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In the United States, post myocardial infarction care has previously been noted to differ among races and, in particular, the use of invasive techniques is known to be lower in African American patients. As less than one‐fifth of American acute care hospitals perform coronary revascularisation, it is important to study patients admitted to those hospitals without these facilities if we are to understand this disparity fully.
Popescu and colleagues studied patterns of care between black and white patients according to whether they were admitted to a hospital with or without cardiac revascularisation services. To do this they retrospectively studied 1215924 black and white patients aged 68 and over, all of whom had been admitted between January 2000 and June 2005. The main outcome measures studied were the risk‐adjusted rates of 30‐day coronary revascularisation and 1‐year mortality; for patients admitted to hospitals without revascularisation facilities, the frequency of transfer to a tertiary centre was also measured.
Overall, black patients were less likely to be transferred from hospitals without revascularisation facilities (25.2% vs 31.0%; p<0.001). Regardless of whether the hospital had revascularisation services or not, black patients were less likely to undergo revascularisation than white patients (34.3% vs 50.2% in hospitals with revascularisation services, 18.3% vs 25.9% in those without; p<0.001) and also had higher 1‐year mortality (35.3% vs 30.2%, 39.7% vs 37.6%; p<0.001). These results remained constant even after adjustment for sociodemographics, comorbidity and illness severity.
Therefore even after transfer, black patients were less likely to receive revascularisation. What are the reasons for these differences? Perhaps patient preferences, clinical presentation, or unmeasured socioeconomic factors are influential. Although this study does not answer this question, our understanding of the problem is at least enhanced.
Popescu I, Vaughan‐Sarrazin MS, Rosenthal GE. Differences in mortality and use of revascularization in black and white patients with acute MI admitted to hospitals with and without revascularisation services. JAMA 2007;297:2489–95.
Patients with peripheral vascular disease (PVD) are at high‐risk for future cardiovascular events. Feringa et al examined the use of dobutamine stress echocardiography (DSE) to determine the prognosis of patients with known or suspected PVD.
Eight hundred and fifty‐two patients with known or suspected PVD (mean age 63 years, 70% male) were enrolled. All had ankle‐brachial index measurements, and left ventricular function was assessed by two‐dimensional echocardiography before DSE was performed. End points examined included all‐cause mortality and hard cardiac events (cardiac death or non‐fatal myocardial infarction).
Mean follow‐up was 7.6 years, during which 288 patients (34%) died and 216 (25%) had hard cardiac events. The mean left ventricular ejection fraction (LVEF) was 50%, and stress induced ischaemia was noted in 352 patients (41%). After multivariate analysis with adjustment for clinical risk factors and ankle‐brachial index, each 5% decrease in LVEF was associated with increased all‐cause mortality (hazard ratio (HR)=1.05, 95% confidence interval (CI) 1.02 to 1.09) and hard events (HR=1.14, 95% CI 1.08 to 1.21). Stress‐induced ischaemia demonstrated by DSE also independently predicted all‐cause mortality (HR=2.01) and hard events (HR=2.06). Estimation of LVEF and the presence of stress‐induced ischaemia provided incremental prognostic information over clinical data and ankle‐brachial index values (p<0.001).
DSE may provide additional prognostic information in this high‐risk subset of patients, presumably by detecting subclinical coronary artery disease. Where conveniently available, DSE should be considered in the management of patients with suspected or known PVD. However, consideration of the cost involved versus any potential benefit must be made.
Feringa HHH, Elhendy A, Karaglannis S, et al. Improving risk assessment with cardiac testing in peripheral arterial disease. Am J Med 2007;120:531–8.
The Framingham Coronary Heart Disease Risk Score allows clinicians to estimate a person's risk of coronary artery disease by taking into account the traditional cardiac risk factors. However, this score does not include chronic kidney disease (CKD).
Weiner and colleagues studied 15 717 subjects aged 45–74 from two large trials, the Atherosclerosis Risk in Communities (ARIC) trial and the Cardiovascular Health Studies (CHS) trial, in both of which the Framingham risk score has been previously validated. Using sex‐ and race‐specific Cox models they evaluated the 5‐year risk of coronary heart disease and mortality events associated with CKD after adjustment for the Framingham risk, the absolute risk of events caused by kidney disease in excess of and in comparison with traditional risk factors, and the impact of kidney disease on the Framingham equations in a biracial, community‐based cohort.
Seven hundred and fifty‐six (4.8%) of the patients had CKD, with most having stage 3 disease. While, as expected, the Framingham risk score independently predicted cardiac and mortality events in all subgroups, CKD also predicted cardiac and mortality events in all subgroups, except cardiac events in white women. After adjustment for traditional cardiac risk factors, the increase in cardiac and mortality events per 1000 person‐years attributable to CKD was 4.3 and 13.7 for white men, 16.1 and 40.5 for African American men, 1.2 and 5.8 for white women and 13.6 and 14.2 for African American women.
CKD is an important predictor of cardiac and mortality events with a magnitude similar to that of diabetes mellitus, and the risk is particularly notable in African Americans. However, overall it does not improve the ability of the Framingham equations to predict cardiovascular risk.
Weiner DE, Tighiouart H, Griffith JL, et al. Kidney disease, Framingham risk scores, and cardiac and mortality outcomes. Am J Med 2007;120:552.e1–8.
Rosiglitazone, a thiazolidinedione, reduces blood glucose and glycated haemoglobin levels. The original trials of the drug were not adequately powered to ascertain the effects of the drug on micro‐ or macrovascular complications of diabetes, including cardiovascular morbidity and mortality.
Nissen et al performed a meta‐analysis comprising 42 clinical trials, which compared rosiglitazone with either placebo or active comparators. A total of 15565 patients were randomly assigned to regimens that included rosiglitazone, and 12282 were assigned to comparator groups. Eligible studies had to last for at least 24 weeks. The prespecified primary end points were myocardial infarction and death from cardiovascular causes. The mean age of subjects was 56 years and the mean baseline glycated haemoglobin 8.2%.
One hundred and fifty‐eight cases of myocardial infarction and 61 deaths from cardiovascular causes were identified. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% CI 1.03 to 1.98; p=0.03) and the odds ratio for death from cardiovascular causes was 1.64 (95% CI 0.98 to 2.74; p=0.06). Hence rosiglitazone was associated with a significant increase in the risk of myocardial infarction and a borderline significant increase in death from cardiovascular causes.
This meta‐analysis has a number of strengths, including the use of major cardiovascular events as a primary end point and the inclusion of data from unpublished studies. However, across the trials there was no standard method for identifying or validating outcomes and the total number of events was low, with the result that there was little or no power to detect potential differences between the trials. The possibility that the findings were due to chance can therefore not be excluded. Nonetheless, overall the data suggest a cardiovascular risk associated with rosiglitazone use and this should be carefully considered by both prescribers and patients until more precise estimates of treatment risk are identified.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71.
Patsy BM, Furberg CD, eds. Rosiglitazone and cardiovascular risk. N Engl J Med 2007;356:2522–4.
Cardiac injury or haemodynamic overload results in the activation of a number of different intracellular signalling pathways and transcriptional factors. This results in the so‐called “heart failure phenotype” of myocyte hypertrophy, re‐expression of an embryonic gene pattern (including upregulation of structural fetal genes such as β‐myosin heavy chain and downregulation of adult structural genes such as α‐myosin heavy chain) and extracellular matrix remodelling.
Van Rooij and colleagues have previously reported on a signature pattern of micro‐RNA (miRNA) expression associated with hypertrophy and heart failure in both mouse models and humans. These are small RNAs that rather than encoding proteins, pair with their target messenger RNAs (mRNAs) in a sequence‐specific manner. This results in negative regulation of mRNA expression. miRNAs usually lead to decreased gene expression but may also result in upregulation of genes by negatively modulating the expression of gene inhibitors. Downregulation of miRNAs may result in upregulation of genes that have previously been suppressed. Overexpression of individual stress‐inducible miRNAs was shown by the authors to induce hypertrophic growth in isolated cardiac myocytes and to result in a dilated cardiomyopathy in transgenic mice. This suggests that individual miRNAs are sufficient to cause heart failure.
In their latest study, deletion of miR‐208, a cardiac‐specific miRNA encoded by an intron in the gene that encodes the α‐myosin chain, protects mice against cardiac myocyte hypertrophy, upregulation of the β‐myocyte heavy chain and myocardial fibrosis in response to thyroid signalling and haemodynamic overload. The results suggest that miR‐208 is a tissue‐specific nodal point, integrating stress signals and coordinating the expression of downstream molecules that contribute to the development of the heart failure phenotype. On the basis of the predicted binding of miR‐208, a previously unknown mediator of thyroid induced cardiac remodelling was identified—thyroid hormone receptor associated protein1 (THRAP‐1).
Heart failure is a complex condition and it is not likely that identification of disease‐specific miRNA targets will lead to the replacement of current therapeutic strategies in the near future. However, by identifying the signature miRNAs for various diseases it may become possible to elicit potential targets within a disease pathway, leading to new therapeutic strategies in not only heart failure but other conditions such as hypertension and cancer.
Mann DL. MicroRNAs, the failing heart. N Engl J Med 2007;356:2644–5.
Van Rooij E, Sutherland LB, Qi X, et al. Control of stress‐dependent cardiac growth and gene expression by a microRNA. Science 2007;316:575–9.
In the past decade there has been much confusion about the effects of hormone replacement therapy (HRT) on coronary artery disease. It had been hypothesised that postmenopausal oestrogen treatment delays atherosclerosis, but this was not borne out by randomised clinical trials. The Women's Health Initiative Coronary Artery Calcium Study (WHI‐CACS) aimed at identifying the relationship between oestrogen treatment and coronary artery calcium scoring.
Participants in the trial were postmenopausal women aged between 50 and 59 years, who had undergone hysterectomy and were randomly assigned to receive oral conjugated equine oestrogens or placebo. One thousand and sixty‐four women underwent cardiac computed tomography (CT) after a mean of 7.4 years of oestrogen treatment. Coronary artery calcium (or Agatston) scores were measured at a central reading centre without knowledge of the randomisation status. The mean coronary artery calcium score was significantly (p=0.02) lower among women receiving oestrogen (83.1) than those receiving placebo (123.1). After adjusting for coronary risk factors, the multivariate odds ratios for coronary artery calcium scores of more than 0, 10, and 100 in those receiving oestrogen compared with placebo were 0.78 (95% CI 0.58 to 1.04), 0.74 (0.55 to 0.99) and 0.69 (0.48 to 0.98), respectively. The corresponding odds ratios among women with at least 80% adherence to the study oestrogen or placebo were 0.64 (p=0.01), 0.55 (p<0.001) and 0.46 (p=0.001). For coronary artery calcium scores of >300 (vs <10), the multivariate odds ratio was 0.58 (p=0.03) in an intention‐to‐treat analysis and 0.39 (p=0.004) among women with at least 80% adherence.
Overall, those randomised to receive oestrogen had significantly lower coronary artery calcification scores than those assigned to placebo. The intention‐to‐treat analyses showed that treatment with oestrogen reduced coronary calcification by 42% and that reduction was even more marked in those women who adhered to oestrogen treatment (61%). This outcome was unaffected even after multivariable adjustment and is supportive of oestrogen having cardioprotective benefits in younger menopausal women.
These data support the “timing hypothesis” for HRT—the benefits of HRT in preventing atherosclerosis only occur when treatment is started before the development of advanced atherosclerosis. HRT is not beneficial when given to older women owing to the underlying biological characteristics of the vessel wall and the different vascular response in older more atherosclerotic vessels. However, it is important to emphasise that HRT should not be considered as a strategy to prevent cardiovascular disease in women. Continuing trials such as KEEPS (Kronos Early Estrogen Prevention Study) and ELITE (Early versus Late Intervention Trial with Estradiol) will further explore the optimal timing and potential cardiovascular benefits of HRT.
Manson J, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary‐artery calcification. N Engl J Med 2007;356:2591–62.
Mendelsohn ME, Karas RH. HRT and the young at heart. N Engl J Med 2007;356:2639–41.
Drug‐eluting stents have been shown to have lower rates of restenosis and target lesion revascularisation rate, but problems remain with late malapposition, hypersensitivity reactions, impaired endothelial response and late stent thrombosis. In an attempt to overcome these limitations an absorbable magnesium alloy was used to construct a new stent with complete absorption at 2 months in animal models.
The PROGRESS‐AMS (Clinical Performance and Angiographic Results of Coronary Stenting with Absorbable Metal Stents) clinical trial was a non‐randomised multicentre study that assessed the efficacy of an absorbable magnesium alloy coronary stent (n=63). Eligibility criteria included symptomatic ischaemic heart disease or silent ischaemia and a discrete de novo lesion in a coronary artery with reference diameter between 3.0 and 3.5 mm, lesion length 13 mm, with diameter stenosis 50–99%.
At 4 months an assessment of angina status, major adverse cardiac events (MACE) and any interventional treatment after discharge were documented, and all patients underwent a coronary angiogram and intravascular ultrasound examination. Patients were followed up for 12 months.
The primary end point of this feasibility study was cardiac death, non‐fatal myocardial infarction or clinically driven target vessel revascularisation at 4 months. The rate of MACE was expected to be 30% and defined as cardiac death, Q‐wave myocardial infarction and target lesion revascularisation. Secondary end points included MACE at 6 and 12 months and target lesion or target vessel revascularisation at 4, 6 and 12 months.
The study stents were deployed in the target lesion and achieved a residual diameter stenosis of 12.6% (SD 5.6%; range −1% to 27%) with no rise in creatine kinase greater than twice the upper limit of normal. No fatal or non‐fatal Q‐wave myocardial infarction, in‐hospital death or target lesion revascularisation was recorded during hospital stay and no acute stent thrombosis occurred. During the first 4 months MACE were recorded in 15 (24%) of the 63 patients (95% CI 14% to 36%), all of which were target lesion revascularisation. Angiography demonstrated a good scaffolding of the vessel, with an acute luminal gain of 1.41 mm (SD 0.46 mm). Late in‐segment luminal loss was equal to 0.83 mm (SD 0.51 mm), resulting in a net gain of 0.58 mm (SD 0.57 mm) after 4 months. No edge effect was noted. Elastic recoil was equal to 7% (15%). In‐segment diameter stenosis after 4 months was 49.66% (16.25%). After intravascular ultrasound the stent struts were echo reflective and well apposed to the vessel wall. At 4‐months' follow up the reflectivity was diminished, but the original position could still be identified. The overall target lesion revascularisation rate was 45% at 1 year.
Biodegradable magnesium stents can achieve an immediate angiographic result similar to the results for other stents and are safely degraded after 4 months. Modifications will be necessary to decrease the high rate of restenosis seen at 1 year, which required further revascularisation procedures in 45%. The renarrowing of the arterial lumen was due to a combination of negative remodelling and an excessive healing response and was similar to that previously seen with balloon angioplasty. It is thought that the stent was absorbed too rapidly and therefore the artery was not sufficiently supported, resulting in negative remodelling. Further adjustments to stent design might result in an optimal duration of stent absorption to limit this. Once this is achieved controlled release of an antiproliferative drug from the stent to limit the excessive healing response might be possible.
Bioabsorbable stents are at an early stage of product development but may prove to be a solution to the problems of permanent implants. The initial participants will need to be followed up closely for a prolonged period of time to avoid the situation that arose with conventional drug‐eluting stents of late events. However, we may yet be standing at the dawn of a new era for percutaneous intervention.
Erbel R, Di Mario C, Bonnier M, et al. Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective non‐randomised multicentre trial. Lancet 2007;369:1869–75.
Ormiston J, Webster M, eds. Absorbable coronary stents. Lancet 2007;369:1839–40.
An early invasive management strategy for high‐risk non‐ST elevation acute coronary syndromes (ACS) has been shown to save lives. But how can we be sure that the high‐risk patients are indeed the ones targeted for intervention?
Andrew Yan and colleagues from the University of Toronto evaluated 4414 patients with non‐ST elevation ACS in two multicentre prospective registries—ACS 1 (1999–2001) and ACS 2 (2002–3). Patients were stratified into low‐, intermediate‐ and high‐risk groups based on tertiles of the calculated GRACE (Global Registry of Acute Coronary Events) score.
Over the 4‐year period studied, the in‐hospital use of cardiac catheterisation increased from 38.8% in the initial registry to 63.5% in the second (p<0.001). In the ACS 1 Registry the rates of cardiac catheterisation in the low‐, intermediate‐ and high‐risk groups were 48.0%, 41.1% and 27.3%, respectively, whereas in the ACS 2 Registry these values were 73.8%, 66.9% and 49.7%, respectively (p<0.001 for trend for both). After adjusting for other cofounders, intermediate‐ and high‐risk patients remained less likely to undergo cardiac catheterisation than low‐risk patients (p<0.001). A similar inverse relationship between risk and the use of in‐hospital revascularisation and drugs was also noted.
Therefore in this study although the use of invasive cardiology techniques increased, the use of evidence‐based invasive and pharmacological treatments seemed to be targeted more towards lower‐risk patients. Clinical factors that are not always recorded in databases may explain this treatment–risk paradox. A more careful risk–benefit analysis on a patient‐by‐patient basis may help to overcome it.
Yan AT, Yan RT, Tan M, et al. Management patterns in relation to risk stratification among patients with non‐ST elevation acute coronary syndromes. Arch Intern Med 2007;167:1009–16.
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
Dr Alistair Lindsay, Dr Katie Qureshi