After the summer holidays, the European Society of Cardiology Congress has brought us back to work.
Among the many interesting pieces of news reported in Paris, at least two trials demonstrated that often in medicine "less is more". First, the Prolonging Dual Antiplatelet Treatment after Grading Stent-induced Intimal Hyperplasia (PRODIGY) trial demonstrated that dual antiplatelet therapy after drug eluting stenting for 24 months when compared with 6 months does not reduce the risk of ischemic events, but on the contrary doubles the bleeding risk. Further confirmations of these findings in different clinical settings and patients (e.g. those with stable angina or acute coronary syndromes) and for new antiplatelet agents are warranted
The Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP AMI) trial failed to demonstrate a benefit on infarct size or other clinical end-points of intra-aortic balloon pump in patients with acute ST-elevation myocardial infarction without shock.
But sometimes "more is indeed more". The Italian Elderly ACS randomized trial demonstrated that in patients older than 75 years with non-ST-elevation acute coronary syndromes coronary angiography and early revascularization within 48 hours is superior to an initially conservative strategy at least in those with positive myocardial biomarkers.
Finally, the quest for the optimal treatment of left main coronary artery disease has gained by the presentation of the 3-year follow-up of the CREDO-Kyoto PCI/CABG registry, in which PCI resulted a predictor of adverse events for all tertiles of SYNTAX score.

After a long delay, and awaiting the upcoming EuroPCR meeting, we are happy to be back with the METCARDIO newsletter. Several news are worth discussing, including the recent identification of the recipient of the METCARDIO Award.
Pivotal trials recently reported at the American College of Cardiology scientific sessions include the PARTNER, RIVAL, and STICH studies. The PARTNER Cohort A study has demonstrated the non-inferiority of transcatheter aortic valve replacement (TAVI) in comparison to standard surgical therapy in subjects with severe aortic stenosis at high operative risk, despite a short term increase in the risk of stroke.
The RIVAL trial has compared radial versus femoral access for coronary procedures in 7021 patients with acute coronary syndromes, finding similar overall results for the primary end-point (a composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft-related major bleeding at 30 days), even if a benefit was demostrated in selected groups (such as those with ST-elevation myocardial infarction and experience operators).
Finally, the STICH trial has compared best medical therapy plus coronary artery bypass grafting versus best medical therapy only in 1212 patients with heart failure and left ventricular systolic dysfunction. Despite failing to meet the primary study end-point (namely all cause death), bypass grafting did still provide meaningful benefits on patient-relevant clinical end-points.

Incoming news have depicted evolving scenarios for cardiologists, both from clinical and interventional points of view. The Food and Drug Administration (FDA) has finally approved a randomized clinical trial comparing transcatheter aortic valve implantation (TAVI) with the CoreValve device versus traditional surgical aortic valve replacement, not only focusing on inoperable patients, as already happened in the PARTNER trial, but also on subjects with high yet not exceedingly high operative risk.
Another important news comes from the trial by Rodes-Cabau et al. In this non-randomized study, comparing transcatheter aortic valve implantation versus traditional surgical aortic valve replacement in patients with reduced left ventricular ejection fraction (LVEF), transcatheter aortic valve implantation proved superior to surgery as up to 58% of patients undergoing transcatheter intervention recovered their systolic function (left ventricular ejection fraction above 50% at follow-up) versus only 20% of those undergoing sugery. These are very important results, although not coming from a properly randomized experimental trial, given that this transcatheter technique was moving its first steps just a few years ago.
Shifting from macro to micro, contrasting evidence has been produced about specific cytochrome alleles interfering with clopidogrel metabolism (i.e. the CYP2C19 genotype) and the risk-benefit of clopidogrel. Whereas Parè et al have shown no negative effect of loss of function alleles among patients presenting with acute coronary syndromes in the CURE trial and those with atrial fibrillation drawn from the ACTIVE A study, a comprehensive meta-analysis by Mega et al has shown that carriage of only reduced-function alleles appears to be associated with a significantly increased risk of adverse outcomes, particularly stent thrombosis. These differences probably are related to different populations and analytical tools (especially robustness of multivariable models). A possible solution, especially for physicians without an access to genetic testing, will be an increasing shift to new antiplatelet agents, such as prasugrel and ticagrelor, both with specific pros and cons.
Another challenging set of patients are those with a cancer history, and treated with drugs with potential cardiotoxicity. Recently, Yoon et al have demonstrated that patients exposed to anthracycline or trastuzumab and developing left ventricular dysfunction are often treated with a suboptimal heart failure therapy, despite the fact that the Food and Drug Administration has recently warned on the increased risk of diabetes and heart disease derived from gonadotropin releasing hormone agonists used for prostate cancer. A possible solution is the development of a close collaboration between cardiologists and oncologists, as outlined recently in the Third International Symposium of the Cardiology Oncology Partnership.

Recovering from the Transcatheter Cardiovascular Therapeutics (TCT) meeting and awaiting the upcoming Società Italiana di Cardiologia Invasiva-Gruppo Italiano Studi Emodinamici (SICI-GISE) congress, it is appropriate to review some key studies that have been recently published.
Bhatt et al conducted a randomized trial including 3873 patients treated already with aspirin and clopidogrel and allocated to omeprazole versus placebo, and found that omeprazole significantly reduced the risk of gastrointestinal events (1.1% versus 2.9%) without any sign of cardiovascolar hazard (4.9% cardiovascular events at 6 months versus 5.7%), thus disproving previous works (all actually non-randomized analyses) suggesting that proton pump inhibitors had a detrimental interaction effect on the risk-benefit profile of clopidogrel. Indeed, this whole clopidogrel-omeprazole controversy too strongly remind us of the hormone replacement therapy issue, which was wrongly dominated by biased non-randomized trials and could only be settled by much later experimental studies.
The long-term safey of drug-eluting stent implantation for unprotected left main coronary disease has been further confirmed by the ASAN-MAIN investigators. In particular, Park and colleagues compared coronary artery bypass surgery versus percutaneous coronary intervention in 395 patients followed for at least 5 years, demonstrating that percutaneous coronary intervention has similar rates of death, myocardial infarction or stroke, but higher rates of repeat revascularization, in comparison to bypass surgery.
Finally, Elias-Smale et al including Ewout Steyerberg provide compelling evidence in support of the incremental use of computed tomography coronary calcium score to appraise the cardiovascular risk of asymptomatic elderly subjects. In particular, coronary calcium score improved the predictive ability of the Framingham risk score by enabling more appropriate reclassification of 50% of patients included in the intermediate risk stratum (10% to 20% 10-year risk). Whether calcium score can be recommended routinely for risk prediction can however only be demonstrated by a pragmatic randomized clinical trial.

After several months of unexpected pause, it's time for our beloved newsletter. The recent European Society of Cardiology (ESC) and the Transcatheter Cardiovascular Therapeutics (TCT) meetings provide several seminal news worth reporting.
The SHIFT trial has been probably the most important trial reported at the ESC congress. In this study, patients with congestive heart failure not reaching adequate heart rate control were randomized to ivabradine versus placebo. At mid-term follow-up, patients treated with ivabradine had several key clinical benefits, including a significant reduction in cardiac mortality.
The PARTNER trial dominated instead the TCT congress, With a hitherto unheard absolute reduction of more than 20% in the risk of all-cause death at 12 months in patients undergoing transcatheter aortic valve implantation (TAVI) compared with best standard therapy for severe aortic stenosis in inoperable patients.
Should we now change altogether our practice and, respectively, add ivabradine to our pharmaceutical armamentarium for congestive heart failure, and TAVI for inoperable aortic stenosis? Some unresolved issues still loom, including cost-benefit implications, but our informed guess is that these two therapies will indeed play and ever increasing role in our everyday clinical practice.
What about the other studies reported in the last few weeks? We enjoyed in particular the COPPS trial, which showed that colchicine can reduce by a significant absolute 12% the rate of post-pericardiotomy syndrome, the ZILVER PTX trial, which demonstrated the superiority of the polymer-free paclitaxel-eluting peripheral self-expandable stent Zilver PTX over balloon-only angioplasty or bare-metal stent in patients with femoro-popliteal disease, the DES-BTK study, which reported on the superiority of sirolimus-eluting versus bare-metal stents for below-the-knee arterial disease, and the TORPEDO trial, which showed the superiority of invasive management of deep vein thrombosis in comparison to anticoagulation only.

EuroPCR 2010 has recently been organized and plentyful of studies have been reported which are directly relevant for interventional cardiologists. Among the most important are surely the RESOLUTE All Comers study, the SPIRIT V Diabetes trial, and the TALENT study.
The RESOLUTE All Comers trial has compared the zotarolimus-eluting Endeavor Resolute stent versus the everolimus-eluting Xience/Promus stent in 2300 patients undergoing percutaneous coronary intervention. After a follow-up of 12 months, Endeavor Resolute was non-inferior to the Xience/Promus stent, with, respectively, 8.2% versus 8.3% target lesion failure. Despite this encouraging result for the primary end-point, stent thrombosis was significantly more frequent with Endeavor Resolute (1.2% versus 0.3%, p=0.01), thus calling into question previous assumptions of greater safety of the Endeavor platform.
The SPIRIT V Diabetes trial focused on 324 diabetics undergoing percutaneous coronary interventio and randomized to implantation of Xience/Promus versus the paclitaxel-eluting Taxus Liberté stent. After 9 months, the primary end-point of angiographic in-stent late lumen loss was significantly lower with Xience/Promus than with Taxus Liberté (0.19 mm versus 0.39 mm, p=0.001). Yet, this angiographic superiority did not translate into significant reductions in repeat revascularizations, which actually appeared to favor Taxus Liberté, with target lesion revascularization in, respectively, 8.4% versus 3.8% (p=0.16). Nonetheless, Xience/Promus was associated with non-significantly fewer myocardial infarctions, suggesting that thinner struts may confer clinically relevant benefits in patients with diffuse disease (0.5% versus 1.9% for Q-wave myocardial infarction, 2.8% versus 6.7% for non-Q-wave myocardial infarction).
Finally, Sciahbasi et al reported on the TALENT trial, which randomized 1540 patients to right versus left trans-radial access for percutaneous coronary procedures (both diagnostic and interventional). They intriguely found that left radial access reduced fluoroscopy time (average difference of 19 seconds, p=0.0025) and dose-area product (average difference 1.4 Gray/cm2, p=0.004) for diagnostic procedures. However, statistical significance was no longer maintained when focusing on interventional procedures only or case performed only by experience operators. Thus, left radial access could be proposed as the access site of choice for trainees and/or cases unlikely to need intervention.

How is ST segment elevation myocardial infarction managed in Europe nowadays? A report from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of a collaborative analysis from national working groups recently published by Widimski et al investigated acute reperfusion therapy in 30 countries, finding that primary percutaneous coronary intervention (PCI) is the preferred treatment in 16 countries. However, thrombolysis is still preferred in as much as 8 countries, preferentially located in the Balkans and Southern Europe. As expected, primary PCI, whenever feasible, was associated with lower in-hospital mortality. The superiority of primary PCI over thrombolysis was maintained after many years. Nonetheless, time from first medical contact to needle/balloon was higher in primary PCI patients, and the much desired 2 hours or less are still a mirage in many countries.
An update of the largest randomized study on this topic with the longest follow up available, the DANAMI-2 trial, has been recently reported by Nielsen et al. After nearly 8 years, the interventional approach to ST segment elevation myocardial infarction still overcomes pharmacologic treatment for the composite primary endpoint of all-cause mortality or myocardial infarction. Nielsen and colleagues concluded that primary PCI should be the preferred reperfusion strategy, but stressed the importance of inter-hospital time delay to be less than 120 minutes. We absolutely agree with this point.
And now, we cannot omit our daily bread, so let's give a look at one of the most interesting meta-analysis recently disclosed. Lee and colleagues recently published on the results of a well done and sleek review on drug-eluting stents (DES) and bare-metal stents (BMS) for saphenous vein graft (SVG) interventions. A total of 19 studies including 3420 patients was analyzed, and the results rewarded the DES because patients in this group experienced fewer revascularizations, myocardial infarctions and had a strong trend towards higher survival after an average follow-up of 20 months. To note, only 2 out of 19 studies were randomized. Thus, DES use in SVG interventions now seems encouraging... awaiting another randomized clinical trial, maybe with newer generation DES.

Awaiting the EuroPCR congress and recovering from the exciting news of the American College of Cardiology Scientific Sessions, two important and thought-provoking studies have been reported. Both studies challenge apparent dogmas in cardiovascular disease, and should be thus carefully read and analyzed.
Fowkes et al have provided another blow to the hypothesis that aspirin can be beneficial at large in the primary prevention of cardiovascular disease, by randomizing over 29,000 patients with peripheral artery disease to low-dose aspirin or placebo, and following them for more than 8 years. Despite such large sample size and long-term follow-up, no significant change in the rate of cardiovascular events occurred in favor of aspirin, despite an evident trend for an increase in bleeding. Thus, given also the indidivual patient data meta-analysis by Patrono et al, aspirin cannot be recommended any longer in the primary prevention of cardiovascular disease. Nonetheless, we do recommend to consider and discuss individually wiht patients the risks and benefits of aspirin (as well as in the near future of generic clopidogrel), as patients at high thrombotic risk but low bleeding risk may still benefit from antiplatelet therapy in primary prevention.
Patel et al also poignantly challenge a common approach in cardiovascular medicine, i.e. diagnostic coronary angiography in patients with suspected coronary artery disease. In their cross-sectional work including almost 400,000 patients, they show that coronary angiography disclosed absence of or only mild coronary artery disease in almost 40% of subjects. Thus, they conclude that a substantial portion of these tests are unnecessary and thus should be preceded by more thorough risk stratification. Whereas risk stratification is always beneficial, as long as it does not inappropriately delay life-saving treatment, the idea that negative coronary angiograms are non-contributory is wrong, as many tests in the whole realm of medicine are ordered to exclude a disease or a condition, rather than just to confirm it. Indeed, evidence based medicine experts, including those of the Centre for Evidence Based Medicine do recommend both tests with high specificity to rule in disease (SpIn) and tests with high sensitivity, such as coronary angiography, to rule out disease (SnOut).

This year American College of Cardiology Scientific Sessions have confirmed their role as probably one of the most authoritative North American cardiological conferences. Among the key trials just recently reported, a number have provided very important and seminal findings.
Specifically, the ACCORD trial compared a target of systolic blood pressure lower than 120 mm Hg versus a target of 140 mm Hg in 4733 patients with diabetes mellitus at high risk of cardiovascular events. The investigators found no important difference in the rate of death, but a sensible reduction in the risk of stroke with a more stringent blood pressure control, despite more frequent serious adverse events.
The fenofibrate substudy of the very same ACCORD trial compared fenofibrate versus placebo on top of simvastatin in 5518 patients with type 2 diabetes mellitus at high risk of cardiovascular events, finding no meaningful benefit of fenofibrate on the risk of death, or on the composite end-point of death, myocardial infarction or stroke.
The twin randomized trials by Park et al have begun addressing the issue of the most appropriate duration of dual antiplatelet therapy following drug-eluting stent implantation. Despite a sound rationale for the superiority of a treatment regimen lasting more than 12 months after revascularization, this trial did not show any significant benefits of continuing clopidogrel plus aspirin beyond 1 year.
The EVEREST II trial has provided much awaited results of percutaneous mitral valve repair versus surgical repair in 279 patients with mitral regurgitation. The study demonstrated that percutaneous repair with the MitraClip device has similar safety and efficacy in comparison to open surgery, thus providing a momentous paradigm shift in the management of this frequent cardiovascular condition.
Finally, the RACE II Investigators have confirmed the benefit of a conservative approach in the management of heart rate in patients with chronic atrial fibrillation. Specifically, 614 patients were randomized to a soft rate-control strategy (resting rate less than 110 beats per minute) versus a strict one (resting rate less than 80 beats per minute), and following the patients for 2 years. The rate of adverse clinical events was similar in the two groups, thus demonstrating that there is no need to routinely pursue a low heart rate in stable patients with permanent atrial fibrillation.

Eagerly awaiting upcoming scientific conferences such as JIM, ACC, and EuroPCR, February should not be considered an interlocutory month. In fact, scientific journals keep on publishing the results of very interesting studies in our area of interest. The reader will thus understand how, as usual, the selection is not easy.
First of all, we would like to highlight the results of a well conducted meta-analysis from Valgimigli et al published in the European Heart Journal (2010;31:35-49). These authors sought to evaluate the impact of tirofiban versus placebo or abciximab on the outcome of 20,000 patients with acute coronary syndrome undergoing percutaneous coronary intervention, and found that tirofiban significantly reduced mortality and mortality plus myocardial infarction in comparison to placebo. When tirofiban was compared to abciximab, it showed similar results regarding 30-day mortality (confidence interval: 0.53-1.54, p=0.70), however a trend towards an increase of death or myocardial infarction was found in the tirofiban group (confidence interval: 0.96-1.45, p=0.11). The investigators hypothesized this result was due to the "old" regimen of drug used in less recent trials such as TARGET, as in fact no differences were found when a 25 mg/kg bolus regimen was used. Both minor bleeds (but not major) and thrombocytopenia were reduced in the tirofiban group.
It is worth mentioning the 1-year results of the multicenter prospective randomized trial CARDIA, just published in the Journal of the American College of Cardiology by Kapur et al (2010;55:432-40), where 510 patients with multivessel coronary artery disease and diabetes were randomized to bypass grafting or percutaneous coronary intervention. The primary study end-point was a composite of mortality, myocardial infarction, or stroke at 12 months and resulted similar in the two arms (10.5% versus 13%, confidence interval: 0.75-2.09), although the prespecified 1.3 noninferiority margin of confidence interval was exceeded. Those patients who were treated with drug-eluting stents, however, (70% of the total) well matched with the bypass population (11.6% versus 12.4%, confidence interval: 0.51-1.71).
Finally, we want to disclose the results of a study from De Labriolle et al, European Heart Journal 2010, that investigated the impact of platelet drop in an all-comers single-center population of patients undergoing percutaneous coronary intervention. Authors interestingly discovered that moderate (25-49%) or severe (?50%) thrombocytopenia developed in 16% of patients, and these patients experienced a significantly higher risk of death or myocardial infarction at 30-day and 1-year follow up. As expected, the worst performance was achieved in the severe thrombocytopenia arm. The authors concluded that among the risk factors for thrombocytopenia, some are modifiable, as thigh-osmolar contrast agents and bivalirudin seem to reduce this risk.

The new year has just begun, yet few major novel studies have been reported in the last few weeks on interventional cardiology topics.
These include the COMPARE trial, by Kedhi and colleagues, which has shown that, among 1800 unselected patients with coronary artery disease, everolimus-eluting stents proved significantly superior to paclitaxel-eluting stents in terms of the composite rate of major adverse cardiac events (6% versus 9% at 12 months), as well of stent thrombosis (1% versus 3%), myocardial infarction (3% versus 5%), and repeat revascularization (2% versus 6%), despite similar rates of all-cause death (2% versus 2%). We also wish nonetheless to focus the attention of visitors of this website on 2 recent publications which can prove very interesting. In the first article, Holmes et al provide a thorough viewpoint on the importance and details of the mentor-mentee relationship, crucial in both clinical practice and clinical research, and often disregarded or approached in an inappropriately informal way, especially in European countries. The other interesting work is the study by Hannan et al, comparing the clinical suggestions given by interventional cardiologists after completion of coronary angiography to those of other colleagues. This study poignantly shows that, among 16142 patients with significant coronary artery disease, those managed by interventional cardiologist were more likely to receive recommendations for percutaneous revascularization and fewer recommendations for coronary artery bypass surgery, often in disagreement with explicit American College of Cardiology/American Heart Association guidelines.
Finally, we wish to compliment ourselves with Hlatky et al, authors of the meta-analysis entitled "Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials", and winner of the 2009 METCARDIO Award, explicitly aimed at awarding the most influential and rigorous meta-analysis published in 2009 on interventional cardiology topics.