The implantable cardioverter-defibrillator (ICD) has consistently demonstrated benefit in reducing sudden cardiac death in patients at high risk of ventricular arrhythmias, but inappropriate ICD activations are a common occurrence with potential adverse effects on patient well-being and increased costs for health services. Strategies to reduce the frequency of inappropriate device activation without reducing efficacy in life-threatening situations would therefore be highly beneficial.

In the multi-centre MADIT-RIT trial, 1500 patients with a primary-prevention ICD implant were randomly assigned to a series of pre-specified programming configurations with the primary objective to determine whether high-rate therapy (with initiation at a heart rate of ≥200 beats per minute) or delayed therapy (with a 60-second delay at 170 to 199 beats per minute, a 12-second delay at 200 to 249 beats per minute, and a 2.5-second delay at ≥250 beats per minute) was associated with a decrease in occurrence of inappropriate antitachycardia pacing or shocks. Secondary end-points included death from any cause and the first episode of syncope. The results strongly favoured the novel programming algorithms. During an average follow-up of 1.4 years, high-rate and delayed therapy were associated with reductions in a first inappropriate therapy (HR with high-rate vs. conventional, 0.21; 95% CI, 0.13 to 0.34; P<0.001; HR with delayed vs. conventional, 0.24; 95% CI, 0.15 to 0.40; P<0.001) and an impressive reduction in all-cause mortality (HR with high-rate vs. conventional, 0.45; 95% CI, 0.24 to 0.85; P=0.01; HR with delayed vs. conventional, 0.56; 95% CI, 0.30 to 1.02; P=0.06). There was no difference in rates of syncope between any of the groups.

Conclusion

In this large randomised study, programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher – or with a prolonged delay in therapy at 170 beats per minute or higher – was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up, with no evidence of adverse effects.

• Moss AJ, Schuger C, Beck CA, Brown MW, Cannom DS, Daubert JP, Estes NA 3rd, Greenberg H, Hall WJ, Huang DT, Kautzner J, Klein H, McNitt S, Olshansky B, Shoda M, Wilber D and Zareba W. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med. 2012 Dec 13;367(24):2275-83.

In the United States, 30-day risk standardised readmission rates for heart failure (HF), acute myocardial infarction (MI), and pneumonia are now publicly reported. In order to better facilitate interventions targetted at reducing readmission rates, Dharmarajan et al. investigated readmission diagnoses and timings among Medicare beneficiaries readmitted within 30 days after hospitalisation for HF, MI, or pneumonia.

Medicare fee-for-service claims between 2007 and 2009 were analysed to identify patterns of 30-day readmission by patient demographic characteristics and time after hospitalisation for HF, acute MI, or pneumonia. The authors examined the percentage of 30-day readmissions occurring on each day (0-30) after discharge, and the most common readmission diagnoses. The relationship between patient demographic characteristics and readmission diagnoses and timing was also investigated.

The authors identified 329,308 readmissions within thirty days from a total of 1,330 557 HF hospitalisations (24.8%), 108,992 readmissions from 548,834 MI hospitalisations (19.9%), and 214,239 readmissions from 1,168 624 pneumonia hospitalisations (18.3%). 35.2% of HF patients were admitted for the same condition, compared to 10.0% of MI cases, and 22.4% of pneumonia cases; the majority of readmissions for each condition were within 15 days of hospitalisation. Neither readmission diagnoses nor timing substantively varied by age, sex, or race.

Conclusions:

For patients hospitalised with heart failure, acute MI, or pneumonia, 30-day readmissions are frequent throughout the month after hospitalisation, and result from a similar spectrum of diagnoses regardless of age, sex, race, or time after discharge.

• Dharmarajan K, Hsieh AF, Lin Z et al. Diagnoses and Timing of 30-Day Readmissions After Hospitalization for Heart Failure, Acute Myocardial Infarction, or Pneumonia. JAMA 2013;309:355-363.

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.

Deteriorating renal function in patients with heart failure is a common situation, affecting approximately a third of patients presenting with acute pulmonary oedema, and is associated with worse outcomes. Due to the potentially nephrotoxic nature of many heart failure therapies, renal failure leads to difficult treatment decisions regarding ongoing diuretic therapy.  Few options yet exist in this challenging clinical situation, however one potential option is mechanical ultrafiltration devices but currently there is a lack of evidence to support their use.

In this multicenter, randomized, open-label study a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion were allocated in a 1:1 fashion either to a strategy of stepped pharmacologic therapy or ultrafiltration. The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after group assignment with patients followed for a total of 60 days. The results did not support the use of ultrafiltration which was inferior to pharmacologic therapy with respect to the bivariate end point (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level in the pharmacologic-therapy group was -3.5±46.9 μmol/l, as compared with +20.3±61.9 μmol/l in the ultrafiltration group (P=0.003). There was no significant difference in weight loss seen between the two groups (P=0.58). Added to this, a higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03), mainly related to device and access issues.

Conclusions

In this randomized study involving patients with acute decompensated heart failure and poor renal function, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration.  Ultrafiltration was also associated with a higher adverse event rate.

• Bart BA, Goldsmith SR, Lee KL, Givertz MM, O’Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, Lewinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E; the Heart Failure Clinical Research Network. Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome. N Engl J Med. 2012 Nov 6. [Epub ahead of print]

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

Approximately 10-20% of patients are unable to tolerate statins or the higher doses needed to achieve LDL cholesterol goals. Perprotein convertase subtilisin/kexin type 9 (PCSK9) mediates the binding and trafficking of LDL receptors, and in phase 1 studies a human monoclonal antibody to to PCSK9 (AMG145)lowered LDL levels. The Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects (GAUSS) trial aimed to assess the efficacy and safety of AMG145 in patients with a documented history of muscle-related adverse effects with statins.

In this 12-week, randomized, double-blind, placebo and ezetimibe-controlled study, 160 patients from 33 international sites were randomised equally to 1 of 5 groups: AMG145 alone at doses of 280 mg, 350 mg, or 420 mg; AMG145 at 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks. All patients had intolerance to one or more statins because of muscle-related events. The primary endpoint was the percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol.

After 12 weeks of treatment, mean changes in LDL cholesterol levels were −67 mg/dL (−41%) for the AMG145, 280-mg, group; −70 mg/dL (−43%) for the 350-mg group; −91 mg/dL (−51%) for the 420-mg group; and −110 mg/dL (−63%) for the AMG145 420-mg/ezetimibe group compared with −14 mg/dL (−15%) for the placebo/ezetimibe group (P < .001). Myalgia was the most common adverse event related to treatment seen during the study, occurring in 5 patients (15.6%) in the 280-mg group (n = 32); 1 patient (3.2%) in the 350-mg group (n = 31), 1 patient (3.1%) in the 420-mg group (n = 32), 6 patients (20.0%) receiving 420-mg AMG145/ ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe.

Conclusions:

Subcutaneous administration of a monoclonal antibody to PCSK9 – one of several in production – led to significant reductions in LDL cholesterol levels, and was tolerated well in the short-term.

• Sullivan D, Olsson AG, Scott R et al. Effect of a Monoclonal Antibody to PCSK9 on Low-Density Lipoprotein Cholesterol Levels in Statin-Intolerant Patients. The GAUSS Randomized Trial. JAMA 2012;308:2497-2506.

In 1953 a report from the Armed Forces Institute of Pathology reported a 77% prevalence of coronary atherosclerosis among US soldiers killed in the Korean War. This revolutionary study demonstrated that atherosclerosis was present in a large number of young patients without clinical evidence of heart disease. A new study aimed to estimate the current prevalence of coronary and aortic atherosclerosis in the US armed forces, to assess the impact of risk factor reduction and lifestyle measures.

This was a cross-sectional study of all US service members who died of combat or unintentional injuries between October 2001 and August 2011. Coronary atherosclerosis severity was classified as: minimal (fatty streaking only), moderate (10%-49% luminal narrowing of 1 or more vessels), and severe (>49% narrowing of 1 or more vessels).

Of the 3832 service members included, the mean age was 25.9 years and 98.3% were male. 8.5% showed evidence of any coronary atherosclerosis, and severe coronary atherosclerosis was found in only 2.3%. Those with atherosclerosis were significantly older than those without (30.5 years vs. 25.3 years; P<.001), and a greater prevalence of dyslipidaemia, hypertension, and obesity was noted.

Conclusions:

This study suggests that the prevalence of early atherosclerosis in the modern era may be lower than in previous decades. However, it is not clear how the findings of this military study extend to the general population, particular given the recent rise in rates of diabetes and obesity.

• Webber BJ, Seguin PG, Burnett DG et al. Prevalence of and Risk Factors for Autopsy-Determined Atherosclerosis Among US Service Members, 2001-2011. JAMA 2012;308:2577-2583.

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.

The decision to anticoagulate a patient with atrial fibrillation involves a balance between the risks of thromboembolism against those of haemorrhage, with both risks imperfectly predicted by even the best stratification scoring systems.  Although warfarin reduces the risk of stroke in patients with atrial fibrillation, its use remains limited by several limitations.  Apixaban is a novel direct factor Xa inhibitor, previously found to be superior to warfarin at prevention of stroke or systemic embolism in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.

Lopes et al. attempted to determine how the results of anticoagulation with apixiban differed depending on the patients’ baseline risk of ischaemic events (CHADS2 & CHA2DS2-VASc) and bleeding (HAS-BLED) and found that apixaban consistently outperformed warfarin in terms of reducing the risk of clinical events (stroke, bleeding, and mortality) irrespective of CHADS2, CHA2DS2-VASc or HAS-BLED score.  In addition, Apixaban also appeared to be even more effective in reducing the risk of intracranial bleeding in patients with higher HAS-BLED scores. In individuals with HAS-BLED scores of >3, apixaban reduced the risk of intracranial bleeding 78% compared with warfarin, whereas the risk of intracranial bleeding was reduced 34% compared with warfarin in patients with HAS-BLED scores of 0 to 1.

Although apixaban is one of a number of novel oral anticoagulants that have been shown to have a clinical advantage over warfarin, it is the only one that has been shown to be associated with a reduction of both thromboembolism and haemorrhage, in addition to a reduction in all-cause mortality. This secondary analysis adds weight to the benefits of apixaban over warfarin in patients requiring anticoagulation for atrial fibrillation and reduction in intracranial bleeds in those with the highest risk of bleeding may provide physicians with an safer alternative therapy in these patients.

Conclusions:

Apixaban has benefits over warfarin that are consistent across the spectrum of stroke and bleeding risk, suggesting that the CHADS2,CHA2DS2VASc, and HAS-BLED scores may be less relevant for patients taking apixaban than they are for patients taking warfarin.

• Lopes RD, Al-Khatib SM, Wallentin L, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and bleeding in atrial fibrillation: a secondary analysis of a randomized controlled trial. Lancet 2012; DOI:10.1016/S0140-6736(12)60986-6.