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Little data exist on the prevalence, incidence and prognostic value of ECG abnormalities in asymptomatic postmenopausal women. Denes et al looked at the ECGs of 14749 women enrolled in the Women's Health Initiative Study, all of whom were healthy postmenopausal women randomised to receive oestrogen and progestin or placebo. The Novacode criteria were used to stratify ECG abnormalities. End points included coronary heart disease (CHD) and cardiovascular disease (CVD) events.
Overall, there were 118 incident events among 9744 women with normal ECGs, 91 among those with minor abnormalities and 37 among those with major abnormalities. The incident annual CHD event rates per 10000 women with absent, minor or major ECG abnormalities were 21 (95% CI 18 to 26), 40 (95% CI 32 to 49) and 75 (95% CI 54 to 104), respectively. The adjusted hazard ratios for CHD events were 1.55 for minor and 3.01 for major baseline abnormalities. After 3 years of follow‐up, 5% of women who had a normal ECG at baseline developed new ECG abnormalities, with an annual CHD event rate of 85 per 10000 women. There were no significant interactions between assignment for hormone treatment and ECG abnormalities for prediction of risk of cardiovascular end points. For prediction of CHD events, the addition of ECG findings to the Framingham risk score increased the area under the receiver operating characteristic curve from 0.69 to 0.74.
Therefore, in this study, all ECG abnormalities were independently associated with an increased risk of cardiovascular events and mortality, and this information was incremental to the established methods of risk stratification.
Denes P, Larson JC, Lloyd‐Jones DM, et al. Major and minor ECG abnormalities in asymptomatic women and risk of cardiovascular events and mortality. JAMA 2007;297:978–85.
Are patients admitted with myocardial infarction over the weekend at higher risk than those admitted during the week?
Using the Myocardial Infarction Data Acquisition System (MIDAS), Kostis and colleagues retrospectively examined all admissions for myocardial infarction in the state of New Jersey between 1987 and 2002 (n=231164).
Patients admitted at weekends were less likely to undergo invasive cardiac procedures, especially on the first 2 days of hospitalisation (p<0.001). In the interval from 1999 to 2002 (59786 admissions), mortality at 30 days was significantly higher than for those patients admitted over weekends (12.9% vs 12%, p=0.006). The difference became significant the day after admission (3.3% vs 2.7%, p<0.001) and persisted at 1 year (1% absolute difference in mortality). The difference in mortality at 30 days persisted after adjustment for demographic characteristics, coexisting conditions and site of infarction (hazard ratio (HR) 1.048; 95% CI 1.022 to 1.076; p<0.001), but it became non‐significant after adjustment for invasive cardiac procedures (HR 1.023; 95% CI 0.997 to 1.049; p=0.09).
These findings suggest that the higher mortality rates at weekends are mediated in part by the lower rate of invasive procedures. The authors suggest that more appropriate staffing, or regionalisation of the care of patients with myocardial infarction, may prevent some of these deaths.
Kostis WJ, Demissie K, Marcella SW, et al. Weekend versus weekday admission and mortality for myocardial infarction. N Engl J Med 2007;356:1099–109.
Out‐of‐hospital cardiopulmonary resuscitation (CPR) consists of chest compressions and mouth‐to‐mouth resuscitation. However, the reluctance of bystanders to undertake mouth‐to‐mouth ventilation has been identified as a substantial barrier to potentially life‐saving CPR. Few clinical studies have investigated the effect of bystander CPR by chest compressions without mouth‐to‐mouth ventilation (cardiac‐only resuscitation).
The SOS‐KANTO Study Group from Japan performed a prospective observational study of patients in Tokyo who had an out‐of‐hospital cardiac arrest; on arrival at the scene, paramedics assessed the technique of bystander resuscitation. The primary end point was a favourable neurological outcome 30 days after cardiac arrest.
A total of 4068 patients who had an out‐of‐hospital cardiac arrest witnessed by bystanders were included; 439 (11%) received cardiac‐only resuscitation from bystanders, 712 (18%) received conventional CPR and 2917 (72%) received no bystander CPR. Cardiac‐only resuscitation resulted in a higher proportion of patients with favourable neurological outcomes than conventional CPR in patients with apnoea (6.2% vs 3.1%; p=0.0195), with a shockable rhythm (19.4% vs 11.2%, p=0.041), and with resuscitation that started within 4 min of arrest (10.1% vs 5.1%, p=0.0221). However, there was no evidence of any benefit from the addition of mouth‐to‐mouth ventilation in any subgroup. The adjusted OR for a favourable neurological outcome after cardiac‐only resuscitation was 2.2 (95% CI 1.2 to 4.2) in patients who received any resuscitation from bystanders.
The results of this study suggest that current CPR guidelines need to be revised. In cases of primary cardiac arrest, where blood remains initially well oxygenated, chest compressions maintain a reasonable cerebral perfusion pressure and do not necessarily need to be interrupted.
SOS‐KANTO Study Group. Cardiopulmonary resuscitation by bystanders with chest compression only (SOS‐KANTO): an observational study. Lancet 2007;369:920–6.
Previous radiotherapy regimens for breast cancer used in the 1970s have been associated with an increased risk of cardiovascular disease. More recent studies looking at the link between cardiovascular disease and modern chemotherapy regimens have been less conclusive.
In this study, 4414 10‐year survivors of breast cancer treated between 1970 and 1986 were followed up for a median of 18 years. Over this period, 942 cardiovascular events were observed (corresponding to 62.9 excess cases per 10000 when compared with general population rates). Breast irradiation on its own was not associated with an increased risk of cardiovascular disease, but radiotherapy regimens in the period 1970–9 to either the left or the right side of the internal mammary chain was (hazard ratio (HR)=2.55 for myocardial infarction, and 1.72 for congestive heart failure). However, internal mammary chain radiotherapy after 1979 declined over time towards unity, whereas the risk of congestive heart failure and valvular dysfunction remained raised. Patients who underwent radiotherapy and adjuvant chemotherapy (with cyclophosphamide, methotrexate and fluorouracil) after 1979 had a higher risk of CHF than patients who were treated with radiotherapy only (HR=1.85). Smoking and radiotherapy together were associated with a more than additive effect on the risk of myocardial infarction (HR=3.04).
Therefore, despite modern radiotherapy regimens for breast cancer, rates of cardiovascular disease and particulary heart failure remain high. In addition, patients with breast cancer who have been irradiated should be advised to refrain from smoking to reduce their risk of cardiovascular disease.
Hooning MJ, Botma A, Aleman BMP, et al. Long‐term risk of cardiovascular disease in 10‐year survivors of breast cancer. J Natl Cancer Inst 2007;99;365–75.
The original ICTUS (Invasive versus Conservative Treatments in Unstable Coronary Syndromes) Study compared an invasive with a non‐invasive strategy for non‐ST elevation acute coronary syndromes (nSTE‐ACS); at 1 year, the trial reported no difference in rates of death, myocardial infarction and rehospitalisation. Long‐term outcomes after a 4‐year follow‐up were reported in this month's Lancet.
Overall, the trial enrolled 1200 patients with nSTE‐ACS from across 42 hospitals in The Netherlands. All had an increased cardiac troponin levels, and were randomly assigned to either an early invasive strategy, or to more conservative treatment, where catheterisation was performed only if the patient had refractory angina or recurrent ischaemia. The main end points for the follow‐up study were death, recurrent myocardial infarction or rehospitalisation for anginal symptoms within the 3 years after randomisation, and cardiovascular mortality and all‐cause mortality within 4 years.
The in‐hospital revascularisation rate was 76% in the early invasive group and 40% in the selective invasive group. After 3 years, the cumulative rate for the combined end point was 30% in the early invasive group compared with 26% in the selective invasive group (hazard ratio 1.21; p=0.09). Myocardial infarction was more frequent in the early invasive group, but rates of death or spontaneous myocardial infarction were not different. No difference in all‐cause mortality (7.9% vs 7.7%; p=0.62) or cardiovascular mortality (4.5% vs 5.0%; p=0.97) was seen within 4 years.
The results here are in contrast with the long‐term follow‐up results of the larger RITA‐3 and FRISC‐II Trials. One possible explanation could be the relatively high (58%) revascularisation rate in the conservative arm over the entire study period.
Hirsch A, Windhausen F, Tijssen JGP, et al. Long‐term outcome after an early invasive versus selective invasive treatment strategy in patients with non‐ST‐elevation acute coronary syndrome and elevated cardiac troponin T (the ICTUS Trail): a follow‐up study. Lancet 2007;369:827–35.
In the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) Trial, 13819 patients with moderate‐ and high‐risk acute coronary syndromes (ACS) undergoing an early invasive strategy were randomised to one of three treatment strategies: heparin and glycoprotein IIb/IIIa inhibitors, bivalirudin and glycoprotein IIb/IIIa inhibitors, or bivalirudin alone. Following angiography, 7789 patients underwent percutaneous coronary intervention (56%); the effect of the three different strategies on the primary 30‐day end points of composite ischaemia (death, myocardial infarction or unplanned revascularisation for ischaemia), major bleeding and net clinical outcomes (composite ischaemia or major bleeding) was assessed in this subgroup. Analyses were performed by intention to treat.
In all, 2561 patients received heparin and glycoprotein IIb/IIIa inhibitors, 2609 received bivalirudin and glycoprotein IIb/IIIa inhibitors and 2619 received bivalirudin alone. There was no significant difference in the proportion of individuals with composite ischaemia, major bleeding or net clinical outcomes at 30 days between those who received bivalirudin and glycoprotein IIb/IIIa inhibitors and those who received heparin and glycoprotein IIb/IIIa inhibitors (composite ischaemia: 243 (9%) patients vs 210 (8%) patients, p=0.16; major bleeding: 196 (8%) patients vs 174 (7%) patients, p=0.32; net clinical outcomes: 389 (15%) patients vs 341 (13%) patients, p=0.1). Rates of composite ischaemia were much the same in those who received bivalirudin alone and in those who received heparin plus glycoprotein IIb/IIIa inhibitors (230 (9%) patients vs 210 (8%) patients, p=0.45); however, significantly fewer individuals experienced major bleeding among those who received bivalirudin alone (92 (4%) patients vs 174 (7%) patients, p<0.001), resulting in a trend towards better 30‐day net clinical outcomes (303 (12%) patients vs 341 (13%) patients, p=0.057).
These findings suggest that bivalirudin alone can safely replace heparin and glycoprotein IIb/IIIa inhibitors, with similar rates of bleeding and less ischaemia at 30 days. In this sense, these findings mirror those of the REPLACE‐2 (Randomised Evaluation of PCI Linking Angiomax to reduced Clinical Events) Trial, but in a more complex population. But the advantage of bivalirudin as shown by these findings is attributable solely to reduced rates of bleeding; for high‐risk patients other treatment options should still be considered.
Stone GW, White HD, Ohman Em, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) Trial. Lancet 20007;369:907–19.
The debate continues about the long‐term safety of drug‐eluting stents (DES), and this month the New England Journal of Medicine devotes an entire issue to the subject.
Maisel WH. Unanswered questions—drug‐eluting stents and the risk of late thrombosis. N Engl J Med 2007;356:981–4.
Farb A, Boam AB. Stent thrombosis redux—the FDA perspective. N Engl J Med 2007;356:984–7.
Curfman GD, Morrissey S, Jarcho JA, et al, eds. Drug‐eluting coronary stents—promise and uncertainty. N Engl J Med 2007;356:1059–60.
This study evaluated 6033 patients with drug‐eluting stents (DES) and 13378 patients with bare‐metal stents (BMS) from 2003 to 2004. The outcome analysis covered a period of 3 years. The primary end point was a composite of death or myocardial infarction. Secondary end points were death, myocardial infarction, revascularisation and restenosis. The study did not show a significant difference between DES and BMS in the primary end point at 3 years of follow‐up, although there was a suggestion of an increased risk of death after 6 months for those with DES (12.7 more events per 1000 patients, adjusted relative risk (RR) 1.20, 95% CI 1.07 to 1.35). At 3 years, mortality was significantly higher in the patients with DES (adjusted RR 1.18, 95% CI 1.04 to 1.35), and from 6 months to 3 years, the adjusted RR for death in this group was 1.32 (95% CI 1.11 to 1.57). Stent selection was not randomised in this study, hence the observed differences may be due to confounding factors such as physician bias in stent selection. There were also differences between the treatment groups: those with DES were slightly younger and more likely to be female with a higher prevalence of diabetes mellitus, hypertension, heart failure and renal dysfunction. No details on long‐term use of clopidogrel were available.
Lagerqvist B, James SK, Stenestrand U, et al. Long‐term outcomes with drug‐eluting stents versus bare‐metal stents in Sweden. N Engl J Med 2007;356:1009–19.
Two articles compared sirolimus‐eluting (SES) with bare‐metal stents (BMS). The first study was a pooled analysis of 1748 patients (428 with diabetes) in four randomised trials evaluating the safety of sirolimus and BMS; RAVEL, SIRIUS, E‐SIRIUS, C‐SIRIUS. There was no significant difference in survival rate at 4 years—93% in the SES group compared with 94.6% with BMS group (hazard ratio (HR) for death 1.24, 95% CI 0.84 to 1.83, p=0.28). In the 428 patients with diabetes, a significant difference in survival rate was observed in favour of the BMS group compared with the SES group (95.6% vs 87.8%; HR for death in the SES group 2.9, 95% CI 1.38 to 6.10, p=0.008). The lower survival rate in patients with diabetes was because of the increased numbers of deaths from both cardiovascular and non‐cardiovascular causes. Rates of myocardial infarction and stent thrombosis were similar in the two groups.
A second article performed an analysis of individual data on 4958 (1411 with diabetes) patients enrolled in 14 randomised controlled trials comparing SES and BMS (mean follow‐up interval 12.1–58.9 months). The overall risk of death (hazard ratio (HR) 1.03, 95% CI 0.8 to 1.3) and the combined risk of death or myocardial infarction (HR 0.97, 95% CI 0.81 to 1.16) were not significantly different for patients with SES compared with patients with BMS. There was a significant reduction in the combined risk of death, myocardial infarction or re‐intervention (HR 0.43, 95% CI 0.34 to 0.54) associated with the use of SES. There was no significant difference in the overall risk of stent thrombosis with SES versus BMS (HR 1.09, 95% CI 0.64 to 1.86). However, there was evidence of a slight increase in the risk of stent thrombosis associated with SES after the first year.
Spaulding C, Daemen J, Boersma E, et al. A pooled analysis of data comparing sirolimus‐eluting stents with bare‐metal stents. N Engl J Med 2007;356:989–97.
Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus‐eluting stents with bare‐metal stents. N Engl J Med 2007;356:1030–9.
Two studies compared sirolimus‐eluting stents (SES) with paclitaxel‐eluting stents (PES). The first was a patient‐level pooled meta‐analysis of data from 4 (RAVEL, SIRIUS, E‐SIRIUS, C‐SIRIUS) double‐blind trials in which 1748 patients were randomised to receive either SES or bare‐metal stents (BMS) and 5 (TAXUS I, II, IV, V,VI) double‐blind trials in which 3513 patients were randomly assigned to either PES or BMS. The 4‐year rates of stent thrombosis (as defined by study protocols) were as follows: 1.2% SES versus 0.6% BMS (p=0.20) and 1.3% PES versus 0.9% BMS (p=0.30). After 1 year, there were five episodes of stent thrombosis in SES versus none in BMS (p=0.025) and nine with PES versus two with BMS (p=0.028). The 4‐year rates of target lesion revascularisation (TLR) were much reduced with either SES or PES when compared with BMS. Rates of death and myocardial infarction did not appreciably differ between DES and BMS.
Although overall rates of stent thrombosis did not significantly increase with either DES or BMS, they are both associated with a small but significant increase in the incidence of late stent thrombosis between 1 and 4 years after stent implantation. Additionally, they are both associated with marked reductions in ischaemic TLR and target vessel revascularisation.
The final paper applies the Academic Research Consortium (ARC) definition of stent thrombosis across randomised trials involving 878 patients treated with SES, 1400 with PES and 2267 with BMS, and pooled the 4‐year follow‐up data. The cumulative incidence of stent thrombosis (original protocol definitions) was 1.2% for SES versus 0.6% for BMS (95% CI −0.4 to 1.5, p=0.20) and 1.3% in PES versus 0.8% in BMS (95% CI −0.3 to 1.4, p=0.24). When the ARC criteria for definite or probable stent thrombosis are applied, the incidence is as follows: 1.5% SES versus 1.7% BMS (95% CI −1.5 to 1.0, p=0.70) and 1.8% in the PES group versus 1.4% in the BMS group (95% CI −0.7 to 1.4, p=0.52). The incidence of definite or probable events occurring 1–4 years after implantation was 0.9% for SES versus 0.4% for BMS and 0.9% for PES versus 0.6% for BMS.
Although clinical end points have primary importance for the patient, they may fail to discriminate between small differences in the risk of stent thrombosis, as the condition accounts for a small fraction of the total number of these events. Death from stent thrombosis accounts for about 10% of the total number of deaths reported in these studies. Events were observed in patients with both BMS and DES in the presence of both aspirin and clopidogrel. This demonstrated ongoing risk despite dual antiplatelet treatment, and suggests that although dual antiplatelet regimens have a protective effect, this alone may not be sufficient to eliminate the occurrence of late thrombotic events. This analysis included all trials used to support the Food and Drug Administration approval of the two DES. On the basis of rates observed in these trials (ie, assuming a thrombosis rate of 1% with BMS and assuming an absolute increase of 1% in the rate of thrombosis with DES), a randomised trial with a power of 90% to detect a doubling of the risk of stent thrombosis would require approximately 8000 subjects. Whether the incidence curves for the events associated with DES and BMS will remain convergent or separate beyond 4 years is unknown, and follow‐up for a longer period will be required.
Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus‐ and paclitaxel‐eluting coronary stents. N Engl J Med 2007;356:998–1008.
Mauri L, Hsieh W, Massaro JM, et al. Stent thrombosis in randomised clinical trials of drug‐eluting stents. N Engl J Med 2007;356:1020–9.
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
Dr Alistair Lindsay, Dr Katie Qureshi