., Abst 5036].
|
Fig. 31. Change in flow-mediated vasodilatation after treatment with pycnogenol or placebo [Enseleit, F. et al., Abst P4045]. |
Obesity
Among scarce news directly related to the treatment of obesity reported during the meeting, a pooled analysis confirmed the feasibility of lowering body weight with phentermine/topiramate for at least 56 weeks of treatment, resulting in a significant, meaningful improvement in the cardiometabolic risk profile, with significant drops in lipids and inflammatory biomarkers [Tonstad, S. et al., Abst P4676; Davidson, M. et al., Abst P5457] (Fig. 32).
|
Fig. 32. Percentage of patients maintaining ³5%, ³10 or ³15% weight loss after 56 weeks of treatment with phentermine/topiramate or placebo [Tonstad, S. et al., Abst P4676]. |
Diabetes, glucose intolerance, insulin resistance and metabolic syndrome
Diabetes is a well-established cardiovascular risk factor, and in fact, novel analyses from the TRACE study population of patients with an acute myocardial infarction documented, an increased risk of death at 10 and 15 years in patients with diabetes (82.7 and 91.1%, respectively) than in patients without such abnormality (60.2 and 72.9%, respectively). Indeed intensive control of glucose was demonstrated to bring about a decrease in platelet activation during non-ST segment elevated myocardial infarction [Vivas, D. et al., Abst P3000].
Compared to insulin and sulfonylureas, treatment of patients with type 2 diabetes or insulin resistance with metformin brought about improvements in diastolic function [Andersson, C. et al., Abst P792; Wong, A.K.F. et al., Abst P4846].
Concerning the thiazolidinediones, treatment of type 2 diabetes patients undergoing zotarolimus-eluting stent implantation with pioglitazone resulted in decreased inflammatory activation and reduced neointima formation [Ahn, C.M. et al., Abst P3001], whereas in experimental studies with rosiglitazone, favorable modulation of coronary lipid metabolism reducing the risk for atherosclerosis progression and in-stent restenosis [Pels, K. et al., Abst P5552] and prevention of cardiovascular remodeling and atrial fibrillation inducibility [Liu, T. et al., Abst P4105] were demonstrated in diabetic animal models. Independent studies also documented effects against cardiac fibrosis and dysfunction when rosiglitazone was combined with losartan [Shim, C.Y. et al., Abst P4856].
The dual peroxisome proliferator-activated receptor-γ and -a agonist aleglitazar improved LDL particle size distribution towards a less atherogenic profile in patients with type 2 diabetes [Nicholls, S.J. et al., Abst P5545] and reduced the proinflammatory status and improved HDL functionality in experimental models of metabolic syndrome, supporting an atheroprotective effect [Corsinik, A. et al., Abst P1544]. In the experimental arena, the cannabinoid CB2 receptor agonist JWH-133 also exhibited antiatherosclerosis activity while improving endothelial function and vascular oxidative stress in similar animal models [Hoyer, F. et al., Abst P1531].
Experimental studies with the dipeptidyl peptidase-IV inhibitor vildagliptin indicated cardioprotection against ischemia secondary to the improvements in glucose levels [Hausenloy, D.J. et al., Abst P3193], although the effect did not result in improved postischemic remodeling over the long term [Yin, M. et al., Abst P3314]. In the case of sitagliptin, although the agent had no effect on myocardial metabolism in normoglycemic animal models, it improved glucose tolerance and weight gain and attenuated myocardial fatty acid oxidation in diabetic animal models, suggesting benefits in diabetic cardiomyopathy [Lenski, M. et al., Abst 5200].
Other risk factors
Effective smoking cessation was accomplished with varenicline, which with an educational, motivational program also resulted in improved cholesterol levels and blood pressure, leading to a marked improvement in the overall cardiovascular risk profile [Hecht Von Saldern, D. et al., Abst P3988].
Regarding lifestyles, in addition to other known benefits, new results indicated that adherence to a Mediterranean diet offered protection against metabolic syndrome, atherosclerosis, degenerative disease, renal impairment and dyslipidemia in healthy individuals [Kastorini, C.M. et al., Abst P4019; Sofi, F. et al., Abst P4022; Katsorini, C.M. et al., Abst P4023; Chrysohoou, C. et al., Abst P4028; Panagiotakos, D.B. et al., Abst P4030; Chrysohoou, C. et al., Abst P4032], improved the cardiovascular risk profile more effectively than a low-fat diet [Nordmann, A.J. et al., Abst 5215] and blunted the negative impact of depression on cardiovascular outcomes in survivors after an acute coronary syndrome [Chrysohoou, C. et al., Abst P2167]. Also in the context of diet, consumption of brightly colored fruits and vegetables (containing carotenoids and flavonoids) afforded protection against coronary heart disease [Oude Griep, L.M. et al., Abst P4020], with one particular compound, resveratrol, inhibiting endothelial cell migration and monocyte chemoattractant protein-1-induced monocyte migration and regulating proliferative and apoptotic phenomena in smooth muscle cells, explaining the cardioprotective effects against neovascularization and atherosclerosis [Cicha, I. et al., Abst P4096; Daniel, J.M. et al., Abst P4763], while high green tea consumption was associated with a lower likelihood for developing silent lacunar infacts [Tsubota-Utsugi, M. et al., Abst P4020]. In the experimental arena, oleuropein from olive oil enhanced preconditioning in cholesterol-fed animal models [Andreadou, I. et al., Abst P4021].
Amiodarone
is a standard therapy for atrial fibrillation, but adding ivabradine resulted
in better prevention of recurrences compared to the combination with bisoprolol
in a study in patients with paroxysmal or persistent atrial fibrillation
[Adamyan, K.G. et al., Abst P750] (Fig. 33). Because of its heart rate-lowering effects, ivabradine
was also used effectively as a treatment for inappropriate sinus node
tachycardia [Borbola, J. & Abraham, P., Abst P1587; Benezet-Mazuecos, J. et
al., Abst 3586], while in the experimental arena the heart rate-reducing effect
of the agent in models of hypercholesterolemic atherosclerosis resulted in
enhanced collateral artery growth [Schirmer, S.H. et al., Abst 3748]. Use of
amiodarone followed by early cardioversion effectively restored normal sinus
rhythm at 24 hours compared to digoxin with metoprolol or diltiazem in patients
with atrial fibrillation following coronary artery bypass graft surgery, although
no differences were apparent over the long term [Atar, I. et al., Abst P754].
On the other hand, adding dronedarone to standard therapy for atrial
fibrillation or flutter arose as a cost-effective treatment option, according
to novel analyses of the ATHENA trial results from a Canadian perspective
[Berg, J. et al., Abst P1444]; further geographical analyses of the drug’s
potential indicated consistent reduction of cardiovascular hospitalization and
death despite differences across regions regarding patient characteristics and
background therapy [Hohnloser, S.H. et al., Abst P4152]. The same was confirmed
in a pooled analysis of the three major clinical trials with dronedarone
[Duray, G.Z. et al., Abst P4150] (Fig. 34). In the experimental laboratory ranolazine was shown to
prevent atrial fibrillation inducibility by acetylcholine or rapid pacing
[Aidonidis, I. et al., Abst P4106], whereas vernakalant was shown to selectively
prolong atrial but not ventricular refractoriness, supporting its safety in the
treatment of atrial fibrillation [Bechard, J. et al., Abst P4137].
Fig. 33. One-year recurrence rates in patients receiving
amiodarone combined with ivabradine or bisoprolol [Adamyan, K.G. et al., Abst
P750].
|
Fig. 34.
Overall incidence of cardiovascular
hospitalization or death across placebo-controlled trials with
dronedarone [Duray, G.Z. et al., Abst
P4150].
|
Besides
atrial fibrillation, studies investigating treatment of supraventricular
extrasystole suggested potential for the histamine H1 receptor blocker
quifenadine, at least in children receiving background antiarrhythmic therapy,
although in monotherapy the efficacy of the agent was inferior to that of amiodarone
[Balykova, L. et al., Abst P5621]. Regarding ventricular arrhythmias,
flecainide was reported effective in a series of patients with refractory
catecholaminergic polymorphic ventricular tachycardia resulting in incessant
exercise-induced ventricular arrhythmia [Van Der Werf, C. et al., Abst 2840],
whereas a comparative study indicated nonsignificant borderline superiority of
amiodarone over nifekalant for facilitating out-of-hospital defibrillation of
cardiopulmonary arrest, although without differences regarding preservation of
brain function [Amino, M. et al., Abst P4806]. In that setting, atropine did
not improve long-term neurological function in out-of-hospital pulseless
cardiac arrest with electrical activity [Yagi, T. et al., Abst P4811]. On the
contrary, in the preclinical arena, the HERG potassium channel opener NS-1643
shortened the QT interval and effective refractory period, but induced the risk
of arrhythmia [Bentzen, B.H. et al., Abst 5027].
Besides
antiarrhythmic agents, the cyclooxygenase-2 inhibitor nimesulide showed a
preventive effect against episodes of atrial fibrillation that was explained by
the link between atrial fibrillation and inflammation [Grigoryan, S. et al., Abst
P737], whereas the leukotriene synthesis inhibitor zileuton prevented ischemic
PQ and QT prolongation and increased heart rate variability in patients with
angina [Dropinski, J. et al., Abst P5631]. Moving to experimental preclinical
findings, antiarrhythmic potential was attributed to peoniflorin, a herbal product
that blocked L-type calcium, sodium and inward-rectifying potassium currents
without affecting transient-outward, slow-delayed-rectifying and HERG potassium
currents [Wang, R. et al., Abst P5622]. In vitro ventricular antiarrhythmogenic
activity was also confirmed with ranolazine [Milberg, P. et al., Abst P5633]
and demonstrated with the calcium channel blocker K-201 [Sacherer, M. et al.,
Abst P5619].
In addition
to controlling rhythm, the management of atrial fibrillation requires
anticoagulation to prevent thromboembolism and stroke, an effect that was
demonstrated with warfarin, at least when dosed at the recommended therapeutic
range [Azoulay, L. et al., Abst 1024] (although pharmacogenomic variability in
response to the agent was noted based on the vitamin K epoxy reductase and
CYP2C9 genotypes [Colombo, M.G. et al., Abst P5532]). Indeed, oral
anticoagulation markedly reduced major adverse cardiovascular event rates in
patients with atrial fibrillation undergoing percutaneous coronary
interventions, especially in the very elderly [Ruiz Nodar, J.M. et al., Abst
P3616]. In that sense, the AVERROES study demonstrated a marked benefit of
apixaban over aspirin in the prevention of strokes, the favorable, high
statistically significant results resulting in premature study discontinuation
[Connoly, S.J., Presentation 3768] (Fig. 35). Furthermore, the favorable impact of betrixaban on
pharmacodynamic markers of coagulation in patients with atrial fibrillation was
confirmed in the phase II EXPLORE-Xa study [Connolly, S.J. et al., Abst P726].
In addition, a phase II study demonstrated the safety and tolerability of
YM-150, a novel activated factor X inhibitor, used as anticoagulant in patients
with atrial fibrillation [Turpie, A.G.G. et al., Abst 1194], whereas
preclinical results with BMS-262084, a
nonpeptide small-molecule activated factor XI, also suggested potential as
antithrombotic with a low risk for bleeding [Wong, P. et al., Abst P2316]. On
the other hand, the potential interactions between herbal extracts and warfarin
used as anticoagulant for atrial fibrillation, resulting in suboptimal
anticoagulation, were emphasized, and raised as a matter of concern that should
result in increased awareness [Chan, H.T. et al., Abst P742]. As an additional
topic, atrial fibrillation ablation without interrupting warfarin was
considered safe and effective for preventing thromboembolic complications,
provided the INR was monitored especially for potential excess anticoagulation
during heparin administration [Hayashi, T. et al., Abst P745].
Fig. 35. Annual stroke/systemic embolism rates in patients
receiving apixaban or placebo [Connoly, S.J., Presentation 3768].
The results
of a comparative trial indicated that rivaroxaban can be used as effectively as
unfractionated heparin or enoxaparin for preventing thrombosis on mechanical
valves, offering a competitive oral alternative to conventional anticoagulation
[Kaeberich, A. et al., Abst P579]. Rivaroxaban also tested positive as a
treatment for symptomatic deep vein thrombosis, as demonstrated in the EINSTEIN
DVT study [Buller, H., Presentation 3770]. Note that exposure to rivaroxaban
was noted to be increased in patients with acutely decompensated or stable
heart failure [Gheorghiade, M. et al., Abst P4865], while its activity on
thrombin generation was magnified by concomitant P2Y12 receptor blockade with
ticagrelor [Perzborn, E. et al., Abst 5064], and concomitant clopidogrel
enhanced the preventive activity of rivaroxaban against stent thrombosis in
experimental studies [Becker, E. et al., Abst 5063].
Studies
discussed in Stockholm corroborated the potential of treprostinil in the management
of pulmonary hypertension, improving survival even in patients with severe
disease [Sadushi-Kolici, R. et al., Abst P4511], and that of bosentan in the
treatment of pulmonary hypertension associated with congenital heart failure in
patients with Down’s syndrome [D’Alto, M. et al., Abst P4512], and in that of
severe pulmonary hypertension associated with interstitial lung disease
[Argiento, P. et al., Abst P4510].
New studies
discussed in Stockholm corroborated the effectiveness of sildenafil [Jing, Z.C.
et al., Abst P4509] and vardenafil [Jing, Z.C. et al., Abst 346] in the
treatment of pulmonary hypertension, and concluded on the equiefficacy of
sildenafil and bosentan against the disease, including cases of chronic
thromboembolic pulmonary hypertension [Palazzini, M. et al., Abst P3804] (Fig. 36). In the
experimental arena, suppression of pulmonary vascular remodeling and
hypertension was demonstrated after phosphodiesterase inhibitor therapy in
models of monocrotaline-induced pulmonary hypertension [Tsai, T.H. et al., Abst
P620]. In the case of sildenafil, pharmacokinetic modeling revealed feasibility
in the treatment of pediatric pulmonary hypertension at doses of 10 or 20 mg
for children weighing up to and over 20 kg, respectively [Watt, S. et al., Abst
P4506].
|
Fig. 36.
Change in pulmonary vascular resistance (left)
and the six-minute walking distance (right) after four months of treatment
with sildenafil or bosentan [Palazzini, M. et al., Abst P3804].
|
Advancements
in the treatment of pulmonary hypertension were discussed, with results of a
clinical trial demonstrating the efficacy and safety of the prostanoid IP
receptor blocker selexipag, which significantly reduced pulmonary vascular
resistance and enhanced patients’ functional capacity compared to placebo
[Torbicki, A. et al., Abst 345] (Fig. 37). Hemodynamic benefits were similarly attributed to
infusional fasudil, which reduced pulmonary vascular resistance and increased
the cardiac index more effectively than inhaled iloprost [Jiang, X. et al., Abst
P4505]. On the contrary, 12-week data from a placebo-controlled trial did not
demonstrate differences in pulmonary vascular resistance resulting from add-on
inhaled aviptadil [Galie, N. et al., Abst 347]. In the preclinical area, the
thromboxane A2
receptor blocker daltroban [Kylhammar, D. et al., Abst P4500] and the guanylate
cyclase stimulator BAY-41-8543 [Hedelin, P. et al., Abst P4501] were shown to
prevent acute hypoxic pulmonary vasoconstriction and decrease pulmonary artery
pressure.
Fig. 37. Change in the six-minute walking distance after 17
weeks of treatment with selexipag or placebo [Torbicki, A. et al., Abst 345].
Improvements
in long-term patency after endovascular therapy for femoropopliteal disease
resulted from treatment with cilostazol [Kumada, Y. et al., Abst P3082]. In the
experimental setting, improvements in tissue perfusion and proinflammatory
mediators in models of atherosclerotic limb ischemia resulted from treatment
with sildenafil [Tousoulis, D. et al., Abst P5378].
While
fondaparinux was reported equieffective and interchangeable with enoxaparin as
a treatment for non-high-risk acute pulmonary thromboembolism [Meneveau, N. et
al., Abst P3797] (Fig. 38),
both being comparable to unfractionated heparin [Meneveau, N. et al., Abst
P3796], normalization of thrombin generation and cessation of bleeding were
accomplished with recombinant factor VII in patients receiving fondaparinux and
developing life-threatening bleeds [Schiele, F. et al., Abst P1361], although
the risk for major bleeding under fondaparinux was considered low, and was not
reduced by the use of lower doses, according to new insight into clinical trial
results [Jolly, S., Presentation 3774]. Note that at least in the case of
enoxaparin, prolonging treatment for one month after venous thromboembolism
resulted in improved one-year outcomes by facilitating blood flow restoration
[Vorobyeva, N.M. et al., Abst P5374].
Fig. 38. Endpoint outcome rates in patients receiving
enoxaparin, fondaparinux or unfractionated heparin [Meneveau, N. et al., Abst
P3797].
Influenza
A/H1N1 vaccination in patients with HIV infection resulted in transient
endothelial dysfunction for at least 48 hours [Xaplanteris, P. et al., Abst
P697].
The a2-adrenoceptor agonist medetomidine
centrally enhanced vagal acetylcholine release, increasing baroreflex-induced
release of the mediator [Shimizu, S. et al., Abst 1851].
Intrapericardial
cisplatin and triamcinolone acetonide offered effective alternatives in the
treatment of neoplastic and radiation-induced pericarditis, respectively
[Maisch, B. et al., Abst P2107].
Cholecalciferol
supplementation offered a good approach for preventing ischemic heart disease
and improving cardiorenal outcomes following heart transplantation [Kharlamov,
A.N. et al., Abst P2120].
Hydration
with sodium bicarbonate was superior to isotonic saline for preventing renal
impairment during contrast angiography [Meguro, K. et al., Abst P2127], but
acetylcysteine, especially combined with ascorbate, proved superior to
hydration alone [Grygier, M. et al., Abst P3970].
The
chimeric natriuretic peptide CD-NP decreased fibrosis and improved diastolic
dysfunction in experimental models of renal failure [Martin, F.L. et al., Abst
P3216].
By lowering
urate levels, allopurinol dose-dependently prevented cardiovascular events and
death in patients with elevated urate [Wei, L. et al., Abst P4700].