Varenicline (Champix) is a partial agonist to nicotine receptors, and is approved for smoking cessation therapy. However, the FDA has raised concern about a possible increase in the incidence of cardiovascular events of patients taking the drug in randomised trials. In this meta-analysis, Prochaska et al. looked at 22 randomised controlled trials of current tobacco users and compared cardiovascular events in those given varenicline compared to those given placebo. Cardiovascular adverse events were defined if they occurred during drug treatment or within 30 days of discontinuation. All the trials included in the analysis were double blind and placebo controlled, and two included participants with active cardiovascular disease, while eleven enrolled patients with a history of cardiovascular disease. Rates of cardiovascular serious adverse events were 0.63% in the varenicline groups and 0.47% in the placebo groups. The summary estimate for the risk difference (0.27%, P=0.15) was not significant either clinically or statistically.

Conclusions:

In this meta-analysis, the use of verenicline was not associated with any significant increase in serious adverse cardiovascular events.

• Prochaska JJ, Hilton JF. Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis. BMJ 2012;344:e2856 doi: 10.1136/bmj.e2856

Autologous stem/progenitor cells have been investigated for several years as a novel therapy for patients with advanced ischaemic heart disease, particularly those with ongoing angina or heart failure.  In particular, for patients with ischaemic cardiomyopathy, autologous bone marrow mononuclear cells (BMCs) have been shown to be safe and possibly effective.  However, none of the trials performed to date have been sufficiently powered to investigate clinical outcome measures.

The FOCUS-CCTRN trial (First Mononuclear Cells injected in the United States conducted by the  Cardiovascular Cell Therapy Research Network) was a phase II randomised double-blind, placebo-controlled trial.  All patients were symptomatic with either NYHA class II-III heart failure or CCS class III-IV angina and a left ventricular ejection fraction of 45% or less, a perfusion defect detected by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization but receiving maximal medical therapy.  The study took place at five large US research sites between 2009 and 2011.  Patients were randomised to receive either 100 million isolated BMCs injected transendocardially, or placebo.  The main outcome measures, assessed at six months, were: change in left ventricular end systolic volume (as assessed by ECHO), maximal oxygen consumption, and reversibility on SPECT.  Phenotypic and functional analyses of the cell product were performed by a biorepository core laboratory.

92 patients were randomised, 61 to BMCs and 31 to placebo.  However, there were no statistically significant changes seen in left ventricular end-systolic volume (p=.73), maximal oxygen consumption (p=.17), nor perfusion defects (p=.84).  Several secondary outcome measures, including regional wall motion, the percent myocardial defect, and clinical improvement, also showed no improvement.

Conclusions:

In this study of patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs -compared with placebo – did not improve left ventricular function, maximal oxygen consumption, or reversibility of myocardial ischaemia.

• Perin C, Willerson JT, Pepine CJ et al.  Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function,and Perfusion in Chronic Heart Failure.  The FOCUS-CCTRN Trial.  JAMA 2012;307:1717-1726.

The number of electronic cardiac devices, including pacemakers and cardioverter-defibrillators, being implanted each year is increasing.  As a result, there has been a 210% increase in the incidence of device infection between 1993 and 2008 in the United States.  Cardiac device infective endocarditis (CDIE) is significant in that it is associated with a higher mortality rate than device infection without endocarditis.

Athan et al. examined prospective data from the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS), collected from 61 centers in 28 countries over a six year period.  All patients were hospitalised adults with definite endocarditis as defined by the modified Duke endocarditis criteria.  The authors examined in-hospital and 1-year mortality.

CDIE was diagnosed in 6.4% of patients with definite infective endocarditis.  CDIE generally occurred in older patients (median age, 71.2 years), was caused by staphylococci (66.6% of patients), and was associated with contact with health care services (45.8%).  37.3% of patients also had co-existing valve involvement (especially the tricuspid valve).  In-hospital and one-year mortality rates were 14.7% and 23.2%, respectively.  Removal of the device was associated with an increased chance of survival at one year (hazard ratio 0.42 when compared to patients who did not undergo device removal).

Conclusion:

Patients with cardiac device infective endocarditis have high rates of mortality and concomitant valve infection.  Early device removal is indicated to improve survival at one year.

• Athan E, Chu VH, Tattevin P et al.  Clinical Characteristics and Outcome of Infective Endocarditis Involving Implantable Cardiac Devices.  JAMA 2012;307:1727-1735.

Clopidogrel is an inactive prodrug that requires hepatic bioactivation via several cytochrome P450 enzymes, including CYP2C19. A number of different alleles of CYP2C19 have been identified; depending on the allele present the enzymatic activity of CYP2C19 can be normal, or reduced.

The *1 allele is the normal copy that has full enzymatic activity. The *2 and *3 alleles are the most common variants and result in complete loss of enzymatic activity. Consequently, carriers of the *2 and *3 alleles have reduced formation of clopidogrel’s active metabolite and demonstrate reduced clopidogrel-induced platelet inhibition.

In the Lancet, Roberts et al. publish the first evidence of successful validation and clinical application of a point-of-care genetic test in medicine. They use a rapid, bedside test to identify carriers of the CYP2C19*2 allele and assessed a pharmacogenetic approach to dual antiplatelet treatment after PCI.

The RAPID GENE study randomised patients undergoing PCI to either standard therapy or rapid point-of-care genotyping to identify carriers of the CYP2C19*2 and treat them with prasugrel (10mg) instead of clopidogrel (75mg) post-PCI.

The primary endpoint was the proportion of CYP2C19*2 carriers with high on-treatment platelet reactivity (P2Y12 reactivity unit [PRU] value of more than 234) after 1 week of dual antiplatelet treatment, which is a surrogate marker that has consistently tracked closely with adverse cardiovascular events following PCI.

With regards to the gene testing, the point-of-care test had a sensitivity of 100% (95% CI 92·3–100) and a specificity of 99·3% (96·3–100). Clinically, 187 patients completed follow-up (91 genotyping group, 96 standard treatment) and there were 23 individuals in each group carried at least one CYP2C19*2 allele. None of the 23 carriers in the rapid genotyping group had a high PRU value at day 7, compared with seven given standard treatment (p=0·0092).

Conclusion:

This proof-of-concept study shows that a rapid pharmacogenetic approach is feasible to guide antiplatelet therapy in the setting for PCI. However, large randomised trials using clinical end-points are required to fully assess the success of this strategy.

Reference:

• Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, Dick A, Marquis JF, O’Brien E, Goncalves S, Druce I, Stewart A, Gollob MH, So DY.  Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial.  Lancet. 2012 Mar 29. doi:10.1016/S0140-6736(12)60161-5.

In recent years an increasing emphasis has been placed on the need for improved primary prevention of cardiovascular disease.  To this end, using evidence from clinical trials and epidemiological studies, the American Heart Association (AHA) has suggested seven ideal cardiovascular health behaviours (metrics), including: not smoking; being physically active; having normal blood pressure, blood glucose and total cholesterol levels, and weight; and eating a healthy diet.  However, no previous study has investigated the relationship between the prevalence of these lifestyle factors and cardiovascular mortality on a national scale.

Therefore this paper used the National Health and Nutrition Examination Survey (NHANES) in the USA to examine the time trends of these 7 cardiovascular health behaviours among 44 959 persons 20 years or older and to estimate their relationship to the risk of all-cause and cardiovascular (CVD) mortality.  The main outcome measures included all-cause, cardiovascular, and ischemic heart disease (IHD) mortality.

The authors found that few study participants met all 7 cardiovascular health metrics (2.0% in 1988-1994, 1.2% in 2005-2010). Overall 2673 all-cause, 1085 cardiovascular, and 576 IHD deaths occurred over a median follow-up period of 14.5 years. Among participants who achieved 1 or fewer cardiovascular health behaviours, age- and sex-standardized absolute risks were 14.8 deaths per 1000 person-years for all-cause mortality, 6.5 for cardiovascular mortality, and 3.7 for IHD mortality. Among those who met 6 or more metrics, corresponding risks were 5.4 for all-cause mortality, 1.5  for CVD mortality, and 1.1 for IHD mortality. When comparing participants who met 6 or more vs 1 or fewer cardiovascular health metrics, adjusted hazard ratios were 0.49 (95% CI, 0.33-0.74) for all-cause mortality, 0.24 (95% CI, 0.13-0.47) for CVD mortality, and 0.30 (95% CI, 0.13-0.68) for IHD mortality.

Conclusions:

This study found that few people displayed optimal cardiovascular lifestyle behaviour, but that doing so was associated with a significantly lower risk of  overall and cardiovascular mortality.

• Yang Q, Cogswell ME, Flanders D et al.  Trends in Cardiovascular Health Metrics and Associations With All-Cause and CVD Mortality Among US Adults.  JAMA 2012; 307(12): 1273-1283.

While the last 5 years have seen an incredible expansion in the use of transcatheter aortic-vlave replacement (TAVR) for patients with severe aortic stenosis who are not considered suitable for surgery, long-term outcomes data remain scant.  The randomised Placement of Aortic Transcatheter Valves (PARTNER) trial found that, as compared with standard therapy, TAVR reduced symptoms and decreased death at one year.  Two year follow-up data from the trial have now been published.

 Of the 358 patients who underwent randomisation at 21 centres, 43.3% had died at two years, compared to 68.0% in the standard therapy group (p<0.001).  The rates of cardiac death were similarly higher in the standard therapy group (31.0% vs 62.4%; p<0.001).  Rates of hospitalisation were also higher in the standard therapy group (72.5%) compared to the TAVR group (35.0%; P<0.001).  However, the rate of stroke was noted to be higher in the TAVR group, due to more ischaemic events in the first 30 days following the procedure, and thereafter due to the occurrence of more haemorrhagic strokes.

Conclusions:

Patients with severe aortic stenosis who are not felt suitable for surgery may benefit from TAVR, which was seen to reduce mortality and hospital admissions.  However the mortality benefit may be limited to patients who do not have extensive co-existing conditions, and an increased risk of stroke is seen.

• Makkar RR, Fontana GP, Jilaihawi H et al.  Transcatheter Aortic-Valve Replacement for Inoperable Aortic Stenosis.  NEJM 2011, published ahead of print.  DOI: 10.1056/NEJMoa1202277

Known vascular risk factors can explain only about half of all cardiovascular disease, leaving much to be discovered about other causes of stroke and heart attack. Persistent inflammation has been implicated in the pathogenesis of coronary heart disease, but causality has not been established for any specific inflammatory mediator.

In The Lancet, two genetics consortia focus on the interleukin-6 pathway upstream of C-reactive protein. In classic IL6R signalling, soluble interleukin-6 activates the membrane-bound receptor in hepatocytes and leucocytes, thereby initiating downstream pro-inflammatory cascades that increase hepatic production of C-reactive protein, fibrinogen, and other acute-phase reactants.  Both groups looked at a common variant in the gene that encodes the receptor for IL6, the Asp358Ala variant, which is believed to impair IL6R signalling and dampen inflammation.

The IL6R Genetics Consortium and Emerging Risk Factors Collaboration studied Asp358Ala in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in a collaborative meta-analysis of 82 studies involving 125,122 participants, and found no association of Asp358Ala with conventional risk factors.  They also compared its frequency in 51,441 patients with coronary artery disease and in 136,266 controls and found, for every copy of Asp358Ala inherited, the mean concentration of IL6R increased by 34.3% and interleukin-6 by 14.6%, and mean concentration of CRP was reduced by 7.5% and fibrinogen by 1%. Importantly, for every copy of Asp358Ala inherited, risk of CHD was reduced by 3.4%.

The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium pooled data from 40 studies including up to 133,449 individuals, and found Asp358Ala was associated with increased circulating log interleukin-6 concentration (increase per allele 9.45%) as well as reduced C-reactive protein (decrease per allele 8.35%,) and fibrinogen concentrations (decrease per allele 0.85%). In 25,458 coronary heart disease cases and 100,740 controls, the IL6R variant was associated with decreased odds of coronary heart disease events (per allele odds ratio 0.95).

The monoclonal antibody tocilizumab (licensed for treatment of rheumatoid arthritis) reduces systemic and articular inflammation through Blockade of IL6R. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium went on to show a similar pattern of effects to the Asp358Ala variant with IL6R blockade from infusions of tocilizumab (4–8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials.

Conclusions:

These results from two large genetics consortia provide the first real evidence that the interleukin-6 receptor protein has a causal role in the development of coronary heart disease. The findings are important because they indicate that targeting IL6R blockade could provide a novel therapeutic approach for the prevention of coronary heart disease that warrants testing in randomised trials.

References:

1. IL6R Genetics Consortium and Emerging Risk Factors Collaboration IL-6 pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.
   Lancet 2012; DOI:10.1016/s0140-6736(11)61931-4.
2. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6RMR) Consortium. The IL-6 receptor as a target for prevention of CHD: A Mendelian randomization analysis.
   Lancet 2012; DOI:10.1016/s0140-6736(12)60110-X.

Whist epinephrine (adrenaline) is commonly used during cardiopulmonary resuscitation (CPR), both in and out of hospital, its effectiveness is poorly established.  Although some animal studies have suggested a short term benefit due to increased cerebral and coronary perfusion, an increase in myocardial oxygen consumption and ventricular arrhythmias has also been documented.  The purpose of this analysis was to determine how the use of epinephrine in CPR performed before hospital arrival (out-of-hospital arrest) was associated with immediate and 1-month survival.

The study was a prospective, nonrandomised, observational propensity analysis of data from 417,188 out-of-hospital cardiac arrests in Japan between 2005 and 2008.  The main outcome measures were the return of spontaneous circulation before hospital arrival, survival at one month after cardiac arrest, survival with good or moderate cerebral performance, and survival with no, mild, or only moderate neurological disability.  Outcomes were compared between those who were and were not administered epinephrine

Return of spontaneous circulation before hospital arrival was observed in 2,786 of 15,030 patients (18.5%) in the epinephrine group and 23,042 of 402,158 patients (5.7%) in the no-epinephrine group (P < .001); the difference remained significant in propensity-matched patients: 2446 (18.3%) vs. 1400 (10.5%) of 13,401 (P < .001).  However, both among all patients and propensity-matched patients, negative associations were observed between prehospital epinephrine and long-term outcome measures (adjusted ORs: 1-month survival, 0.46 [95% CI, 0.42-0.51]; CPC 1-2, 0.31 [95% CI, 0.26-0.36]; and OPC 1-2, 0.32 [95% CI, 0.27-0.38]; allP < .001).

Conclusions:

Prehospital epinephrine administration following cardiac arrest was associated with an increased likelihood of the return of spontaneous circulation, but also with significantly poorer outcomes at one month.  This study therefore highlights the need for further research into how epinephrine is best used in the out-of-hospital arrest setting.

• Hagihara A, Hasegawa M, Abe T, et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012; 307:1161-1168.
• Callaway CW. Questioning the use of epinephrine to treat cardiac arrest. JAMA 2012; 307:1198-1200.

Approximately 40% of strokes are classified as cryptogenic or as having no identifiable cause.  Some of these cryptogenic strokes may be due to an embolus from the venous circulation crossing into the systemic circulation through a patent foramen ovale (PFO).  While PFOs are certainly common in the general population – with a prevalence of around 25% – they do appear to be more common in patients with cryptogenic stroke, with some series reporting the prevalence to be as high as 56%.  Closure with a percutaneous device is often recommended, but it is not known whether this intervention reduces the risk of recurrent stroke as compared with standard medical therapy alone.

In the multicentre, randomized, open-label, CLOSURE I study, these two strategies were compared in 909 patients between 18 and 60 years of age who presented with a cryptogenic stroke or transient ischemic attack (TIA) and had evidence of a PFO. The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years. Using a STARflex closure device, the rate of effective closure were 86%.  However,the results demonstrated no benefit for intervention with a cumulative incidence of the primary end point of 5.5% in the closure group as compared with 6.8% with medical-therapy (HR, 0.78; 95% CI, 0.45 to 1.35; P=0.37). The respective rates for stroke were 2.9% and 3.1% (P=0.79) and 3.1% and 4.1% for TIA (P=0.44).  Periprocedural major vascular complications occurred in 3.2% of patients in the closure group  and within 6 months left atrial thrombus was found in 1.1% of patients, 50% of whom went on to have a second stroke.

Conclusions

In this well-conducted and adequately powered study, patients with cryptogenic stroke or TIA who had a PFO accrued no extra benefit from device closure than with medical therapy alone for the prevention of recurrent stroke or TIA.

• Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, Felberg R, Herrmann H, Kar S, Landzberg M, Raizner A and Wechsler L. Closure or medical therapy for cryptogenic stroke with patent foramen ovale.  N Engl J Med. 2012 Mar 15;366(11):991-9.

The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is one of the most widely used cardiac risk models for predicting mortality after cardiac surgery and forms the basis of many pre-operative discussions surrounding risk/benefit ratios and gaining informed consent for a procedure.  First published in 1999 and derived from an international European database, the system has been highly successful, but with time and improvements in cardiothoracic techniques and mortality, it is now clear that model overpredicts risk and is no longer appropriately calibrated. In the EuroSCORE II project the aim was to update this system and make it more relevant to contemporary practice.

Using an online data collection system, prospective risk and outcome data on 22 381 patients undergoing major cardiac surgery in 154 hospitals in 43 countries was gathered.  Care was taken to recruit data from a wide variety of hospitals and not just centres of excellence to avoid ascertainment bias.  Information was obtained on a variety of patient elements beyond the traditional existing EuroSCORE risk factors with the primary outcome being mortality at the base hospital and secondary outcomes being mortality at 30 and 90 days.  Compared with the original EuroSCORE database (in brackets), the mean age was greater 64.7 (62.5) with 31% females (28%). Also, more patients were New York Heart Association class IV, had extracardiac arteriopathy and renal and pulmonary dysfunction.  Overall mortality was 3.9% (4.6%). When applied to the current data, the old risk models overpredicted mortality (actual: 3.9%; additive predicted: 5.8%; logistic predicted: 7.57%). Using logistic regression modelling to identify the most pertinent and predictive risk factors the new EuroSCORE II (http://euroscore.org/calc.html) was constructed and in  subsequent testing in a validation cohort of 5553 patients performed well (actual mortality: 4.18%; predicted: 3.95%) with well-maintained discrimination and an area under the receiver operating characteristic curve of 0.8095.

Conclusions

Cardiac surgical mortality has significantly reduced in the last 15 years despite older and sicker patients. EuroSCORE II is better calibrated than the original model and preserves powerful discrimination providing patients and surgeons with improved pre-operative risk prediction.

•  Nashef SA, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, Lockowandt U. EuroSCORE II. Eur J Cardiothorac Surg. 2012 Apr;41(4):734-45.