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 Meta-analysis and Evidence-based Medicine Training in Cardiology
The metcardio.org website is dedicated to meta-analysis and evidence-based medicine training in cardiology. It is sponsored by the Meta-analysis and Evidence-based medicine Training in Cardiology (METCARDIO) Group, currently headquartered in Turin, Italy, and formerly known as the Center for Overview, Meta-analysis, and Evidence-based Medicine Training (COMET). The focus of the metcardio.org website is on clinical research methods and evidence-based cardiovascular medicine with a specific interest in interventional cardiology and peripheral cardiovascular interventions. Nonetheless, there is plenty of training and research opportunities for other evidence-based endeavors, eg in anesthesiology, critical care medicine, and psychiatry.





The year is ending and it is time for a look back at what we have achieved as cardiology community, and what awaits us in the future. Indeed, several seminal studies have been reported in the last few months, including the SYNTAX (SYNergy between PCI with TAXUS and Cardiac Surgery) trial and the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial. The SYNTAX trial has definitely challenged the role of bypass surgery for patients with multivessel and/or unprotected left main coronary disease, showing that in such patients percutaneous coronary intervention (PCI) with drug-eluting stents (DES) can provide equivalent results in terms of death, myocardial infarction, stroke, or stent thrombosis/graft occlusion. Conversely, the JUPITER study has further confirmed the present and future role of inflammation in coronary heart disease, and the pivotal benefits that statins can provide even in patients apparently not at high risk of adverse events.
However, this year has not been all about positive news and achievements. Unfortunately, Jacques Puel has died a few months ago. This outstanding and pioneering French interventional cardiologist was the first ever to implant a stent in a human coronary artery (actually a Wallstent). He could claim many other achievements, including hundreds of publications. Most likely, his most appropriate epitaph lies in his own words in the book edited by Michel Bertrand in 2006 on the history of interventional cardiology: thanks to a stent "coronary stenosis is defeated but atherosclerosis remains. The solution to atherosclerosis will be found in pharmacological stabilisation and prevention. Not for many years now have the complications of urinary bihlarziosis been treated with a small reed", as the ancient Egyptians used to do (from Bertrand ME, The evolution of cardiac catheterization and interventional cardiology, Iatric Press, 2006). Despite this sad note, the METCARDIO staff wishes everybody a Merry Christmas, Happy New Year, and Happy Holidays.

Exciting news and pivotal pieces of evidence have been reported at the recent American Heart Association (AHA) Congress in New Orleans. Several interesting data have been reported, but our focus has particularly been on the ATLAS, JPAD, JUPITER, and TIMACS trials, which we hereby report to our worldwide readership (see figure below).
The ATLAS-TIMI 46 (Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in Subjects with Acute Coronary Syndrome – Thrombolysis in Myocardial Infarction 46) trial, compared the factor Xa inhibitor rivaroxaban versus placebo in patients with acute coronary syndromes (ACS) already treated with aspirin alone or aspirin plus clopidogrel. After 6 months, rivaroxaban lead to significant reductions in death, myocardial infarction or stroke, but substantially increased bleedings (up to 14.5% in subjects already on dual antiplatelet therapy).
FFR
Geographical location of contacts to metcardio.org during the last month
The JPAD (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) trial randomized 2539 Japanese patients with type-2 diabetes mellitus but without any previous symptomatic episode of atherothrombosis to low-dose (80 to 100 mg daily) aspirin versus placebo. After more than 4 years of follow-up, aspirin did not reduce fatal or non-fatal atherosclerotic events in this relatively low risk context (5.4% versus 6.7%, p=0.16), even if fatal events appeared significantly less common in the aspirin group (0.08% versus 0.8%, p=0.0037).
The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial, indeed the single most important study presented at AHA and, possibly, this whole year, compared 20 mg of rosuvastatin daily versus placebo in apparently healthy subjects without increased low-density lipoprotein (LDL) cholesterol but with increased high-sensitivity C-reactive protein (CRP) levels. Thanks to significant reductions in both LDL and CRP, rosuvastatin lead to sensibly fewer cardiovascular events and deaths. The only evident adverse effect was an increase in the occurrence of diabetes, however clearly offset by the major across-the-board clinical benefits.
The TIMACS (Timing of Intervention in Patients With Acute Coronary Syndromes) trial randomized more than 3000 patients with acute coronary syndromes to an early invasive or a delayed invasive management strategy, showing that they provided similar results in term of overall survival and freedom from myocardial infarction or stroke (9.7% versus 11.4%, p=0.15), even if an early invasive approach lead to fewer episodes of refractory myocardial ischemia. Among higher risk subjects, an early invasive approach proved actually capable of reducing the risk of death, myocardial infarction or stroke (14.1% versus 21.6%, p=0.005), but these findings should be viewed in light of the subgroup analysis context.

Exciting news and pivotal pieces of evidence have been reported at the recent Transcatheter Cardiovascular Therapeutics (TCT) Congress in Washington, DC. Among the dozens of interesting studies reported, the FAME, HORIZONS, NAPLES and ODESSA trials are for sure among the most interesting ones.
The FAME trial, comparing angiography versus fractional flow reserve (FFR) to guide the management of multivessel coronary artery disease, has shown that the latter strategy is associated with
FFR
Optical coherence tomography (OCT)
significant clinical and economic benefits. Specifically, a total of 1005 patients with multivessel coronary disease were randomized to angiography-guided percutaneous coronary intervention (PCI, n=496) or FFR-guided PCI (in which only lesions with FFR lower or equal to 0.80 were attempted, n=509). After 12 months, FFR-guided PCI lead to significant reductions in death, myocardial infarction or repeat revascularization (respectively 18.4% vs 13.2%) and significantly lower costs.
The HORIZONS trial, a factorial study appraising the role of bivalirudin and paclitaxel-eluting stents in acute myocardial infaction (AMI), has provided important insights on the most appropriate invasive management of AMI. Among more than 3000 patients, paclitaxel-eluting stents proved significantly superior to bare-metal stents in reducing repeat revascularization without increasing any risk of death, myocardial infarction or stroke. Moreover, peri-procedural anticoagulation with bivalirudin lead to increased 12-month survival in comparison to unfractioned heparin plus glycoprotein inhibitors.
The NAPLES study, despite its relatively small size (n=335), provided interesting insights on the risk of peri and post-procedural bleeding in diabetics randomized to bivalirudin (n=167) or unfractioned heparin plus tirofiban (n=168), showing that bivalirudin significantly reduces major or minor bleeding after PCI in comparison to unfractioned heparin plus tirofiban (1.8% vs 7.7%), despite no significant impact on major bleedings only (0.6% vs 1.8%).
Finally, the ODESSA study, appraising by means of optical coherence tomography (OCT) the neointimal coverage of drug-eluting and bare-metal coronary stents, has demonstrated that OCT can provide important insights on stent coverage after PCI. Moreover, 6-month OCT data suggest that zotarolimus-eluting stent struts are more homogeneously and more completely covered than struts of paclitaxel or sirolimus-eluting stents (respectively 0.02% rate of malapposed or uncovered struts vs 4.3% and 8.2%), thus behaving in a fashion strikingly similar to bare-metal stents (0.9%).

It is Fall again, which means it is time for us to review and comment on the recent ESC 2008 congress. Definitely another successful session organized by the ESC team. Over 20,000 attendees were present and lots of interesting science were presented in the setting of a beautiful mid-European city, Munich.
For our interventional cardiology aficionados the results of the SYNTAX trial were both disappointing and encouraging. Indeed in this head-to-head trial comparing percutaneous coronary intervention (PCI) with paclitaxel-eluting (TAXUS) stents with coronary artery bypass grafting (CABG) in patients with triple vessel coronary artery disease (CAD) and/or left main disease, CABG proved to be, once again, superior to PCI in terms of reduction of major adverse cardiovascular and cerebrovascular events (MACCE). There was indeed a highly significant absolute 5.6% reduction in the rate of MACCE (death, stroke, MI and repeat revascularization) for the CABG treated patients (number-needed-to-treat 18 patients). Those who are familiar with the historical PCI vs CABG randomized controlled trials will however recognized that the gap is getting narrower, and while the MACCE rate in the CABG arm has been relatively stable over time (12%), the MACCE rate in the PCI group is at its lowest (18%). The true supporters of a PCI-based strategy will also raise the question on whether 'all outcomes in MACCE are created equal?'.
FFR
A typical case of coronary fractional flow reserve (FFR)
The need for a combined end-point that is sensitive enough to detect differences and be rapidly compared between studies has lead to the widespread use of MACCE as endpoint of choice. Nevertheless it should be clear that although death and repeat revascularization are weighed equally in the MACCE rate they are in no means equal from a clinical standpoint. Let's thus look at some of the individual endpoints in the SYNTAX trial. There are no doubts that while CABG and PCI are associated with an equal number of symptomatic total occlusions (graft occlusion 3.4% vs stent thrombosis 3.3%), the number of clinically-driven repeat revascularization is almost 3-fold higher in the PCI group (11.1% vs 4.4%, P<0.001). At contrary, the MACCE rate excluding revascularization (death, MI, stroke) was virtually identical between PCI and CABG (7.6% vs 7.7%, P=0.98). Caution however should be used as the study was underpowered to detect differences in this secondary endpoint.
The increased rate of stroke in the CABG arm is somewhat alarming. In line with prior observations, CABG seems to be associated with a >3-fold higher risk of peri-operative stroke (2.2% vs 0.6%, P=0.006).
ESC discussant Dr. Hamm (Bad Nauheim, Germany) pointed out that both PCI and CABG performed favorably compared to historical cohorts. While acknowledging limitations of the SYNTAX trial, primarily being the relative short follow up (12 months), it may be conceivable to conclude that in patients with triple vessel CAD and/or left main disease eligible for both PCI [with Taxus stents] or CABG (based on clinical and angiographic criteria) either revascularization strategy is associated with a similar survival at 12-months, a greater need for repeat intervention in the PCI arm, and an excess of early morbidity (stroke) in the CABG arm. How about the patients who are not eligible for both treatments? We are thankful for the SYNTAX investigators to have generated 2 separated registries for CABG (in PCI-ineligible patients) and for PCI (in CABG-ineligible patients). The discrepancy between outcomes in the 2 registry arms highlights the need for individualized treatment of patients. Every interventionalist will agree to the statement that some angiographic characteristics make the patient not an ideal candidate for PCI. These patients, most of them without a high surgical risk score, should be treated with CABG as their outcome is no different than patients randomized to CABG (MACCE rate 8.8% vs 7.7%). The patient who is not a candidate for CABG, on the other hand, is a high-surgical risk patient, by definition. The ineligibility for CABG is associated with a 20.4% MACCE rate when patients are treated with PCI. While this likely reflects more comorbidities and angiographic characteristics less favorable to complete revascularization, it also highlights that CABG-ineligible patients undergoing PCI are a very high-risk cohort and further studies may be required to prevent adverse outcome in this subgroup of patients.

The ESC however is not all about interventions. A great deal of new data has been presented for preventive cardiology, acute ischemic syndromes, heart failure and arrhythmias. While we most certainly cannot cover the entire ESC session, we would like to point some landmark studies.
Do statins prevent CV events in patients undergoing non-cardiac surgery? Yes, and finally there is a randomized trial to prove it. The DECREASE III study presented at the ESC showed an absolute 8% reduction in MI rates with fluvastatin XR 80 mg daily (11% vs 19%, number-needed-to-treat 13). This is likely related to the so-called pleiotropic effects of statins (CRP levels were indeed reduced by 21%). One issue worth mentioning is that patients had been on fluvastatin for approx 1 month prior to surgery, whether such benefit is seen with shorter duration of treatment is unknown.
RITMO logo
The RITMO Study
The CORONA study has left all of the promoters of widespread use of statins in heart failure waiting for the GISSI-HF study. Indeed, while the CORONA study failed to show a reduction in the primary endpoint with rosuvastatin in heart failure patients, it had shown a reduction in hospitalization rates for heart failure. The GISSI-HF trial was presented at the ESC. The GISSI-HF was a factorial 2x2 trial randomizing heart failure patients to rosuvastatin or placebo and to n-3 PUFA or placebo. Disappointingly, rosuvastatin 10 mg daily in heart failure was not associated with any significant benefit in the GISSI-HF study. ESC discussant Dr. Poole-Wilson (UK) appropriately pointed out that all patients with heart failure were enrolled independently of etiology, left ventricular ejection fraction, or baseline cholesterol/CRP levels. Also one single dose of rosuvastatin was used and a high crossover rate was noted between the 2 arms. Therefore, it is not advisable to prescribe rosuvastatin (or any other statin) in patients with heart failure who do not have any other compelling indications. The safety of the rosuvastatin in the GISSI-HF however suggests that there is no reason to stop statins in patients already taking it for another indication.
The GISSI-HF study however showed a survival benefit in patients with symptomatic heart failure randomized to n-3 PUFA (850-882 mg daily of eicosapentaenoic acid and docosahexaenoic acid as ethyl esters). This is in line with the findings of the GISSI-prevenzione trial studying post-AMI patients. The benefit observed with the GISSI-HF was rather small. There was a 9% relative risk reduction and an approximate 2% absolute reduction at 5 years (number-needed-to-treat for 5 years to prevent 1 death is 50). While we agree that the relatively low cost and safety of the n-3 PUFA make them a nice addition to the medical armamentarium for heart failure patients, we suspect that there may be some patients that benefit more than others and we wonder if dose-response relations and mechanisms of action should be further investigated. It is surprising indeed that while mortality was significantly reduced with a P value of 0.045, no differences in MI rate, heart failure admission rate, or sudden death rate were noted raising the question of how such borderline mortality benefit was achieved. Once again we are extremely grateful to the GISSI group for designing, conducting, and presenting data in a timely fashion that are so relevant for patient care.
The UKPDS investigators are also to be congratulated for presenting the 10-year follow up of the UKPDS study. The 10-year UKPDS results show for the first time that aggressive glucose control with sulphonylurea/insulin or metformin based strategies is associated with a reduction in macrovascular complications. This trial demonstrates the hyperglycemia'atherosclerosis paradigm. The study however also provides several other teaching points. First, in order for better glycemic control to translate in less cardiovascular events a long follow up (>5 years) is needed. Second, the means by which glucose is controlled may be more important that the glycemic control itself. Indeed while both intensive arms were associated with benefit, the sulphonuylurea/insulin based strategy was associated with an absolute 3.5% 10-year reduction in mortality (number needed to treat for 10 years: 29 patients), the metformin-based strategy [in overweight patients] was associated with a striking 7.2% absolute risk reduction at 10 years (number needed to treat for 10 years: 14 patients).
Thanks for reading metcardio.org and stay tuned for News from TCT 2008, as well as from the RITMO Study, an ongoing multicenter prospective observational study focusing on management strategies for unprotected left main coronary artery disease.

Summer time is, as usual, spent between holidays and preparations for major Fall congresses, and thus, few big news are available. However, the publication
Coronary perforation
A typical coronary perforation
of the long-term results of the Stent Or Surgery (SOS) trial, suggesting a survival benefit with surgical bypass grafting in comparison to bare-metal coronary stenting, are worth reading (Booth et al, Circulation 2008). How can we explain such difference in long-term outcomes? Several have been proposed. For sure, percutaneous coronary intervention is a relatively safe procedure, yet complications, occasionally life-threatening, do occur (eg coronary perforation, depicted in the above picture).
Other interesting data have been provided by Korean investigators, who have performed coronary computed tomography angiography as a screening tool in asymptomatic patients (Choi et al, JACC 2008). They have found that, among 1,000 subjects (average age 50 years, 63% males) without symptoms of coronary heart disease, 5% of them had significant (>50% diameter stenosis) coronary artery disease, with as many as 2% had severely obstructive (>75% diameter stenosis) coronary artery disease.
Implications of these results would be great if we were to adopt such a screening tool in everybody. Moreover, what would be our strategy in case an asymptomatic subject is found with significant coronary artery disease? Further research is sorely needed before coronary computed tomography angiography becomes misused and abused, especially given its well known limitations in diagnostic precision and accuracy (eg Hamon et al, JACC 2006).

Winter is just past and the raising temperature is probably affecting the scientific environment fuelling a very "hot debate" around the issue of contaminated heparin and the discrepancies between US and EU recommendation guidelines on antithrombotics for acute coronary syndromes (ACS). First of all, let's introduce the problem. In January 2008, FDA (US Food and Drug administration) received reports of suspicious clusters of hypersensitivity reactions in patients undergoing dialysis since November 2007. The heparin sodium manufactured by Baxter Healthcare was soon recognised as a common feature. This finding led Baxter Healthcare to recall nine lots of heparin sodium for injection. Later on, there were continuing reports of allergic-type reactions after injection of heparin also in patients in other clinical settings. On February 2008, Baxter Healthcare recalled all remaining lots. Germany was the second country, on March, announcing a heparin recall. As a reaction the FDA posted descriptions of analytic methods on its Web site to screen for heparin contaminants. This screening revealed that contamination of the heparin supply involved at least 12 countries. In April, 81 fatalities in US patients receiving heparin since January 2007 have been reported due to severe anaphylactoid reactions.
Bench testing of coronary stents
Bench testing of coronary stents
That would be already enough to disturb the sleep of interventionalists worldwide. Even more disturbing is that it appears as a "deliberate act" to increase profits in Chinese workshops. An investigator for the US Committee on Energy and Commerce, noted that the contaminant, oversulfated chondroitin sulphate (OSCS), was apparently added to crude heparin in China at some stage in the production process by "unidentified parties".
This contaminant mimics heparin and is much cheaper in terms of production cost compared to crude heparin. It has been postulated that such contaminant was added to increase profits. This case depicts two separate faces of the FDA: once the crisis was identified, the FDA acted promptly, but a poor performance as a regulatory agency may have contributed to the crisis itself. Precisely, it has been reported that FDA failed to inspect the Chinese facility prior to approving Baxter's application to supply its heparin from that plant. Of note, FDA inspected the wrong facility. A matter of concern is also the fact that Baxter's own records indicate that they were aware that the plant had never been inspected by FDA, and when they eventually inspected the plant theirself, no anomalies have been reported to the FDA committee. However, the question "Would Inspection of the Plant Have Made a Difference?" still stand. Intentional contamination is difficult to detect. The relationship of interventionalist with anticoagulant drugs is by the time being further complicated by the discrepancies in US/European guidelines on antithrombotics for ACS.
The ACC/AHA gave enoxaparin and fondaparinux a "class 1 rating" for conservatively and invasively managed patients. Class 1 means "evidence or general agreement" that the treatments are useful or effective. On the other side of the Atlantic ocean, the ESC gave enoxaparin a "class 2 rating". Class 2 means "conflicting evidence or divergence of opinion" about the usefulness of enoxaparin, and did not recommend fondaparinux for patients undergoing "urgent" invasive procedures. Do discrepancies on recommendations undermine confidence in the integrity of guideline development? Maybe. ACC/AHA might have placed greater weight than the ESC on the results of a meta-analysis that showed that enoxaparin compared with heparin reduced MI and did not increase bleeding. ESC probably gave more value to the results of the SYNERGY trial (which showed that enoxaparin was as effective as heparin at the expense of more bleeding in invasively treated patients) and the OASIS-5 trial in which enoxaparin was as effective as fondaparinux but caused more bleeding and was associated with excess strokes and deaths at day 30). The disparate recommendations for fondaparinux probably also reflect differences in the interpretation of the OASIS-5 trial, in which an excess of catheter thrombosis in patients treated with fondaparinux undergoing PCI has been reported. However, the chairs of both the US and European guidelines committees stated that the two sets of guidelines were not as different as had been suggested.
The Chair of the AHC/AHA guidelines committee, Dr Jeffery Anderson, in an interview on a major medical website, pointed out that although the ESC doesn't recommend fondaparinux for patients getting urgent revascularization, the ACC/AHA recommendation for fondaparinux was for an invasive strategy within 48 hours along with heparin co-administration. Dr Jean-Pierre Bassand, head of the European ACS guidelines committee, during an interview for the same website said that ESC guidelines state that fondaparinux is not recommended for the small minority of ACS patients who need immediate intervention (about 5% of patients). He also added that Fondaparinux had a 1A recommendation for all other patients, but if they subsequently undergo PCI unfractionated heparin could be added. Bassand agreed that the European and US guidelines did differ somewhat on their recommendations for enoxaparin. He said the European committee had decided to focus primarily on the most up-to-date trial with enoxaparin, the SYNERGY, mainly considering the increased risk of bleeding seen with enoxaparin.
From the interventionalist's point of view, some concerns still remain: 'early invasive approach of ACS' should be consistently defined. It is conceivable that both US and EU patients do not care about discrepancies when they are about to get into the Cath Lab. Guidelines should provide a clear, rational, and practical approach to the matter. Possibly univocal.

Further news but much less hype are coming from the EuroPCR 2008 Congress recently held in Barcelona. Indeed, more data in support of existing technologies and devices have been reported, togheter with some interesting details on other topics, including intravascular ultrasound (IVUS).
Indeed, an engaging debate on the risk and cost-benefit balance of IVUS during percutaneous coronary intervention (PCI) was held, spurred by a 210-patient randomized study comparing IVUS-guided PCI versus standard PCI, and suggesting equivalent results for both approaches. Several trials were also reported, including the two-year results of the SPIRIT III study have confirmed the safety and efficacy of Abbott's Xience V stent in comparison to Boston Scientific's Taxus stent (actually Boston Scientific is also
IVUS before and after PCI
IVUS of a coronary artery before (left) and after (right) stenting
distributing an equivalent version of Xience V with the brand name of Promus). Similarly favorable data have been reported for Terumo's Nobori and Xtent's Custom devices. Conversely, further data suggesting the relative inferiority of Taxus in comparison to Cordis' Cypher have been reported from a non-randomized study performed in Denmark by Kaltoft et al.
Concomitantly, the New England Journal of Medicine has just published results of the FINESSE and HORIZONS-AMI trials, which will obviously have a major impact on present and future management of acute myocardial infarction. Indeed, the FINESSE trial compared primary PCI without any facilitating drug regimen versus primary PCI facilitated by earlier abciximab administration or administration of abciximab plus reteplase. Despite some benefits on surrogate end-points, this 2452-patient study showed equivalent results on hard events for all the three strategies. The HORIZONS-AMI trial randomized 3602 patients with acute myocardial infarction to undergoing primary PCI to bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitors. Despite an early increase in stent thrombosis with bivalirudin, this drug lead to higher survival rates already at 30 days, suggesting that it could become the standard antithrombotic during primary PCI.
Finally, safety and efficacy of sirolimus-eluting stents in clearly off-label indications such as bifurcations, chronic total occlusions, or ostial lesions seem corroborated by the recent 3-year results of the SCANDSTENT study, which randomized 322 patients to sirolimus-eluting versus bare-metal stents, finding significantly lower adverse clinical events for these drug-eluting devices, as well as favorable trends for stent thrombosis.

It's April. The Spring is finally upon us, which means it's time to discuss the results of new studies presented at the American College of Cardiology (ACC) and Society for Cardiovascular Angiography and Interventions (SCAI) joint annual session. The conference was, as usual, rich in breaking news and late-breaking clinical trials. Preventive cardiology was likely the most covered topic at ACC 2008.
The ENHANCE study gained international interest mostly due to real or perceived conflicts in study design and reporting by the sponsoring body, fueling the ongoing debate on how much should the sponsoring agency be involved in data analysis and reporting. The study found no additive value of ezetimibe on top on simvastatin on the primary endpoint on carotid artery intimal media thickness (IMT, used as surrogate marker for atherosclerotic complications) in patients with familial hypercholesterolemia. The intriguing finding of a dissociation between low density lipoprotein (LDL) lowering effects and IMT changes represents the known question on whether pleiotropic statin effects independent of LDL lowering are the real mediators of IMT regression as seen with rosuvastatin (Ballantyne et al) and LDL changes only reflect intensity of the statin effects. While the ENHANCE study does not suggest harm of exetimibe and may be underpowered to show real benefit, we anticipate that a shift in the use of ezetimibe will occur in the following months while awaiting for larger clinical trials with ezetimibe, and statin therapy remains the mainstay of anti-atherogenic and cholesterol-lowering therapy. Of note the JUPITER study testing the use of rosuvastatin in apparently healthy subjects without hypercholesterolemia but with elevation in C-reactive protein levels was halted early due to a significant reduction in mortality associated with rosuvastatin, once again suggesting an anti-inflammatory/anti-atherogenic effect of statins which is at least partially independent of lipid-lowering.
Four additional primary prevention trials are worth mentioning. The PERISCOPE study showed that when compared to an insulin secretagogue, glimepiride, the insulin-sensitizer, pioglitazone, was associated with a significant greater reduction in fasting glucose and insulin, a more favorable effect on lipids and blood pressure, and a small yet significant reduction in coronary atheroma burden (vs a significant increase with glimepiride). These data paired with the finding of a significant association with improved survival deriving from a meta-analysis of >16,000 patients presented by Lincoff et al, suggest that pioglitazone may become the preferred agent for diabetic treatment in patients with atherosclerotic disease.
Has the ALLHAT study told us all we need to know regarding management of hypertension? Apparently no, according to the ACCOMPLISH study. In the study, 11,400 patients were randomized to a combination of benazepril/diuretic (which would be in line of current recommendations of using a diuretic as first line therapy) vs benazepril/amlodipine. The benazepril/amlodipine combination was associated with a superior blood pressure control and with a significant reduction in adverse cardiovascular and cerebrovascular event rates. The ONTARGET study on the other hand tested whether hypertensive patients at high risk for vascular events had similar outcome when treated with an angiotensin-receptor blocker, telmisartan, vs an ACE-inhibitor, ramipril. Compared to ramipril, telmisartan was associated with a similar effect on blood pressure control and similar event rates but significantly less cough and angioedema. The combination of telmisartan/ramipril was also tested showing no significant additional benefit vs ramipril or telmisartan monotherapy.
Distal left main disease
Distal left main disease
Significant innovation has been presented also at the joint ACC-i2 and SCAI interventional meeting. The MULTISTRATEGY study enrolled 745 and randomized to abciximab or tirofiban and in a 2x2 factorial fashion to drug-eluting stent or bare-metal stent implantation in patients presenting with ST-elevation myocardial infarction (STEMI). This study is the second head-to-head comparison of tirofiban vs abciximab and the first to address this issue in patients with STEMI. No differences in reperfusion were noted between the 2 drugs. A superiority of the drug-eluting stents vs bare-metal stents was also confirmed. The BRAVE-3 study however questioned the role of abciximab in patients with STEMI treated with a 600 mg loading dose of clopidogrel. The ISAR-REACT-3 study reconfirmed the apparent safety of a bivalirudin based strategy for anticoagulation in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes. A subanalysis of the TRITOM-TIMI-38 study showed that the benefits of using prasugrel over clopidogrel are particularly obvious in the subgroup of patients undergoing PCI with a significant reduction in clinical endpoints as well as in angiographically defined stent thrombosis.
Responsiveness to anti-platelet treatments (aspirin and clopidogrel) has been consistently associated with adverse short- and long-term outcome. Can assessment of platelet reactivity, however, guide treatment? A small randomized trial from France by Bonello et al seems to prove that doubling the dose of clopidogrel load prior to intervention to reach a platelet reactivity <50% was associated with a significant reduction in MACE (0% vs 10%, p=0.007) and no increase in bleeding. Of note the dose of clopidogrel was as high as 2400 mg with a mean of 1620 mg.
Should left main percutaneous coronary intervention become standard of care? According to a meta-analysis on 1278 patients by Biondi-Zoccai et al on drug-eluting stent use and a large matched cohort study (2240 patients) in Korea on stenting in general presented by Seung et al in selected patients coronary stenting for left main disease yields similar results when compared to coronary artery bypass surgery. Both studies are however limited by non-randomized design. Buszman et al presented the results of a small randomized trial on 105 patients with left main disease randomized to PCI or surgery showing similar early and mid-term results for the occurrence of major adverse cerebro-cardiovascular events.
When is late too late for revascularization of the infarct-related artery? The Occluded Artery Trial (OAT) showed no benefit of late revascularization of a totally occluded artery in the cohort of patients presenting 3 to 28 days after myocardial infarction. A substudy of the OAT presented at the ACC suggests that no benefits were observed even in the group of patients revascularized earlier than 72 hours from the event, although this cohort included approximately 300 patients. A recent meta-analysis by Abbate et al pooled data from 10 randomized trials including also 4 studies in which angiographic documentation of total occlusion was not an inclusion criteria, and showed that in this cohort of 3560 patients late revascularization is associated with survival and cardiac remodeling benefit. An embedded meta-regression suggested that some subgroups may benefit more than the others such as those with subtotal infarct-related artery occlusion. A substudy of the OAT presented by Steg et al showed that absence of collaterals to the infarct-related artery predicted a significant benefit of late revascularization in terms of prevention of heart failure. Altogether these data suggest that the population of patients presenting late after AMI is heterogeneous and there may not be a 'one size fits all'.

The 2007 meta-analysis of Stettler and colleagues, awarded by the metcardio.org group as the most influential meta-analysis of the year, gave an important insight on the "overall" safety of drug-eluting stents in coronary arteries. However the debate continues. New data coming from several large cohorts invert the tendencies shown with previous registries in which hard endpoints such as mortality and myocardial infarctions appeared higher after drug-eluting stents as opposed to bare metal stents.
Thrombectomy in STEMI
Thrombectomy in STEMI
The updated SCARR registry showed that in more recent years the increased rates of death and myocardial infarction disappeared as compared to the first years of use of drug-eluting stents, suggesting probably a "learning curve" in the use of drug-eluting stents with somewhat modified implantation techniques (more aggressive optimization of the initial angiographic result and systematic avoidance of small edge dissections).
Other two recent registries from North America (Tu et al, and Marroquin et al) also showed substantial safety of drug-eluting stents if not even a reduction in hard endpoints. While drug-eluting stents are often considered as a class, data from an important "all-comer" randomized trial (the SORT-OUT II study) comparing sirolimus-eluting
Thrombus in STEMI
Thrombus in STEMI
and paclitaxel-eluting stents with only clinical endpoints and no angiographic follow up, shows no major differences between the two devices (Galløe et al). However new drug-eluting stents (specifically zotarolimus-, everolimus- and biolimus-eluting) are entering more and more the market and new data are needed to prove their benefits and drawbacks.
On the contrary, the issue of revascularization in multivessel patients is still a major issue. Despite the decline in referring patients for coronary artery bypass graft (as percutaneous coronary intervention is easier to perform and allows prompt recovery of the patients), surgery is still an extremely effective technique. A recent USA registry still confirms the superiority of surgery over percutaneous coronary intervention also in the drug-eluting stent era (Hannan et al). In our opinion, this important piece of information should be kept in mind when dealing with multivessel patients. Moreover, in scientific and methodological terms, surgery should always be considered when planning new randomized trials as one of the treatment arms among the different revascularization strategies considered when treating patients with multivessel disease. A simple comparison of two different percutaneous techniques in studies encompassing patients with multivessel disease prone to undergo multivessel percutaneous coronary intervenitons can be clinically misleading.
Lastly, the TAPAS trial, a pivotal study in patients with acute ST-segment elevation myocardial infarction has shown extremely encouraging results with the use of a simple and cheap manual thrombus aspiration device, used before stent implantation, as compared to the "classical" balloon pre-dilatation (Svilaas et al). These findings broaden previous data that came from smaller studies (REMEDIA and DEAR-MI) and suggest that this technique - simple to perform, easy to use and quite inexpensive - is effective in a cohort of patients where interventional cardiology already provides extremely good results, and thus where showing benefits can be difficult. A meta-analysis of the studies comparing manual thrombus aspiration versus conventional treatment is more than welcome to prove whether these devices can homogeneously reduce mortality in acute myocardial infarction patients.

This month we celebrate >1,000 visits to the metcardio.org website since its birth in late October 2007 wth an interesting and provocative newsletter.
A new year has just started, yet the noisy debate of the previous is still echoing in our minds. Indeed, 2007 can be acknowledged as the most troubled year in the history of percutaneous coronary intervention (PCI) despite its 30th anniversary. As well as the 1st year-over-year decrease (by nearly 10%) in the total number of PCI ever, the % of PCI with drug-eluting stents (DES) in the United States fell from 88% (2006) to approximately 62%. The publication of several studies questioning safety, effectiveness, and appropriate utilization of DES specifically lighted up the debate. Moreover, the use of PCI itself has been questioned.
New studies emerged at the European Society of Cardiology (ESC) and Transcatheter Cardiovascular Therapeutics (TCT) conferences. A step back first, in December 2006 the Food and Drug Administration (FDA) panel meeting on DES safety re-evaluated the newer Academic Research Consortium (ARC) definitions, including very late stent thrombosis (VLST) events, thus showing no statistically significant increase in VLST for DES compared to bare metal stents (BMS) (0.35%/year over 5 years after implantation vs 0.25%/year) (Cutlip et al, Circulation 2007). However, the FDA panel highlighted the importance of "in-label" use of such devices and endorsed prior recommendations to prolong dual antiplatelet therapy to 12 months where tolerable. Thus the concerns surrounding "off-label" use (coronary grafts, in stent restenosis and so on) still standed (Grines et al, Circulation 2007). The BASKET-LATE study, along with Camezind's and Nordmann's study-level meta-analyses also put a sinister shadow on the possible increased risk of death or myocardial infarction with DES. The Swedish Coronary Angiography and Angioplasty Registry (SCAAR) analysis seemed to confirm such data. On the other hand, in the patient-level meta-analysis of more than 3,000 patients followed for up to 4 years in the TAXUS Stent pivotal randomized trials such concerns have been denied (Stone et al, New Engl J Med 2007).
Several other studies with either high DES utilization cohorts (Western Denmark, NY State), or the use of propensity-matched DES and BMS patient groups (Tu et al, New Engl J Med 2007) suggested a lower mortality rates in DES patients. Finally, a meta-analysis of all published mortality data containing nearly 150,000 patients suggests that DES may actually reduce mortality by up to 23%, relative to BMS (Stettler et al, Lancet 2007). Of note, some of the opinions in favor of the lower mortality with DES came from a possible conflict of interest background.
New concerns emerged regarding the appropriate use/overuse of these devices. Despite the December 2006 FDA panel finding that DES had insufficient data on safety and efficacy in "off-label" use, some physicians concluded that such category of patients had the most to gain from reduced restenosis, that is just confusing in our opinion. Additional studies (TAXUS V-ISR, TAXUS-V small vessel, HORIZONS, SYNTAX), are being completed. They aim at demonstrating the safety and efficacy of the TAXUS Stent in many of these extended uses, possibly supporting the future expansion of FDA approved uses.
Additional confusion regarding the appropriate use of PCI was introduced by the COURAGE trial. The limitations of this study are clear (mild symptoms, post-angiography selection, BMS instead of DES, and an unanticipated (nearly 33%) cross-over from medical therapy to revascularization at a median of 11 months after randomization). However the COURAGE trial gave us evidence of a very common "real world" situation. PCI with BMS in highly selected, mildly symptomatic stable angina patients resulted in a better relief from symptoms rather than in a clear survival advantage compared to optimal medical therapy. More recently, a substudy of COURAGE clearly showed evidence of less ischemia in stable patients in which a complete revascularisation has been performed.
Thus, no discussion about the life-saving effect of PCI in the acute setting but COURAGE data strongly reassess the clinical utility of PCI in stable setting. In conclusion, we look forward reading new definite data regarding such pivotal issues, possibly objective and without any hidden interest.

Besides our best wishes for a happy new year, the editorial board of METCARDIO would like to highlight that METCARDIO efforts have lead to international recognition, thanks to a dedicated
Anterior ST-ACS
Anterior ST-elevation acute coronary syndrome
interview recently published in Circulation, Journal of the American Heart Association.
Among recent novelties, the management of pulmonary embolism is facing major changes, including a more aggressive diagnostic approach by means of urgent computed tomography (Anderson et al, JAMA 2007), as well as availability of dedicated devices for early invasive management (Margheri et al, Am J Cardiol 2008). This could lead, in the forseeable future, to management strategies for pulmonary embolism that resemble those currently recommended for ST-elevation acute coronary syndromes.
Model of coronary artery
Model of coronary artery
Indeed, a recent study published in the Journal of the American Medical Association (JAMA) shows poignantly that in today practice the frequency of false-positive cardiac catheterization laboratory activation for suspected ST-elevation acute coronary syndromes is relatively common (around 14%) in community practice, depending on the definition of false-positive (Larson et al, JAMA 2007). Despite this, such a false-positive rate appears in our opinion appropriate and could be considered as a quality meaure, not unlike to the accepted rate of fale positives faced by prudent surgeons performing exploratory laparotomy for suspected appendicitis (Liu et al, Health Technol Assess 2006).
A recent comprehensive review on efficacy end-points of drug-eluting stents (Pocock et al, J Am Coll Cardiol 2008) is also a worthwhile read. Specifically, these investigators purport that future clinical trials of drug-eluting stents could be designed and targeted toward angiographic surrogate end-points such as late lumen loss and percentage diameter restenosis.
Unfortunately, this seems just a return to the "gold" past of drug-eluting stents, when late loss was the international buzzword. In our opinion, the whole debate on thrombotic risk following drug-eluting stent implantation (eg Bavry et al, Am J Med 2006, and Nordmann et al, Eur Heart J 2006) has definitely demonstrated that only large randomized trials, enrolling thousands of patients, should be the basis of regulatory approval and routine clinical use of new-generation drug-eluting stents.