20-30% of patients taking oral anticoagulants also have ischaemic heart disease that requires treatment by percutaneous coronary intervention (PCI), thereby necessitating dual anti-platelet therapy to prevent stent thrombosis. However, the combination of dual anti-platelet therapy (DAP) and anti-coagulants is associated with a high annual risk of fatal and non-fatal bleeding episodes. This study hypothesised that in patients who must continue with oral anti-coagulants, clopidogrel alone would reduce the risk of bleeding – while not increasing the risk of thrombotic events – compared to clopidogrel and aspirin.

The What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) study was an open-label, randomised, controlled trial carried out at 15 sites in the Netherlands and Belgium between 2008 and 2011. Patients taking oral anti-coagulants and undergoing PCI were assigned to clopidogrel alone, or clopidogrel plus aspirin. The primary outcome measure was any bleeding episode within one year of PCI; analysis was by intention to treat.

Of the 573 patients enrolled in the study, one-year data were available for 279 (98.2%) of patients assigned double therapy (clopidogrel and oral anticoagulant) and for 284 (98.3%) of patients assigned triple therapy (aspirin, clopidogrel, and oral anticoagulant). In patients receiving double therapy, bleeding episodes were noted in only 54 (19.4%) of patients, compared to 126 (44.4%) in patients receiving triple therapy (hazard ration 0.36, p<0.0001). Multiple bleeding episodes were also more common in the triple therapy group (2.2% vs 12.0%), as were blood transfusions (3.9% vs. 9.5%).

Conclusions:

In patients taking oral anticoagulants who underwent PCI, the use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events.

• DeWilde WJM, Oirbans T, Verheugt FWA et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107-1115.

Although bleeding following percutaneous coronary intervention (PCI) has previously been linked with short- and long-term mortality, this association was derived from highly selected randomised controlled trials. This large study used the CathPCI registry to estimate the adjusted population attributable risk of bleeding-related mortality in patients undergoing PCI in the United States.

3 386 688 procedures in the CathPCI Registry performed between 2004 and 2011 were analyzed. The population attributable risk was calculated after adjustment for baseline demographic, clinical, and procedural variables. To calculate the number needed to harm (NNH) for bleeding-related mortality, a propensity-matched analysis was performed.  The main outcome measure was in-hospital mortality.

57 246 bleeding events (1.7%) and 22 165 in-hospital deaths (0.65%) occurred in 3 386 688 PCI procedures.  In the propensity-matched cohort (56 078 procedures with a major bleeding event), major bleeding was associated with increased in-hospital mortality (5.26% vs 1.87%; NNH = 29, P < .001). Although both access-site and non–access-site bleeding were associated with increased in-hospital mortality (2.73% vs 1.87%; NNH = 117, P < .001; and 8.25% vs 1.87%; NNH = 16, P < .001, respectively), the NNH was lower for nonaccess bleeding.  The association between major bleeding and in-hospital mortality was seen in all strata of preprocedural bleeding risk (low: 1.62% vs 0.17%, P < .001; intermediate: 3.27% vs 0.71%, P < .001; and high: 8.16% vs 3.45%, P < .001).

Conclusions:

In this large registry of patients undergoing PCI in the United States, postprocedural bleeding events were associated with an increased risk of in-hospital mortality.  Overall, an estimated 12.1% of deaths were related to bleeding complications.

• Chhatriwall AK, Amin AP, Kennedy KF et al.  Association between bleeding events and in-hospital mortality after percutaneous coronary intervention.  JAMA 2013;309:1022-1029

The anatomical SYNTAX score is advocated in both US and European guidelines to help establish the best revascularisation approach in patients with complex coronary artery disease.  The purpose of this study was to improve the SYNTAX score further by including prognostically important clinical variables, as opposed to the anatomical variables that are used for the current score.

The SYNTAX II score was developed by applying a Cox proportional hazards model to the results of the randomised all-comers SYNTAX trial.  In addition to the anatomical SYNTAX score, baseline features with strong associations to four-year mortality in either the CABG or PCI settings, or in both, were added.  Comparisons of 4-year mortality between CABG and PCI were then made for each patient.  External validation was done in the multinational all-comers DELTA registry (n=2891).

The eight predictors of the SYNTAX II score were: anatomical SYNTAX score, age, creatinine clearance, left ventricular ejection fraction (LVEF), presence of unprotected left main coronary artery (ULMCA) disease, peripheral vascular disease, female sex, and chronic obstructive pulmonary disease (COPD).  The SYNTAX II score significantly predicted a difference in 4-year mortality between patients undergoing CABG and those undergoing PCI; of note, the presence of diabetes was not important for decision making between CABG and PCI.  The concordance indices for internal (SYNTAX trial) and external (DELTA registry) validation were substantially higher than for the anatomical SYNTAX score alone.

Conclusions:

By combining clinical and anatomical predictors, the SYNTAX II score can provide accurate prediction of 4-year mortality from complex coronary artery disease, and guide decision making between CABG and PCI better than the original anatomical SYNTAX score.

• Farooq V, van Klaverern D, Steyerberg EW et al.  Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and vvalidation of SYNTAX score II.  Lancet 2013;381:639-50.

Platelet inhibition is central to the modern management of acute coronary syndromes, but up to one third of patients have a sub-optimal response to drug therapy. Bedside assays can determine the degree of platelet reactivity during treatment but it remains unclear whether the use of such testing to guide therapy leads to improved patient outcomes.

In this multicentre study of 2440 patients scheduled for coronary intervention (approx. 1/3 presenting with an acute coronary syndrome), participants were randomly assigned to platelet-function monitoring, with drug adjustment in patients with a poor response, or to a conventional strategy without monitoring or drug adjustment. For patients in the monitoring group, the VerifyNow P2Y12 and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2 to 4 weeks later. All patients received drug-eluting stents. The primary end point was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation.

In the monitoring group, high platelet reactivity in patients taking clopidogrel (34.5% of patients) or aspirin (7.6%) led to the administration of an additional bolus of clopidogrel, prasugrel, or aspirin along with glycoprotein IIb/IIIa inhibitors during the procedure as per protocol and adjustments to their chronic dosing to meet targets for platelet inhibition. Despite this, there was no benefit seen, with the primary end-point occurring in 34.6% of the patients in the monitoring group, as compared with 31.1% of those in the conventional-treatment group (HR, 1.13; 95% CI, 0.98 to 1.29; P=0.10) with this mainly driven by recurrent myocardial infarction. Results were consistent across sub-groups and the main secondary end point, stent thrombosis or any urgent revascularization, was also no different (4.9% vs. 4.6%; HR, 1.06; 95% CI, 0.74 to 1.52; P=0.77). The rate of major bleeding events did not differ significantly between groups.

Conclusions:

In the largest study of its kind to date, point of care platelet reactivity testing was not helpful, with no significant improvements in clinical outcomes with treatment adjustment according to testing, as compared with standard antiplatelet therapy without monitoring.

• Collet JP, Cuisset T, Rangé G, Cayla G, Elhadad S, Pouillot C, Henry P, Motreff P, Carrié D, Boueri Z, Belle L, Van Belle E, Rousseau H, Aubry P, Monségu J, Sabouret P, O’Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Barthélémy O, Beygui F, Silvain J, Vicaut E, Montalescot G; ARCTIC Investigators. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012 Nov 29;367(22):2100-9.

Two trials in the Journal of the American Medical Association (JAMA) address the impact of bone marrow-derived cell therapy on safety and surrogate endpoints in patients with ventricular dysfunction due to ischaemic heart disease.

In the Timing in Myocardial Infarction Evaluation (TIME) trial, autologous bone marrow mononuclear (BMC) cells were given as an intracoronary infusion at day 3 or day 7 post catheterisation for ST-elevation myocardial infarction. All patients had a left ventricular ejection fraction of <46%, and the primary end points were change in global left ventricular ejection fraction, and regional wall motion in infarct and border zones at 6 months as measured by cardiac MRI. At 6 months, there was no significant increase in left ventricular ejection fraction for the BMC group compared to the placebo group, nor were any significant regional wall differences noted in infarct or border zones. The timing of treatment also had no effect on global or regional ventricular recovery.

In the POSEIDON study, mesenchymal stem cells (MSCs) were delivered myocardially to patients with established ischaemic cardiomyopathy; the goal of the trial was to compare the safety and efficacy of donor (allogeneic) MSCs compared to self-derived (autologous) MSCs. Both allogeneic and autologous MSCs decreased infarct size, but neither increased ejection fraction overall. Only allogeneic MSCs reduced left ventricular end-diastolic volumes, while autologous MSCs were associated with an improved 6-minute walk test and Minnesota Questionnaire score. Both allogeneic and autologous cells were associated with low rates of treatment-emergent adverse effects.

Conclusions:

In these two trials examining the use of bone-marrow derived cells in patients suffering from ischaemic heart disease, the use of bone marrow derived mononuclear cells did not improve ventricular function after acute infarction, while mesenchymal stem cells led to some improvement in functional capacity and ventricular remodelling in established ischaemic cardiomyopathy.

• Marban E, Malliaras K et al. Mixed Results for Bone Marrow-Derived Cell Therapy for Ischemic Heart Disease. JAMA 2012;308:2405-2406.

• Traverse JH, Henry TD, Pepine CJ et al. Effect of the Use and Timing of Bone MarrowMononuclear Cell Delivery on Left VentricularFunction After Acute Myocardial Infarction. The TIME Randomized Trial. JAMA 2012;308:2380-2389.

• Hare JM, Fishman JE, Gerstenblith G et al. Comparison of Allogeneic vs Autologous Bone Marrow–Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients With Ischemic Cardiomyopathy. The POSEIDON Randomized Trial. JAMA 2012;308:2369-2379

Diabetes is one of the principle aetiological factors for coronary artery disease with vascular disease in diabetics displaying a particularly aggressive phenotype, often resulting in multivessel disease. Current evidence suggests that CABG is particularly beneficial in these patients as compared with PCI. however, much of this evidence was either gathered in the era before modern drug eluting stents or is from meta-analyses of smaller studies.

In order to update this evidence the large Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial randomized 1900 patients at 140 international centers with diabetes and multivessel coronary artery disease to undergo either PCI with drug-eluting stents or CABG. The patients’ mean age was 63.1±9.1 years, 29% were women, 83% had three-vessel disease, and approximately 30% were using insulin. Patients were followed for a minimum of 2 years (median 3.8 years) and the primary outcome measure was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke.

The results strongly favoured surgery with 5-year rates of the primary outcome of 26.6% in the PCI group and 18.7% in the CABG group (P=0.005). The benefit of CABG was driven by differences in rates of both myocardial infarction (P<0.001) and death from any cause (P=0.049) although the trial was not specifically powered to detect differences in the latter outcome. Stroke was more frequent in the CABG group with 5-year rates of 5.2% vs 2.4% in the PCI group (P=0.03), but the majority of these were peri-procedural and there was no significant difference maintained with time.

Conclusions:

For patients with diabetes and advanced coronary artery disease, in this large outcomes study CABG was superior to PCI, significantly reducing rates of myocardial infarction and all-cause mortality.

• Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, Yang M, Cohen DJ, Rosenberg Y, Solomon SD, Desai AS, Gersh BJ, Magnuson EA, Lansky A, Boineau R, Weinberger J, Ramanathan K, Sousa JE, Rankin J, Bhargava B, Buse J, Hueb W, Smith CR, Muratov V, Bansilal S, King S 3rd, Bertrand M, Fuster V; the FREEDOM Trial Investigators. Strategies for Multivessel Revascularization in Patients with Diabetes. N Engl J Med. 2012 Nov 4. [Epub ahead of print]

The reduction of low-density lipoprotein (LDL) cholesterol levels has been consistently shown to lead to cardiovascular benefits, but whilst in observational analyses higher levels of high-density lipoprotein (HDL) are associated with a lower risk of coronary events, it remains uncertain whether raising HDL therapeutically reduces cardiovascular risk. One strategy to increase HDL is through inhibition of cholesteryl ester transfer protein (CETP), which is involved in the transfer of cholesteryl ester from HDL to LDL. Despite early disappointment for CETP inhibition with the drug torcetrapib which, likely due to off target effects, had adverse cardiovascular outcomes, interest in this field remains high, and in this large, international, multicentre, phase III study, the drug dalcetrapib was trialled in patients presenting with a recent acute coronary syndrome.

15,871 patients presenting with STEMI, NSTEMI or unstable angina were randomly assigned to receive dalcetrapib 600 mg daily, or placebo, in addition to usual care, which included 98% of participants being prescribed a statin and 91% undergoing revascularisiation. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. As expected, dalcetrapib had a favourable effect on lipid profile raising mean HDL cholesterol by 31 to 40% while having minimal effect on LDL cholesterol or triglycerides. Despite this, after a median follow-up of 31 months the trial was terminated early due to futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (8.0% and 8.3%, respectively; HR, 1.04; 95% CI, 0.93 to 1.16; P=0.52), nor did it have any significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg/l higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both).

Conclusions:

In patients with a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events.

• Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012 Nov 29;367(22):2089-99.

Public reporting of outcomes is designed to motivate clinicians to improve performance, and allow patients to choose high quality hospitals. However, it has also been proposed that these measures prevent physicians from undertaking high-risk cases. The purpose of this study was to determine whether public reporting for percutaneous coronary intervention (PCI) is associated with lower rates of PCI for patients with acute myocardial infarction (MI), or with higher mortality rates in this population.

Data were obtained for fee-for-service Medicare patients who were admitted with acute MI in the US between 2002 and 2010. Logistic regression was used to compare PCI and mortality rates between reporting states and nonreporting states. The main mortality outcome measures were risk-adjusted PCI and mortality rates.

In 2010, patients with acute MI were less likely to receive PCI in public reporting states that in nonreporting states (P=0.003). The greatest differences were noted among 6078 patients with ST-segment elevation MI (P=.002), and the 2194 patients with cardiogenic shock or cardiac arrest (P=.03). However, no differences in mortality were noted. After implementation of public reporting in Massachusetts, the odds of undergoing PCI decreased compared to non-reporting states (P=.03).

Conclusions:

Although there was no overall difference in acute MI mortality between states with and without public reporting, the use of PCI for was lower in three states with public reporting of PCI outcomes.

• Joynt KE, Blumenthal DM, Orav EJ et al. Association of Public Reporting for Percutaneous Coronary Intervention With Utilization and Outcomes Among Medicare Benificiaries With Acute Myocardial Infarction. JAMA 2012;308:1460-1468.

Whilst the role of PCI in the treatment of acute coronary syndromes is rarely debated these days, its use in patients with stable angina remains less certain, particularly since the COURAGE trial which failed to demonstrate a prognostic benefit when compared to optimal medical therapy.  However, few patients in COURAGE had any functional assessment of their coronary stenoses, with the decision to intervene made on angiographic appearances alone.

In the FAME II study, pressure-wire derived fractional flow reserve (FFR) measurements were used to assess the functional significance of lesions with patients then randomised to PCI or optimal medical therapy if an FFR reached significance at ≤0.80.  Patients with an FFR >0.80 were enrolled in a registry and managed with medical therapy.   The primary end point was a composite of death, myocardial infarction, or urgent revascularization. Recruitment was halted prematurely by the safety committee after enrolment of 1220 (888 who underwent randomization and 332 enrolled in the registry) out of a projected 1632 patients.  Follow-up was also cut from a planned 2 years to a mean of 7 months, all due to a highly statistically significant difference between the two study arms.

FFR guided PCI reduced the event rate from 12.7% in the medical-therapy group to 4.3% in the PCI group (HR with PCI, 0.32; 95% CI, 0.19 to 0.53; P<0.001).  This difference was driven almost exclusively by an increase in the rate of urgent revascularization in the medical-therapy group (1.6% vs. 11.1%; HR, 0.13; 95% CI, 0.06 to 0.30; P<0.001) with their being no significant differences in the rates of MI or death from any cause (P=0.89 and P=0.31, respectively).  The medical therapy registry group had very low overall event rates and confirmed this as a generally low risk population.

Conclusions

In patients with stable coronary artery disease, FFR-guided PCI decreased the need for urgent revascularization but had no effect on rates of MI or death.  In patients without significant ischemia, outcomes were good with optimal medical therapy alone.

• De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, Jagic N, Mobius-Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engström T, Oldroyd KG, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Jüni P and Fearon WF.  Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012 Sep 13;367(11):991-1001.

Drug-eluting stents (DES) with biodegradable polymers can allow controlled drug release followed by subsequent degradation of the polymer, leaving a in essence a bare-metal stent.  In patients undergoing primary percutaneous coronary intervention (PCI) for acute ST-elevation myocardial infarction (STEMI), this may prevent the delayed vessel healing that is thought to be caused at least in part by the persistence of durable polymer components.

In this randomised, single-blinded, multi-centre study, 1161 patients presenting with STEMI were assigned in a 1:1 ratio either to receive a biolimus eluting (n=575), or a bare-metal stent (n=582).  The primary endpoint was the rate of major adverse cardiac events, which was a composite of cardiac death, target-vessel related infarction, and ischaemia driven target-lesion revascularisation at one year.

At one year 24 patients (4.3%) receiving a biolimus-eluting stent with a biodegradable polymer suffered a major adverse cardiac event, compared to 49 (8.7%) of patients receiving bare-metal stents (P=0.004); this was largely due to a reduction in target-lesion revascularisation.  There were no statistically significant differences in rates of cardiac death or stent thrombosis.

Conclusion:

The use of biolimus-eluting stents with a biodegradable polymer, when compared to bare-metal stents, led to a lower rate of major adverse cardiac events at one year in patients undergoing primary PCI for STEMI.

• Räber L, Kelbæk H, Ostoijc M et al.  Effect of Biolimus-Eluting Stents With Biodegradable Polymer vs Bare-Metal Stents on Cardiovascular Events Among Patients With Acute Myocardial Infarction.  The COMFORTABLE AMI Randomized Trial.  JAMA 2012; 308(8):777-787.