The need for dual antiplatelet therapy following percutaneous coronary intervention (PCI) also imposes a significant bleeding risk. Chronic kidney disease (CKD) is associated with poorer outcomes following PCI, and in addition a detrimental effect on platelet function is well described. In this study the authors investigated the outcomes of patients with chronic renal impairment (defined here as a creatinine clearance [CrCl] <60ml/min) following PCI.

In a retrospective study of single centre registry data the authors identified a total of 166 patients who had undergone PCI and had an indication for oral anticoagulation; of these, 68 also had chronic renal impairment (CrCl<60mL/min). Patients were contacted by telephone to ascertain details about complications and hospital records were also reviewed. Chronic kidney disease was associated with a higher risk for major bleeding (hazard ratio, 3.44; p=0.004) and all-cause mortality (hazard ratio, 3.50; p=0.003). Noticeably, triple antithrombotic therapy (aspirin, clopidogrel, and warfarin) was associated with a significantly increased risk for a major bleeding complication (hazard ratio, 3.29; p=0.043), regardless of renal function.

While this small study suffers from the problems associated with all retrospective studies it is a useful reminder of the hazards associated with extended periods of antiplatelet and anticoagulant therapy in patients with multiple co-morbidities. In addition, it reminds us that using warfarin with dual anti-platelet therapy more than triples the risk of major bleeding.

• Sergio Manzano-Fernández, Francisco Marín, Francisco J. Pastor-Pérez et al. Impact of Chronic Kidney Disease on Major Bleeding Complications and Mortality in Patients With Indication for Oral Anticoagulation Undergoing Coronary Stenting. Chest 2009;135:983-990

As percutaneous coronary intervention (PCI) continues to evolve, its ability to treat complex coronary artery disease (CAD) continues to improve. The SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) trial was designed to assess whether modern percutaneous techniques have assumed parity with coronary artery bypass surgery (CABG) for the treatment of complex (3 vessel or left main coronary disease) CAD.

This noninferiority, prospective, clinical trial enrolled 1800 patients over a two year period (March 2005-April 2007) from 85 sites in Europe and the United States. A ‘heart team’ consisting of an interventional cardiologist and a cardiac surgeon reviewed each subject’s data including coronary angiography after which a decision was reached on which procedure should be offered to a patient. Patients were treated with the aim of achieving complete revascularization of all vessels at least 1.5mm in diameter with stenosis of ≥50% as identified by the ‘heart team’. In patients who underwent PCI, antiplatelet medication was prescribed on the basis of directions of use for the TAXUS Express stent and local clinical practice. In most centres thienopyridines were continued after 6 months with 71.1% of patients receiving them at 1 year; aspirin was prescribed indefinitely for all patients. The primary clinical endpoint was a composite of major adverse cardiac and cerebrovascular events (MACCE): death from any cause, stroke, myocardial infarction or repeat revascularization throughout the 12 month period after randomization. The 12 month rates of MACCE were analyzed on the basis of the SYNTAX score.

Rates of MACCE at 12 months were significantly higher in the PCI group (17.8% vs 12.4% for CABG p = 0.002), predominantly driven by an increased rate of repeat revascularization with PCI (13.5% vs 5.9%, p < 0.001) and as a result the criterion for noninferiority was not met; but at 12 months the rates of the ‘hard’ endpoints - death and myocardial infarction - were similar between the two groups. Furthermore, stroke was significantly higher with CABG (2.2% vs 0.6% p = 0.003), although an imbalance in the subsequent medical management following the procedure meant that patients in the CABG arm had a lower rate of optimal medical therapy and this may have contributed to their higher risk of stroke.

There has been concern recently about the risk of late stent thrombosis with DES. In the SYNTAX trial the majority of cases of stent thrombosis occurred within 30 days of the procedure and the 12-month rate of stent thrombosis was similar to that of symptomatic graft occlusion in the CABG arm. However it should be noted that stent thrombosis usually has more severe consequences for patients (rate of death 30%, rate of MI >60%) than graft occlusion which usually manifests as angina leading to revascularization.

Some shortcomings need to be noted. The majority (78%) of the patients in the study were men and it is therefore unknown whether the findings are also applicable to women. The definition of MI used in the trial was based on a surgical definition (new Q waves on ECG in association with an increase in CKMB >5X the upper limit of the normal range) and may have resulted in less severe cases of MI being underreported.

For now patients with left main or 3 vessel disease should have their data reviewed by both a cardiologist and a cardiac surgeon to determine the likelihood of safe and effective revascularization by either method. If revascularization is feasible by both modalities then the SYNTAX score may help to identify the treatment with the optimal outcome. Irrespective of modality of revascularization, the importance of optimal medical therapy including antiplatelets, statins and ACE inhibitors must not be forgotten. Further trials, including the NHLBI sponsored FREEDOM trial and the UK based CARDia trial (comparing PCI and CABG in patients with diabetes), will add to the evidence base.

• Serruys PW, Morice MC, Kappetein P et al. Percutaneous Coronary Intervention versus Coronary Artery Bypass Grafting for Severe Coronary Artery Disease. N Engl J Med 2009; 360:961-72
• Lange RA and Hillis LD (ed). Coronary Revascularization in Context. N Engl J Med 2009;360:1024-5

A third of patients hospitalized with an acute myocardial infarction (MI) have persistent occlusion of the infarct related artery at 72 hours, despite the availability of several effective reperfusion strategies. This has led to interest as to whether some of the benefits seen with early opening of the artery could be achieved with later opening, the so called ‘Open Artery Hypothesis’. It is thought that late opening of occluded infarct related arteries after acute MI may improve survival (through lower risks of heart failure and sudden death from cardiac causes), ventricular function (revascularization of hibernating myocardium and improved remodeling) and quality of life. In order to assess this hypothesis, the Occluded Artery Trial (OAT) compared PCI with medical therapy alone in 2166 patients who had an occluded infarct related artery 3-28 days after a MI, finding no evidence of benefit from late arterial opening. This paper reports the quality of life and economic outcomes associated with the use of such a strategy.

951 patients (44% of those eligible) underwent quality of life assessment using a panel of tests including 2 principal outcome measures, the Duke Activity Status Index (DASI) for cardiac physical function (higher scores indicating better function) and the Medical Outcomes Study 36 item Short Form Health Inventory 5 which measures psychological well-being. Structured interviews were performed at baseline, 4, 12 and 24 months. Costs of treatments were assessed for 458/469 patients in the United States (98%) and 2 year cost effectiveness estimated.

At 4 months the medical therapy group, when compared to the PCI group, had a clinically marginal decrease of 3.4 points in the DASI score (p=0.007). At 1 and 2 years the differences were smaller. No significant differences in psychological well-being were observed. For the 469 patients in the United States, cumulative 2 year costs were approximately $7000 higher in the PCI group (p<0.001) and the quality adjusted survival was marginally longer in the medical therapy group. When combined with previously reported lack of advantage of PCI with respect to the primary end point of the OAT trial, these data do not support the practice of routine PCI in patients with stable condition and an occluded infarct related artery after myocardial infarction. The analysis of lifetime cost effectiveness in the COURAGE trial had similar results with an estimated cost / additional QALY with PCI OF $168,000. However it should be remembered that there was a significant cross-over from the medical therapy arm subsequently requiring intervention.

• Mark DB, Pan W, Clapp-Channing NE et al. Quality of Life after Late Invasive Therapy for Occluded Arteries. N Engl J Med 2009;360:774-83

Prasugrel is novel third-generation thienopyridine which is a more potent blocker of the platelet P2Y₁₂ receptor than clopidogrel. The TRITON-TIMI 38 (Trial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibition with prasugrel – Thrombolysis in Myocardial Infarction 38) study compared clopidogrel with prasugrel in the setting of ST elevation myocardial infarction (STEMI).

3534 patients with STEMI were randomly assigned to either prasugrel (60mg loading, 10mg maintenance [n=1769]) or clopidogrel (300mg loading, 75mg maintenance [n=1765]) in a double-blind fashion. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

At 30 days, 6.5% of the patients given prasugrel had reached the primary endpoint compared with 9.5% given clopidogrel (p=0.0017) - this effect continued at 15 months (10.0% vs 12.4%, p=0.0221). The secondary endpoint of cardiovascular death, myocardial infarction, stent thrombosis, or urgent target vessel revascularisation was also significantly reduced at 30 days in patients who received prasugrel (hazard ratio 0.75, p=0.0205) – again this advantage continued up to 15 months (hazard ratio 0.79; p=0.0250). Major bleeding rates in patients who did not undergo bypass surgery did not differ between the two treatment groups at 30 days (p=0.3359) and 15 months (p=0.6451), however bleeding after surgery was greater in the prasugrel group (p=0.0033). Minor bleeding rates showed no differences between groups.

A limitation of the trial is that 600mg of clopidogrel was not used as a loading dose (as is used in many centres), and only 27% of patients were preloaded. This is important as the 30-day reduction in major cardiovascular events seen in the prasugrel arm is similar to that seen when clopidogrel was adequately preloaded in other trials (e.g. PCI-CURE). Nonetheless, for showing that more powerful platelet inhibition is capable of improving outcomes in STEMI, without necessarily increasing bleeding rates, TRITON-TIMI 38 is an important study.

• Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-segment elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomized controlled trial. Lancet 2009; 373:723-31.
• Stone GW. Ischemia versus bleeding: The art of clinical decision-making. Lancet 2009; 373:695-696.

Fractional flow reserve (FFR), calculated using a coronary presure wire, is an index of the physiological significance of a coronary stenosis and is defined as the ratio of maximal blood flow in a stenotic artery to normal maximal flow.  FFR in a normal artery is 1.0 - a value <0.80 identifies ischaemia causing lesions with a diagnostic accuracy of 90%, is more specific than that from myocardial perfusion studies and has a better spatial resolution. In patients with multivessel disease (MVD), identifying a percutaneous coronary intervention (PCI) approach allowing targeted use of stents whilst achieving relief of myocardial ischaemia could both improve clinical outcomes and decrease health costs.

The FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) Trial involved 1005 patients from 20 centres in the United States and Europe. This randomised trial compared treatment with FFR in addition to angiography with treatment guided by angiography alone for patients with MVD for which PCI was deemed appropriate. FFR cannot be performed in a totally occluded artery and a default FFR value of 0.5 was recorded for such vessels. The primary end-point was the rate of major adverse cardiac events (MACE) at 1 year. These were a composite of death, non-fatal MI and any repeat revascularisation. Secondary end-points included functional class at 1 year and the number of anti-anginal medications at 1 year. Quantitative coronary angiography was performed offline and the SYNTAX score was used to assess the extent and severity of coronary disease.  The mean (+/- SD) number of indicated lesions/patient was 2.7 (+/-0.9) in the angiography group and 2.8 (+/-1.0) in the FFR group (p = 0.34). The number of stents used/patient was 2.7 (+/-1.2) and 1.9 (+/- 1.3) respectively (p<0.001). The 1 year event rate was 18.3% in the angiography arm and 13.2% in the FFR group (p=0.02). 78% of patients were free of angina at 1 year in the angiography arm compared to 81% in those treated with FFR (p=0.20).

Whilst this study was well designed there are several limitations.   Little information is given on peri-procedural pharmacotherapy including pre-treatment with thienopyridines, use of antithrombin and glycoprotein IIb IIIa inhibitors. Peri-procedural MI was based on an elevation of CK-MB > 3 times and development of Q waves on the ECG but did not include troponin measurement which is surprising for a trial which enrolled from January 2006-September 2007. The rate for peri-procedural MI in the conventional treatment arm would appear to be quite high and in the order of 7.5%.  Nonetheless, the reduction in clinical events seen is significant and impressive, and if the results can be reproduced in trials in less-experienced centers, then a change in practice may well result.

·      Tonino PAL, De Bruyne B, Pijls NHJ et al. Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention. N Engl J Med 2009;360: 213-24

·      Ellis SG (ed) Redefining the Art and Science of Coronary Stenting. N Engl J Med 2009;360: 292-4

Current ACC/AHA guidelines recommend that in patients with stable angina, noninvasive testing is used to prove mild or moderate ischaemia prior to performing PCI.

Lin et al. performed a retrospective analysis of 23,887 patients who had undergone elective PCI, of whom 44.5% (10,629) underwent stress testing within 90 days prior to PCI.  A wide regional variation (22.1% to 70.6% was seen, and four factors in particular were linked to a decreased likelihood of stress testing: female sex (adjusted odds ratio [AOR], 0.91), age 85 years or over (AOR, 0.83), a history of congestive hear failure (AOR, 0.85), and a history of prior PCI (AOR, 0.45).  Patients with chest pain (AOR, 1.28) and of black race (AOR, 1.26) were more likely to have stress tests prior to PCI.  Lastly, patients treated by physicians performing >150 PCI procedures a year were less likely to receive stress testing.

Inappropriate procedures not only pose a risk to patients, but generate unnecessary costs and waste time.  Furthermore, current Medicare proposals suggest rewarding only those physicians and hospitals that adhere to guidelines.  This paper suggest that many patients are not being adequately investigated prior to PCI.

• Lin GA, Dudley RA, Lucas Fl et al.  Frequency of Stress Testing to Document Ischemia Prior to Elective Percutaneous Coronary Intervention.  JAMA 2008;300(15):1765-1773

Currently both bare metal stents (BMS) and drug-eluting stents (DES) are used during percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).  PCI has been demonstrated to reduce the rate of death or recurrent ischaemia when compared to medical therapy.  To date trials comparing DES and BMS in acute MI have been limited by small size and follow up of 1 year or less; DES were shown to reduce the number of revascularisation procedures for restenosis but no significant differences were identified between DES and BMS at 1 year either in rate of death or subsequent myocardial infarction.

This study was based on an unselected population based cohort of 7217 patients undergoing PCI with stenting for AMI over an 18 month period in Massachusetts between 2003 and 2004.  Propensity score matching was performed on 3 groups of patients:
•    All patients with AMI
•    All patients with AMI with ST elevation (STEMI)
•    All patients with AMI without ST elevation (NSTEMI)
Patients receiving both DES and BMS were excluded form the analysis. The primary outcome was death from any cause within 2 years after the index procedure. Secondary outcomes included recurrent MI and repeat revascularisation.

4016 patients received DES and 3201 received BMS. The 2 year risk adjusted mortality rates were significantly lower for DES than for BMS in all patients with MI (10.7% vs 12.8%, p=0.02). Among patients with STEMI 8.5% vs11.6%, p=0.008) and among patients with NSTEMI (12.8% vs 15.6%, p=0.04). The 2 year risk adjusted rates of recurrent MI were reduced in patients with NSTEMI who were treated with DES and repeat revascularisation rates were significantly reduced with the use of DES compared to BMS for all groups.

The study has a number of limitations:
•    No difference in the rates of clinical sequelae of stent thrombosis were observed but rates of stent thrombosis could not be directly calculated from this data set.
•    The study was observational and despite the propensity score matching utilised, residual confounding cannot be excluded.
•    Data on infarct size, which has been shown to be an important predictor of death in patients with AMI, was not available, nor were the quantitative angiographic findings. This is a potential limitation since DES were not available in the same range of vessel diameters as BMS and small vessel stenting is known to be associated with higher risks both at the time of the index procedure and during follow-up.

Conclusion? It appears safe, and may be more effective to use DES rather than BMS in AMI. Following NICE criteria on size and length may be the best way forwards.

• Mauri L, Silbaugh TS, Garg P etal. Drug Eluting or Bare Metal Stents for Acute Myocardial Infarction. N Engl J Med 2008;359:1330-42

Recently an excess of acute adverse coronary events has been reported among diabetic patients treated with drug eluting coronary stents (DES) who received short-term (<6 months) dual antiplatelet therapy (Circulation 2007;115:1440-55).

Stettler and colleagues extended a previous meta-analysis to 35 trials involving 14,799 patients (3,852 with and 10,947 without diabetes) involving at least 6 months of aspirin and clopidogrel therapy.  Hazard ratios for overall mortality were near one for all comparisons in people with diabetes: sirolimus eluting stents compared with bare metal stents 0.88 (95% credibility interval 0.55 to 1.30), paclitaxel eluting stents compared with bare metal stents 0.91 (0.60 to 1.38), and sirolimus eluting stents compared with paclitaxel eluting stents 0.95 (0.63 to 1.43).  These findings suggest that earlier concerns over increased mortality associated with DES use may in part be due to inadequate duration of antiplatelet therapy.

Among patients with diabetes, DES appears to be as safe and effective as using bare metal stents (BMS), provided patients receive an adequate duration of dual antiplatelet pharmacotherapy.  Therefore, in patients in whom drug compliance might be a problem, an alternative strategy involving BMS or bypass surgery should be considered.

• Stettler C, Allemann S, Wandel S, et al. Drug eluting and bare metal stents in people with and without diabetes: collaborative network meta-analysis.  BMJ 2008;337:a1331.