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Archive for January, 2012

SCIPIO: Stem cells improve ischaemic cardiomyopathy

29 Jan, 12 | by Alistair Lindsay

Ischaemic heart disease remains the leading cause of heart failure in the Western World, and its prevalence continues to rise. Despite marked advances in the treatment of heart failure, heart muscle death remains irreversible.  However, over the last decade the concept of the heart as a terminally differentiated organ has been refuted, and this has lead to an avalanche of research into potential mechanisms of stem cell myocardial regeneration.

In the Stem Cell Infusion in Patients with Ischemic cardiomyopathy (SCIPIO) trial, Bolli et al. report on 81 patients with ischaemic heart disease undergoing CABG for revascularisation with a poor left ventricular ejection fraction (LVEF<40%). They were assigned to receive either intracoronary cardiac stem cells (CSCs) or no treatment at 16 weeks post-surgery. The cells used were c-kit positive autologous CSCs derived from right atrial appendage tissue taken at the time of surgery.

Although the study is still in progress, the initial published results have shown a marked difference in LVEF in patients that received CSCs (30.3% to 38.5% at 4 months, n=14), compared to those who had received no treatment (30.1% to 30.2%, n=7). These effects were more marked at one year with 12.3% increase in LVEF noted (n=8). In those patients that could undergo Cardiac MRI, there was a decrease in infarct size by 24% at 4 months and 30% at one year (n=7).  No adverse events were reported.


These initial results are promising for the future of cell-based therapy of ischaemic heart failure, but further data and longer follow-up is required. Many basic science questions also remain, particularly as regards to which cell-type is used, and how to best to deliver these cells. Therefore, although SCIPIO provides some encouraging results, many fundamental questions remain to be answered.


  1. Bolli R, Chugh AR, D’Amario D, Loughran JH, Stoddard MF, Ikram S, Beache GM, Wagner SG, Leri A, Hosoda T, Sanada F, Elmore JB, Goichberg P, Cappetta D, Solankhi NK, Fahsah I, Rokosh DG, Slaughter MS, Kajstura J, Anversa P. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011 Nov 14. [Epub ahead of print] PubMed PMID: 22088800.

ADHD medications and cardiovascular events

29 Jan, 12 | by Alistair Lindsay

Adults with attention-deficit/hyperactivity disorder (ADHD) are often treated with stimulants such as mephyphenidates and amphetamines, and additionally with a newer non-stimulant agent, atomoxetine.  Placebo-controlled studies have shown that all of these drugs are capable of increasing systolic and diastolic blood pressure in addition to heart rate.  However, no clinical trial to date has been large enough to assess whether these physiological changes lead to an increase in cardiovascular events.  Therefore the aim of this study was to investigate whether the current use of medications used primarily to treat ADHD leads to an increase in the risk of myocardial infarction (MI), sudden cardiac death (SCD), or stroke in adults aged 25-64.  For the purposes of the study, indeterminate use was the first 89 days after end of current use, former use began at 90 days after end of current use and ended at 364 days after last current use, and remote use referred to more than 364 days since the end of the last days supply.

During 806,182 person-years of follow-up, 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke were documented.  The multivariable-adjusted rate ratio (RR) of serious cardiovascular events for current users vs non-users of ADHD medications was 0.83 (95% CI, 0.72-0.96).  The adjusted RR for current users vs remote users was 1.03 (95% CI, 0.86-1.24); for new users vs remote users, the adjusted RR was 1.02 (95% CI, 0.82-1.28).   There was a crude incidence per 1000 person-years of 1.34 (95% CI, 1.14-1.57) for MI, 0.30 (95% CI, 0.20-0.42) for SCD, and 0.56 (95% CI, 0.43-0.72) for stroke.


In this study, the use of ADHD medications was not associated with an increased risk of serious cardiovascular events.  An apparent protective effect may be due to healthy-user bias in this cohort.

  • Habel LA, Cooper WO, Sox CM et al.  ADHD Medications and Risk of Serious Cardiovascular Events in Young and Middle-aged Adults.  JAMA 2011;306:2673-2683.

Long-term efficacy and safety of statins

29 Jan, 12 | by Alistair Lindsay

Alth0ugh an overwhelming amount of evidence now points towards the beneficial effects of statins, most of the large statin studies have only had 5-year follow-up and there have been observational studies that have suggested a long-term increased risk of particular types of cancer, and of other non-vascular morbidity and mortality.

The 20,536 patients in the Heart Protection Study (HPS) were randomised to either simvastatin 40mg once daily or placebo and were followed up within the trial for 5.3 years. Following this period, patients were asked to discuss with their family doctor whether non-trial statin treatment should be prescribed. The patients were then followed up by mailing questionnaries biannually until a total of 11 years, with further details sought from family doctors or hospital records if required. The primary outcome during this period was major vascular-events, non-fatal myocardial infarction or coronary death, fatal or non-fatal stroke, and coronary or non-coronary revascularisation. Secondary outcomes were major vascular events, death from vascular and non-causes, and cancers at all sites.

The previously reported reduction in major vascular events associated with LDL cholesterol reduction was seen in this patient population during the 5 year follow-up period. After the trial ended, statin use and lipid concentrations were similar in the two groups, and in the subsequent 6 years there was no further significant reduction in major vascular events or vascular mortality. During the entire 11 year follow-up period there was no significant difference in total cancer incidence (RR: 0.98; 95% CI 0.92-1.05), nor further analysis looking at specific cancer sites, or non-vascular causes.


This long-term follow-up of patients who have received prolonged statin therapy fails to recognise any hazards from doing so. These results suggest that extended statin therapy is safe with regards to the possible risk of cancer and non-vascular mortality, and has prolonged beneficial effects even after discontinuation of therapy.

  • Heart Protection Study Collaborative Group, Bulbulia R, Bowman L, Wallendszus K, Parish S, Armitage J, Peto R, Collins R. Effects on 11-year mortality andmorbidity of lowering LDL cholesterol with simvastatin for about 5 years in20,536 high-risk individuals: a randomised controlled trial. Lancet. 2011 Dec 10;378(9808):2013-20

Biodegradable polymer stent shows promise in LEADERS

29 Jan, 12 | by Alistair Lindsay

Drug eluting stents have reduced restenosis rates, and the need for further revascularisation after stenting, despite initial concerns over late stent thrombosis. This complication has been attributed to chronic inflammation and neoatherosclerosis induced by the durable polymers used in these stents. Biodegradable stents have been hypothesised to reduce this inflammatory burden, by degrading to leave a polymer/drug-free stent thereby removing the late risk of stent thrombosis.

The LEADERS  (Limus Eluted from A Durable versus ERodable Stent coating)  trial was a multicentre non-inferiority trial looking at the long-term clinical outcomes of biodegradeable polymer biolimus-eluting stents (BES) versus durable polymer sirolimus-eluting stents (SES) in adults with coronary artery disease. 1707 patients were randomly allocated to either the BES or SES arm, and the assessors were masked to this allocation.  At 4 year follow-up, there was non-inferiority in the composite primary end-point of cardiac death, myocardial infarction, or target-vessel revascularisation between the two groups (BES: 18.7% vs SES: 22.6%). There was also a relative risk of 0.62 of stent thrombosis in the BES group compared to the SES arm, which was due to a lower risk of stent thrombosis between years 1 and 4 of follow up (RR: 0.20, p<0.004).

This trial suggests overall non-inferiority of biodegradeable polymer BES compared with durable polymer SES over 4 years of follow-up and an 80% RR reduction when looking at very late definite stent thrombosis occurring 12 months following insertion. This suggests that clinical differences will only be appreciated between these two interventions at four years, and any subsequent superiority trial should have follow-up for at least this length of time.


Four-year follow-up outcomes of the LEADERS trial suggest non-inferiority of the biodegradable biolimus-eluting stent.

  • Giulio G Stefanini, Bindu Kalesan, Patrick W Serruys, et al. Long-termn clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial.  Lancet. Volume 378, Issue 9807, 3–9 December 2011, Pages 1940-1948

Cardiac arrest in marathon runners investigated

29 Jan, 12 | by Alistair Lindsay

Despite the increasingly sedentary nature of society, one participation sport that is thriving is long-distance running with approximately 2 million people participating in marathon or half-marathons in the United States annually. Tragically, this increase in participants has led to an increase in reports of race-related cardiac arrests and in this study by Kim et al the incidence and outcomes of cardiac arrests associated with long-distance running were explored.   The authors studied all marathon and half-marathon races in the USA between 2000 and 2010 in which a total of 10.9 million runners participated, and 59 (51 men) individuals suffered a cardiac arrest (incidence rate, 0.54 per 100,000 participants; 95% CI, 0.41 to 0.70). Using data from post-mortems and interviewing survivors, the vast majority of cases were found to have underlying cardiac disease with nearly half having HCM or probable HCM and nearly 20% having coronary disease. Risk of cardiac arrest was significantly higher in men (0.90 per 100,000; 95% CI, 0.67 to 1.18) than women (0.16; 95% CI, 0.07 to 0.31) and also significantly higher during marathons (1.01 per 100,000; 95% CI, 0.72 to 1.38) than half-marathons (0.27; 95% CI, 0.17 to 0.43) with the majority of arrests occurring during the final third of the race. HCM was associated with a particularly poor outcome and failed to respond to bystander CPR in the majority of cases. Interestingly, deaths from coronary disease did not appear to be from acute thrombosis secondary to plaque rupture but instead was due to demand ischemia in the presence of fixed coronary stenosis


Marathons and half-marathons are associated with a low overall risk of cardiac arrest and sudden death. Cardiac arrest is most commonly attributable to hypertrophic cardiomyopathy or atherosclerotic coronary disease and occurs primarily among male marathon participants.

  • Kim JH, Malhotra R, Chiampas G, d’Hemecourt P, Troyanos C, Cianca J, Smith RN, Wang TJ, Roberts WO, Thompson PD, Baggish AL; Race Associated Cardiac Arrest Event Registry (RACER) Study Group. Cardiac arrest during long-distance running races. N Engl J Med. 2012 Jan 12;366(2):130-40.

Subclinical AF significantly increases stroke risk

29 Jan, 12 | by Alistair Lindsay

Approximately 25% of all strokes are of unknown cause, and it has long been hypothesised that short subclinical episodes of atrial fibrillation (AF) may be an important common etiologic factor.  While several studies have attempted to detect episodes of subclinical AF, most have been hampered by the infrequency of such episodes and the unlikelihood of picking them up even with monitoring over a period of days or weeks.  In the US around 400,000 pacemakers are inserted each year, many of which are able to detect and record episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. In this study Healy et al. evaluated whether subclinical episodes of AF detected by these devices were associated with an increased risk of ischemic stroke.

Recruiting 2580 individuals, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted, patients were monitored for 3 months to detect subclinical AF (episodes of atrial rate >190 bpm for more than 6 minutes) and were followed for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. By 3 months, subclinical AF had been detected in 261 patients (10.1%). Subclinical AF was associated with an increased risk of clinical AF (HR, 5.56; 95% CI, 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (HR, 2.49; 95% CI, 1.28 to 4.85; P=0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical AF detected by 3 months, and none had had clinical atrial fibrillation by 3 months.  Overall, the population attributable risk of stroke or systemic embolism associated with subclinical AF was 13% with subclinical AF remaining predictive even after adjustment for other predictors of stroke (HR, 2.50; 95% CI, 1.28 to 4.89; P=0.008).


Subclinical AF occurred frequently in patients in this study and was associated with a significantly increased risk of ischemic stroke or systemic embolism. .

  • Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C, Morillo CA, Carlson M, Themeles E, Kaufman ES, Hohnloser SH; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012 Jan 12;366(2):120-9.

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