Heart JournalScan

Dual antiplatelet therapy may be beneficial post-CABG

Francesca Brand, Editorial Assistant for Heart — Mon, 08 Feb 2010 16:47:31 +0000

Perioperative aspirin therapy in CABG improves graft patency, prevents ischemic events, and prolongs survival. However, Aspirin resistance is common after CABG, particularly in the immediate post-operative period, in part due to cardiopulmonary bypass causing a pro-inflammatory, pro-thrombotic state. Clopidogrel has revolutionised the practice of interventional cardiology but it remains unknown whether more aggressive antiplatelet treatment with aspirin and clopidogrel may be warranted to improve outcomes after CABG.

To examine this question the authors conduct a retrospective analysis of a multi-centre US database and analysed information on 15,067 adults undergoing CABG between 2003 and 2006. Of these, 3268 (22%) received dual antiplatelet therapy post-operatively. Compared with aspirin alone, aspirin plus clopidogrel was associated with a reduction in in-hospital mortality (0.95% vs. 1.78%; adjusted odds ratio: 0.50; 95% confidence interval: 0.25, 0.99) although there was no significant difference in ischaemic or thrombotic events to account for this. Of note, bleeding events were found to be lower in the combined therapy group than in the aspirin alone group (4.19% vs. 5.17%; adjusted odds ratio:0.70; 95% confidence interval: 0.51-0.97), a highly unexpected finding. In addition, there was no difference in the relative effect of combined treatment between on-pump and off-pump coronary artery bypass grafting suggesting no clinically adverse effect from using cardiopulmonary bypass.

As with all retrospective studies, this analysis is replete with confounders, with no information available regarding reasons for drug initiation, length of treatment, or dose given. The possibility of selection bias is high, with clopidogrel possibly being given to patients who were perceived to be low risk and so may have had a generally more benign clinical course than their contemporaries regardless of treatment allocation. However, the findings are in broad agreement with previous similar studies that also found benefits for clopidogrel in the post-operative period and have demonstrated higher rates of graft patency and late loss than aspirin alone.

Conclusions:

Dual antiplatelet therapy with aspirin and clopidogrel appears safe and may be beneficial following either on- or off-pump coronary artery bypass surgery. However, the results conflict with the findings of the recent CASCADE trial, which found that clopidogrel had no effect on vein graft intimal hyperplasia. The need for a sufficiently powered prospective study with hard clinical end-points to answer this pertinent and important issue remains.

• Kim DH, Daskalakis C, Silvestry SC, Sheth MP, Lee AN, Adams S, Hohmann S, Medvedev S and Whellan DJ. Aspirin and clopidogrel use in the early postoperative period following on-pump and off-pump coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2009;138(6):1377-84.

Journals scanned
American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Lancet; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax

Reviewers
Dr Alistair C Lindsay, Dr Jonathan Spiro, Dr Hussain Contractor

Cardiac Outcomes in Childhood Cancer Survivors

Francesca Brand, Editorial Assistant for Heart — Mon, 08 Feb 2010 16:46:59 +0000

Therapeutic advances in paediatric oncology have led to an increase in the number of adult survivors of childhood cancers. However, it is not currently known whether their long term health is influenced by the cancer therapies they receive.

In this retrospective cohort study, 14358 five year survivors of cancer enrolled in the Childhood Cancer Survivor Study were studied. All had been diagnosed under the age of 21 with leukaemia, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, kidney cancer, neuroblastoma, soft tissue sarcoma, or bone cancer between 1970 and 1986. A comparison group consisted of 3899 siblings of cancer survivors. The main outcome measures studied were the incidence of and risk factors for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities in survivors of cancer compared with siblings.

The cumulative incidence of cardiac disorders among childhood cancer survivors are shown in figure 1. Overall, the cumulative incidence of adverse cardiac outcomes in cancer survivors continued to increase up to 30 years after diagnosis.

http://heart.bmj.com/site/misc/March2.pdf

Figure 1: Cumulative incidence of various cardiac disorders among childhood cancer survivors

Survivors of cancer were significantly more likely than their siblings to report congestive heart failure (hazard ratio (HR) 5.9, p<0.001), myocardial infarction (HR 5.0, p<0.001), pericardial disease (HR 6.3, p<0.001) or valvular abnormalities (HR 4.8, P<0.001). In particular, exposure to >250mg/m2 of anthracyclines increased the relative hazard of congestive heart failure, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. Also, cardiac radiation exposure (>1500 centigray) increased the relative hazard of all four abnormalities by between two- and sixfold compared to non-irradiated survivors.

Conclusions:

A substantial risk for all forms of cardiovascular disease is present in survivors of childhood and adolescent cancers. As this population continues to grow, all healthcare professionals must be aware of the increased cardiovascular risk of this group of patients.

• Mulrooney DA, Yeazel MW, Kawashima T et al. Cardiac outcomes in a cohort of adult survivors of childhood adolescent cancer: retrosepective analysis of the Childhood Cancer Survivor Study Cohort. BMJ 2009 online first

Niacin HALTS progression of carotid thickness in imaging trial

Francesca Brand, Editorial Assistant for Heart — Mon, 08 Feb 2010 16:46:04 +0000

Due to the residual risk that remains with statin monotherapy, cholesterol treatment can be intensified with the use of a secondary agent such a ezetimibe or nicotinic acid. Whist ezetimibe has potent LDL-lowering capabilities, nicotinic acid is also capable of raising HDL-cholesterol and lowering triglyceride levels.
The ARBITER6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL treatment strategies) trial compared the effects of either niacin or ezetimibe added to long-term statin therapy on carotid intima media thickness (CIMT). Patients either with or at risk of coronary heart disease with LDL cholesterol levels <2.6 mmol per liter and HDL cholesterol levels < 1.4 mmol per liter were randomly assigned to receive either extended-release niacin (target dose of 2000mg per day) or ezetimibe (10mg per day). The primary end point was the between-group difference in the change from baseline in the mean common carotid intima-media thickness after 14 months. Niacin therapy was noted to significantly reduce LDL and triglyceride levels, whereas ezetimibe therapy reduced HDL cholesterol and triglyceride levels. When compared with ezetimibe, nicotinic acid therapy led to a greater efficacy regarding the change in mean carotid intima-media thickness over 14 months (p=0.003).

Conclusions:
In this comparative-effectiveness trial, extended release niacin (when combined with statin therapy) led to a significant regression of carotid intima-media thickness when compared to the use of ezetimibe with a statin. However, the population studied already had low levels of LDL cholesterol, which would minimise any potential benefit from ezetimibe. Furthermore, it is not clear whether the benefit seem with niacin is due to the HDL-raising effect of niacin or any of its other pleiotropic effects.

•    Taylor AJ, Villines TC, Stanck EJ et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009; 361: 2113-2122.
•    Blumental RS, Michos ED. The HALTS trial - Halting Atherosclerosis or Halted Too Early? N Engl J Med 2009; 361: 2178-2180.
•    Kastelein JJP, Bots ML. Statin Therapy with Ezetimibe or Niacin in High-Risk Patients. N Engl J Med 2009; 361: 2180-2183.

Dialysis Patients Undergoing PCI Frequently Receive Contraindicated Medications

Francesca Brand, Editorial Assistant for Heart — Mon, 08 Feb 2010 16:45:27 +0000

Several antithrombotic agents commonly used by cardiologists during percutaneous coronary intervention (PCI) are not recommended for use in dialysis patients. Specifically, eptifibatide and enoxaparin are renally excreted and therefore not recommended for use in dialysis patients due to an increased risk of bleeding complications. Tsai and colleagues investigated the use of these agents amongst dialysis patients undergoing coronary intervention and their association with outcomes. The authors used data from 829 US hospitals on 22778 dialysis patients who underwent PCI between 2004 and 2008. The main outcome measure was in-hospital bleeding and death.

Overall, 5084 patients (22/3%) received a contra-indicated antithrombotic - 2375 (46/7%) received enoxaparin, 3261 (64.1%) received eptifibatide, and 552 patients (10.9%) received both. Compared with patients who did not receive a contraindicated antithrombotic, those who did showed higher rates of both in-hospital bleeding (5.6% vs. 2.9%; odds ratio 1.93) and death (6.5% vs. 3.9%; odds ratio 1.68). Following multi-variable adjustment, these risks remained high; odds ratio 1.66 for in-hospital bleeding and 1.24 for death for those who received contraindicated antithrombotics. Lastly, in 10158 patients matched using propensity scores, receipt of contraindicated antithrombotics remained significantly associated with in-hospital bleeding (odds ratio 1.63), but not in-hospital death (odds ratio 1.15).

Conclusions:

The inappropriate use of eptifibatide and enoxaparin in patients with renal impairment is common. Furthermore, their use in this patient group is associated with a significantly increased risk of in-hospital bleeding. This issue is likely to become of even greater importance as the number of dialysis patients undergoing PCI is increasing.

• Tsai TT, Maddoz TM, Roe MT et al. Contraindicated medication use in dialysis patients undergoing percutaneous coronary intervention. JAMA 2009; 302:2458-2464.

Reviewers
Dr Alistair C Lindsay, Dr Jonathan Spiro, Dr Hussain Contractor

Cardiovascular Outcomes in Diabetics Complicated by Comorbidities

Francesca Brand, Editorial Assistant for Heart — Mon, 08 Feb 2010 16:44:56 +0000

Many trials over the last decade have suggested little cardiovascular benefit from treating diabetics to aggressive HbA1c levels of 6.5-7.0%. However, post hoc analyses and other meta-analyses have suggested that a benefit may still be possible if treatment is started before diabetes has become well established.

Greenfield and colleagues conducted a five-year longitudinal observation study to of patients with type two diabetes to determine whether obtaining haemoglobin HbA1c targets of 6.5% or less or 7.0% or less for glycaemic control at baseline led to any clinical benefits for patients with high (vs. low) levels of comorbidity. Patients were initially categorized using the Total Illness Burden INdex (TIBI) into high and low-to-moderate comorbidity subgroups.

2613 patients were succesfully recruited from over 200 diabetes outpatient clinics and general practitioners clinics in Italy. Over the course of follow-up, attaining an HbA1c level of 6.5% or less at baseline was associated with a lower 5-year incidence of cardiovascular events in the low-to-moderate comorbidity subgroup (adjusted HR, 0.60; p=0.005) but not in the high comorbidity subgroup (adjusted HR, 0.92; p=0.61). A similiar trend was when the HbA1c target used was 7.0%.

Conclusions:

In patients with type 2 diabetes, the benefits of aggresive glucose control may be limited in patients with high levels of comorbidity. Comorbidity levels must be considered when deciding on glucose management in type 2 diabetics.

• Greenfield S, Billimek J, Pellegrini F et al. Comorbidity affects the relationship between glycaemic control and cardiovascular outcomes in diabetes. Ann Intern Med 2009; 151: 854-860.

Increased use of antithrombotics increases hospital admissions for bleeding

Francesca Brand, Editorial Assistant for Heart — Mon, 08 Feb 2010 16:44:23 +0000

The safety of multiple antithrombotic drug regimes has not been investigated in clinical trials. Specifically, guidelines for the management of patients with myocardial infarction who also have an indication for warfarin are currently unclear; some recommend the use of clopidogrel and warfarin in combination following coronary stent implantation. As bleeding episodes following myocardial infarction are associated with increased morbidity and mortality, the use of undocumented treatment combinations raises concerns.

Sorensen and colleagues used nationwide registers from Denmark to identify 40812 patients who had been admitted to hospital with first time myocardial infarction (MI) between 2000 and 2005. The authors examined the prescriptions started at discharge to divide the patients in to groups of: monotherapy with aspirin, clopidogrel, or warfarin; dual therapy with any two of the preceeding agents; or triple therapy. The risk of hospital admission for bleeding, recurrent MI, and death were assessed by Cox proportional hazards models with the drug exposure groups as time-varying covariates. The main results are summarised in table 1.

Table 1: Risk of bleeding following myocardial infarction according to antithrombotic agents given

http://heart.bmj.com/site/misc/March1.pdf

Conclusions:
Following myocardial infarction, the risk of hospital admission for bleeding increases with the number of antithrombotic drugs used. The highest risk is seen with triple therapy or the use of clopidogrel and vitamin K antagonists; this combination should only be prescribed on a case-by-case basis.

• Sorensen R, Hansen ML, Abildstrom SZ et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009:374;1967-1974.

New molecular switch linked to hypertrophy

Francesca Brand, Editorial Assistant for Heart — Mon, 08 Feb 2010 16:42:57 +0000

Myocardial hypertrophy is a response to environmental stress that allows augmentation of pump function and reduces wall stress. Importantly, the transition from hypertrophy to heart failure is associated with a decrease in cardiac contractility, ventricular remodeling and fibrosis, and myocyte loss.
One of the most highly characterized hypertrophic signaling cascades involves the calcium dependent serine/threonine protein phosphatase calcineurin. Elevated intracellular calcium levels activate calcineurin, which in turn then dephosphorylates the transcription factor nuclear factor of activated T cells (NFAT) in the cytoplasm. This leads to its translocation to the nucleus and the subsequent activation of hypertrophy-associated genes.
In this paper the authors identify a novel GTPase, cdc42, that was specifically activated in the heart after pressure overload. Mice with a heart-specific deletion of cdc42 developed greater levels of hypertrophy than wild-type controls under neuroendocrine stress, and also transitioned more quickly into heart failure. Furthermore, knockout mice showed enhanced exercise-induced hypertrophy and an increased susceptibility to sudden death. The lack of cdc42 led to an increase in NFAT activity, suggesting that cdc42 is needed to reduce hypertrophy and prevent the transition to heart failure.
Conclusions:
Cdc42 is a novel signaling pathway that may reduce hypertrophy and heart failure when activated. As such it could be a target for novel pharmaceutical therapies designed to decrease myocardial hypertrophy and heart failure in humans.
• Maillet M, Lynch JM, Sanna B et al. Cdc42 is an antihypertrophic molecular switch in the mouse heart. J. Clin. Invest. 2009;119(10):3079-3088
Journals scanned:
American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; Lancet; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax
Reviewers:
Dr Alistair C. Lindsay, Dr Katie Qureshi, Dr Jon Spiro, Dr Hussain Contractor

Figure 1 - http://heart.bmj.com/site/misc/Feb1.pdf

HORIZONS-AMI reports 1 year results

Francesca Brand, Editorial Assistant for Heart — Mon, 08 Feb 2010 16:42:03 +0000

In the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, the direct thrombin inhibitor bivalirudin was found to lower 30-day rates of net adverse clinical events and and haemorrhagic complications in AMI when compared to treatment with heparin and a glycoprotein IIb/IIIa inhibitor (GPI). The trial investigators examined whether these initial benefits could still be seen after one year of follow-up.
3602 patients were assigned to either treatment regime in a 1:1 ratio; the two primary trial endpoints were major bleeding and net adverse clinical events (NACE). 1-year data were available for 1696 patients in the bivalirudin group and 1702 patients in the control group. The rate of NACE was lower in the bivalirudin group than in the control group (15.6% vs. 18.3%, p=0.022), due to a lower rate of major bleeding in the bivalirudin group. However when major bleeds were not included, major adverse clinical events (stroke, death, reinfarction, target vessel revascularisation for ischaemia) were similar (11.9% vs. 11.9%; p=0.005). 1-year rates of cardiac mortality, and all-cause mortality, were both lower in the bivalirudin group that the control group, regardless of the stent type the patient was randomised to (see figure - link below).
Conclusions:
In patients undergoing primary PCI, anticoagulation using bivalirudin reduced net adverse clinical events and major bleeding at one year when compared to conventional therapy (heparin plus glycoprotein inhibitor). Of note, significantly lower rates of recurrent myocardial infarction were noted in the high-risk patient group when treated with bivalirudin.
• Mehran R, Lansky AJ, Witzenbichler B et al. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial

ACE and ARB in combination give no added benefits

Francesca Brand, Editorial Assistant for Heart — Mon, 08 Feb 2010 15:29:40 +0000

Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II-receptor blockers (ARBs) have been shown to be of benefit in patients with heart failure, and in patients who have reduced ventricular function following a myocardial infarction. However, it is less well known whether they provide benefit in patients with ischaemic heart disease (IHD) and preserved ventricular function. Therefore the Agency for Healthcare Research and Quality commissioned this report to review the evidence for the clinical effects and harms of using ACE inhibitors, ARBs, or combination therapy in patients with IHD who are already receiving standard therapy.
The authors reviewed 41 studies that met eligibility criteria. 7 trials, including a total of 32,559 participants, concluded that ACE inhibitors reduced the relative risk (RR) for death (RR, 0.87) and nonfatal myocardial infarction (RR, 0.83), but increased the risk of syncope and cough. Low-strength evidence, suggested that ARBs reduce the RR for the composite endpoint of cardiovascular mortality, nonfatal myocardial infarction, or stroke (RR, 0.88). Moderate-strength evidence showed no overall benefit of the use of combination therapy on the risk of total mortality or myocardial infarction, when compared to using ACE inhibitors alone. Combination therapy did, however, lead to an increased risk of discontinuations due to hypotension (p<0.001) and syncope (p=0.035).
Conclusions:
ACE inhibitors reduce the risk of death, stroke, and myocardial infarction in patients with IHD and preserved ventricular function already on medical therapy; however there was little data to suggest that ARBs do so. The use of both classes of drugs in combination increased the risk of hypotension and syncope, with no additional clinical benefit compared to using ACE inhibitors alone.
• Baker WL, Coleman CL, Kluger J et al. Effectiveness of therapies for stable ischaemic heart disease. Systematic Reviews: Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II–Receptor Blockers for Ischemic Heart Disease. Annals Internal Med 2009, Oct 19. Epublication ahead of print.

Paclitaxel Stents Safe in STEMI

Alistair Lindsay — Sun, 21 Jun 2009 20:28:59 +0000

The Harmonising Outcomes with Revascularisation and Stents in Acute Myocardial Infarction (HORIZONS-AMI) was a prospective open label, multi-centre controlled trial involving patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). It incorporated two factorial randomised phases to allow a comparison of the direct thrombin inhibitor bivalirudin alone with heparin plus glycoprotein IIb-IIIa inhibitor use and a comparison of paclitaxel eluting stents (PES) with bare metal stents (BMS). Two primary clinical end-points were pre-specified: ischaemia driven TLR (analysis powered for superiority) and a composite safety end-point of major adverse cardiovascular events consisting of death, reinfarction, stroke and stent thrombosis (powered for non-inferiority with a 3.0% margin). The major secondary end-point was angiographic evidence of restenosis at 13 months

3602 patients with STEMI underwent randomisation for the pharmacological phase of the trial and of these 3006 underwent randomisation in a 3:1 ratio to the stent phase. 2257 were assigned to PES and 749 received BMS. 1 year follow up data were available for 2186 and 715 patients respectively. Patients with PES, when compared to those receiving BMS, had significantly lower ischaemia driven TLR (4.5% vs 7.5%, HR 0.59, 95%CI 0.43-0.83, p=0.002) and target vessel revascularisation (TVR) (5.8% vs 8.7%, HR 0.65, 95% CI 0.48-0.89, p=0.006), with non-inferior rates of the composite safety end-point (8.1% vs 8.0%, HR 1.02, 95%CI 0.76-1.36; absolute difference 0.1%, 95%CI -2.1 to 2.4, p=0.01 for non-inferiority, p=0.92 for superiority). Both PES and BMS had similar 12 month rates of death (3.5% and 3.5%, p=0.98) and stent thrombosis (3.2% and 3.4%, p=0.77) respectively. The 13 month rate of binary restenosis was significantly lower with PES than with BMS (10% vs 22.9%, HR 0.44, 95%CI 0.33-0.57, p<0.001).

There are some limitations of this study. Firstly, logistic complexities meant that an open label design was necessary. High rates of protocol compliance and the use of blinded clinical event adjudication and core laboratory assessments were measures taken to mitigate potential bias. There was a slightly higher rate of thienopyridine use in the PES arm than the BMS arm in the period between 6 months and 1 year. Very few patients with cardiogenic shock were included in this study and patients with unprotected left main stem disease or bifurcation disease requiring a 2 stent strategy were not included – therefore the results should not be extended to these patient populations. Longer term follow up data will be necessary to characterise the late safety and efficacy profiles of PES in patients with evolving STEMI particularly as the use of dual anti-platelet therapy declines over time after stent implantation. This is particularly important when considering the increased risk of stent thrombosis with DES when compared to BMSwhich may only become apparent at more than 1 year after stent implantation.

Conclusion:

The HORIZONS-AMI trial provides data indicating that PES may be used in patients with evolving STEMI. The data from HORIZONS-AMI show that approximately 30 fewer/1000 patients with PES required TVR at 1 year when compared to BMS.

· Stone GW, Lansky AJ, Pocock SJ et al. Paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction. The New England Journal of Medicine (2009) vol. 360 (19) pp. 1946-59