Evolution in cardiovascular care: highlights and observations from the ESC Congress 2008

Abstract

The European Society of Cardiology (ESC) in Munich represents the second of the three major annual international cardiovascular meetings. The East European involvement in this meeting (in terms of numbers of delegates, if not presentations) continues to emerge, while the representation from North America, Australasia and the Far East represents an increasing proportion. Of note, the cardiovascular nursing representation is much greater than that of 10 years ago, while the basic science presentations may be less noticeable. The format of the meeting has shifted significantly towards plenary clinical commentaries with limited discussion rather than presentations by individuals or groups. In my opinion, the quality of some debate is marginal. Occasionally, a small number of internationally known speakers appear to move effortlessly between multiple presentations in plenary sessions to industry stands all in 1 day!

Multicenter trial reports

At this particular meeting, the major multicenter clinical trials material was relatively limited. Clearly, these data appear in cycles and, on this occasion, there were no major new issues under consideration, nor new drug molecules or treatments to define.

Ivabradine has been under active development for many years, having shown comparable efficacy to atenolol in the International Trial on the Treatment of Angina with Ivabradine vs Atenolol (INITIATIVE) trial and a range of other anti-ischemic therapies in smaller studies. At the European Society of Cardiology (ESC), the primary results of the multicenter Morbidity–Mortality Evaluation of the I_f Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction (BEAUTIFUL) trial were revealed [1]. The study concerned supplemental addition of ivabradine to maximize therapies, including β-blockade, in patients with proven coronary disease and linked systolic ventricular impairment. Given that these patients were already on multiple drug therapies, it was perhaps no surprise that there was no impact on its primary outcome of total mortality, the combination of ivabradine and β-blockade being neither beneficial nor harmful. Clear-cut reductions in hospitalization and revascularization procedures, however, were easily demonstrable in a prespecified secondary analysis of patients with a resting heart rate of over 70 bpm. An important subanalysis of the study placebo data clearly supports the fundamental importance of heart rate suppression in the evolution of vascular events.

A separate study of ivabradine, reported from Canada, further confirmed the efficacy of this agent in chronic stable ischemia when compared with titration of basal β-blockade in stable proven coronary artery disease on exercise time, time to ST depression and time to chest pain symptoms.

Work is still needed to develop this fascinating concept as a direct replacement for β-blockade (i.e., using an I_f channel blocker rather than a β-blocker) in coronary artery disease, with or without left ventricular systolic dysfunction (LVSD). The main reason for the lack of evidence in this area appears to be the regulatory restriction at this moment in time. It would be hoped, given this further evidence of efficacy and the many drawbacks to systemic β-blockade, that some progress towards addressing this comparison can be made, especially since many molecules with I_f-channel blocking properties are beginning to become available.

The GISSI-HF group produced two further contributions in Hot Line clinical trials, reporting on two rather diverse aspects on the periphery of drug therapy in LVSD. Neither demonstrated particularly striking evidence from a clinical or scientific standpoint. Interestingly, this study does give some additional value to the concept of pleiotropic activities of statin therapy. In this patient group, it had been widely predicted that these features, rather than any simple reduction in LDL-cholesterol, which was easily demonstrable, would be beneficial in reducing cardiac or vascular event rates. The impact of rosuvastatin in LVSD paralleled the result seen in the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA) trial, with no evidence of any impact in any clinical setting [2]. There may be no magic dust involved with statin therapy after all and, as the discussant suggested, perhaps the hope for any role for statin therapy in proven LVSD should be abandoned.

The second section contributed by the GISSI HF group addressed the role of omega-3 fatty acid supplements (as Omacor^® capsules) in the same population. Again, a large patient population exposure gave, on the whole, very minimal evidence of a significant impact in a study with nearly 3500 patients in each treatment arm. There were no significant reductions in nonfatal infarction or stroke or, most intriguingly, sudden death. The overall change in mortality was significant but is, at approximately 2% reduction, a modest impact at best. Moreover, why this treatment would affect hospitalizations for heart failure and pump failure deaths is unclear and quite distinct from the presumed impact on arrhythmia and sudden death [3]. While the results were received positively by the presenters and discussants, the practicality of this result and its overall clinical impact remains to be seen.

The Synergy between PCI with Taxus™ and Cardiac Surgery (SYNTAX) trial, addressing the efficacy of a tacrolimus drug-eluting stent technology in multivessel diabetic coronary disease, again reaffirmed the long-term advantage (in terms of major adverse cardiac events [MACE]) of complete surgical revascularization when compared with percutaneous coronary intervention (PCI) [4]. The need for repeat procedural activity on a stent-based strategy was clearly shown and a well-accepted feature of PCI strategies. Equally, and as expected, periprocedural stroke continues to be a major issue in surgery, but even with this, there were clear (if not statistically significant) trends towards a reduced cardiovascular (CV) and all-cause mortality in the surgical arm. This was evident in a study sample of fewer than 1000 patients in each randomized therapy. Accordingly, this is likely to be a clinically valid result, which should guide practice choices. The cascading comments follow predictable affiliations, with the interventional community taking the trials as a reaffirmation that their management is not statistically worse in overall mortality; although, in a larger trial, this would clearly not have been the case. The underpowered Coronary Artery Revascularisation in DIAbetes (CARDia) study (interestingly, like SYNTAX and so many contemporary multicenter trials, designed to be a noninferiority study) closed early and thus failed to add significantly to this debate. However, it revealed a broadly similar pattern to SYNTAX, showing the remarkably low overall death rate, surgical association to stroke as a major drawback and high rates of repeated PCI procedures in these patients. The smaller CARDIA trial also had a mixed PCI strategy, using both drug-eluting and bare metal stents. It seems unfortunate that, even in these high-risk patients, they could not differentiate the strategies in terms of clinical outcome. The overall nonsignificant trends were similar to SYNTAX and favored surgical revascularization in multivessel diabetic coronary disease.

Clinical topics & aspects of therapeutics

F Follath (Zurich, Swizerland) presented a superb practical summary of the folly of neglecting cardiorenal decline induced by over-titrated standard therapies in LVSD. Commonly, multiple therapies combine with hemodynamic changes in stable LVSD patients to provoke serious iatrogenic renal injury. These episodes are potentially reversible and can occur during both introduction and/or titration of standard therapies in otherwise laudable attempts to reach trial goals. However, renal decompensation, generally hinging on inadequate renal and glomerular perfusion, will provoke clinical decompensation through renal, not cardiac, fluid accumulation and secondary diuretic resistance. The recognition of these events or the sequence of changes that underline the etiology is poor among the clinical teams managing these patients, yet the adverse impact in terms of morbidity and mortality is clear. The skill that is required to take epidemiological information on maximizing outcomes by appropriate therapies, yet be able to downtitrate or temporarily withdraw treatment in cardiorenal crises, is an important area not yet recognized in many centers and current community- or hospital-based heart failure programs. Extensive parallel sessions highlighted the impact of chronic renal impairment and the role of biomarkers of renal injury in LVSD [5], clearly showing that work on measures, such as N-acetyl-β-glucosaminidase, neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, all add predictive value by highlighting tubular damage due to iatrogenic or pathological renal hypoperfusion. Whether cystatin C can contribute to this analysis is less clear, and the most appropriate means of defining a threshold for considering mechanical hemofiltration therapies remain uninvestigated, despite the growing interest in the latter strategy.

The value of home biomonitoring and telephone contact with routine cardiologist reviews was compared with regular home nurse contacts in the Home Heart Failure (HOME HF) trial [6]. This interesting community-based trial had an unusual sample composition, with 40% of patients suggested to have normal ejection fraction and yet a large proportion of the patients were on aldosterone antagonists. Somewhat underpowered and rather lacking in detail in its presentation, the trial found little support for regular nurse visits, provided that a range of simple patient-measured biomeasures (e.g., weight, oxygen saturation and blood pressure) remained stable. Improved efficiency of operation would allow fewer nurses to target more high-risk patients and make these services much more cost-efficient.

The value of cardiac-resynchronization therapy in patients with normal QRS duration yet showing evidence of echocardiographic measures of left ventricular dyssynchrony will continue to be explored. The Evaluation of Screening Techniques in Electrically-Normal, Mechanically-Dyssynchronous Heart Failure Patients Receiving Cardiac Resynchronization Therapy (ESTEEM-CRT) trial [7] again reports failure to improve indices of mechanical dyssynchrony, despite suggested symptomatic improvement in the face of static-measured peak oxygen consumption. This often-considered subject awaits clinical end points in a large sample of patients. In a similar vein, the Diovan in Diastolic Dysfunction (DDD) study reported evidence of some improvement in perceived exercise capacity, measured using cardiopulmonary exercise testing of symptomatic diastolic heart failure patients’ symptoms treated with supplemental valsartan, compared to placebo. These were not explained by changes in measured simple cardiopulmonary exercise parameters.

Summary

The ESC of 2008 was a considerable success. The evolution of cardiac care continues but is now adjusted to a more measured pace. The presentation of new results has swung more towards plenary reviews and, for the current attendees, perhaps this is more appropriate. There remains a strong and vibrant core of cardiovascular research that is focused on patient care, and this meeting retains its role as one of the three major global events accordingly.

Financial & competing interests disclosure

Dr MacFadyen received sponsorship from Boerhinger Ingelheim UK to facilitate attendance at this meeting. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.