QT variability strongly predicts sudden cardiac death in asymptomatic subjects with mild or moderate left ventricular systolic dysfunction: a prospective study

This prospective study [1] in a single center was conducted in order to determine whether the QT variability index (QTVI) and the square of the mean QT (QTVN) were predictors of sudden cardiac death (SCD).

Between January 1, 1999 and December 31, 2000, a total of 396 consecutive outpatients with post-ischemic dilated cardiomyopathy with an ejection fraction (EF) between 35% and 40% and no symptoms of cardiac heart failure were enrolled in the study. These subjects underwent a 5-min electrocardiography (ECG) recording to calculate QT variance (QTv ), QT normalized for the square of the mean QT (QTVN), and QT variability index (QTVI). The QT corrected (QTc) was obtained from the initial 12-lead ECG recording. The end points were total mortality, mortality unrelated, and related to SCD. For analysis, data were subgrouped into patients who died of SCD and those who survived; patients who died of causes other than SCD were excluded. These subjects were followed for 5 years.

At follow up, 42 subjects had died (overall mortality rate 11%, 2% per year). Of this total, 23 died of SCD (mortality rate of 6% for SCD, 1.2% per year) and 19 subjects died of causes unrelated to SCD. A multivariant survival model demonstrated that a QTVI ≥80th percentile indicated a high risk of SCD (hazards ratio [HR] 4.6, 95% confidence interval [CI] 1.5–13.4, P=0.006) and, though not to the same extent, a high risk of total mortality (HR2.4, 95% CI 1.2–4.9, P=0.017)). Similarly, the model including QTVI as a continuous variable confirmed a high risk for SCD (HR 2.9, 95% CI 1.3–6.5, P=0.01) and total mortality (HR 2.6, 95% CI 1.3–5.2, P=0.008).

The authors concluded that “our findings in this prospective study conducted in over 400 outpatients from a single [center] indicate that the measures of temporal QT variability we studied, especially the QTVI, are strong predictors of SCD in patients with post-ischaemic dilated cardiomyopathy with a moderately depressed EF and symptomless for CHF” and “we show that patients with a QTVI value equal to or higher than the 80th percentile (≥ -0.47) are at exceedingly high risk for SCD.” They point out that for this population, the incidence of SCD was approximately 1.2% per year, which may not seem excessively high in relative terms, but in absolute terms is very high. They also comment that their findings might suggest that patients with a high QTVI and a moderately depressed EF (35–40%) might be possible candidates to receive an ICD as primary prophylaxis for SCD. They caution, however, that this strategy needs to be confirmed in a larger, multicenter prospective study.

[1] Piccirillo G, Magri D, Magnanti M, et al. QT variability strongly predicts sudden cardiac death in asymptomatic subjects with mild or moderate left ventricular systolic dysfunction: a prospective study. Eur Heart J 2007;28:1344-1350

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Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation

Nonvalvular atrial fibrillation is a major risk factor for stroke that can be diminished by using antithrombotic prophylaxis. This meta-analysis [1] uses data from the initial 16 randomized clinical trials that tested antithrombotic therapies for stroke prevention and 13 additional randomized studies that were conducted following the initial trials to extend observations about the efficacy and safety of antithrombotic therapies for preventing stroke in this patient population.

A search, unrestricted by language, was conducted of OVID and MEDLINE databases from 1966 to March 2007 and of the Cochrane Stroke Group Trials Register as well as querying investigators in the field to identify unconfounded randomized trials that tested long-term (≥12 weeks) use of antithrombotic agents in patients with nonvalvular atrial fibrillation. Information was extracted from these studies by the two coauthors independently for interventions; participants; and occurrences of ischemic and hemorrhagic stroke, major extracranial bleeding, and death. Intention to treat results were used for the primary analysis. Primary and secondary preventions were defined as patients without previous stroke or transient ischemic attack (TIA) and patients with previous stroke or TIA respectively.

Twenty-nine published randomized trials with a mean follow up of 1.5 years were included in this meta-analysis, which resulted in a total of 28,044 participants (35% women) with a mean age of 71 years. In six randomized trials with 2900 participants, adjusted-dose warfarin as compared with placebo or no treatment was associated with a 64% (95% confidence interval [CI], 49–74%) reduction in stroke. In seven trials that included 3990 participants, aspirin alone, as compared with placebo or no treatment, was associated with a 19% (CI, -1–35%) reduced incidence of stroke. When all randomized data from all comparisons of antiplatelet agents and placebo or controls groups were considered, antiplatelet therapy reduced stroke by 22% (CI, 6–35%). In 12 comparisons of adjusted-dose warfarin with antiplatelet therapy alone, warfarin was associated with a 37% (CI, 23–48%) reduction in stroke. For the participants in this meta-analysis, the absolute increases in major extracranial hemorrhage associated with antithrombotic therapy were less than the absolute reductions in stroke. It should be noted, however, that the risk of intracranial hemorrhage for the pooled data for two results with adjusted-dose warfarin compared with aspirin were statistically significant even though the absolute risk increase was small (0.2% per year), and all-cause mortality was reduced substantially (26% [CI, 3–43%]) by adjusted-dose warfarin as compared with the control.

The authors note that “the randomized clinical trials in our meta-analysis … have established a solid evidence base that supports antithrombotic therapy for most patients who have atrial fibrillation.” They concluded that “these results reaffirm recommendations for adjusted-dose warfarin for patients with atrial fibrillation who are deemed to be at high risk for stroke, with antiplatelet therapy for low-risk patients and for those who cannot safely receive warfarin.” They point out, however, that a need remains to identify “antithrombotic agents that are more efficacious than aspirin and that are safer or more easily administered than adjusted-dose warfarin.”

[1] Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146(12):857-867

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Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation

In atrial fibrillation (AF), warfarin has proven to be effective in the prevention of stroke, but studies have shown that it is underutilized, especially among the elderly who are at greatest risk. This inception cohort study [1] addresses this issue by defining the tolerability of warfarin in elderly patients with AF.

Patients were eligible for this study if they were ≥65 years of age, had AF verified by ECG, were new to warfarin (or had taken none within the previous 12 months), had their care established at the study institution, and had their warfarin managed by the on-site anticoagulation clinic. A total of 533 consecutive patients who started on warfarin were identified during January 2001 to June 2001 and 472 of these patients (47% female; 53% male) were enrolled in the study. Of this cohort, 54% were over 75 years of age, 32% were 80 years of age or over and 91% had a stroke risk factor of at least 1. The outcomes of this study included major hemorrhage, time to termination of warfarin, and physician reason for discontinuation.

At 1-year follow up, 134 patients had been taken off warfarin, 16 died of unrelated causes, 16 transferred their warfarin management, and 306 patients remained on warfarin. Higher rates of major bleeding were seen in patients ≥80 years of age in comparison to patients <80 years of age with a cumulative incidence of major hemorrhage of 13.1 per 100 person years vs. 4.75 per 100 person years respectively (P=0.009). Despite trial-level anticoagulation control, increased risk was associated with the first 90 days of warfarin, age ≥80 years and international normalized ratio (INR) ≥4.0. In patients ≥80 years of age, 26% stopped taking warfarin in the first year. For these patients, 81% of the warfarin discontinuation was related to perceived physician safety concerns as compared with 37% of patients under 80 years who discontinued the drug (P<0.001). The rates of major hemorrhage and warfarin terminations were highest among patients with stroke risk scores of ≥3 as measured by the CHADS2 scheme (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack).

The authors suggest that the higher rate of hemorrhage found in this study is likely due to the advanced age of the study population and restriction of the cohort to patients who started warfarin. They point out that their study “reaffirmed the time-dependence of risk that has been shown in other studies.” Several study limitations were noted that included conducting the study in a single academic center that may not reflect other settings, and exclusion of patients whose warafin was managed outside of their clinic as well as patients with higher baseline risks of bleeding. The authors also highlighted several key strengths of the study that included consecutively identifying and following all eligible patients from the first day of warfarin in order to ensure complete capture of adverse events, and management of warfarin by an experienced staff from a long-established and well-organized clinic managed who also were able to directly determine aspirin usage. Moreover, the authors point out that this study “constitutes the largest proportion of patients in this age group represented in a prospective real-world study of AF.” In terms of the clinical implications for the management of anticoagulation in elderly patients, the authors note that the results of their study illustrate the complexity of these patients since patients at highest risk of stroke also experienced major bleeding, and they recommend that strategies to decrease these risks need to be aggressively sought and implemented. Further, they suggest that the benefit of combining aspirin with warfarin for cardiovascular disease needs to be better defined and justified, especially in light of recent guidelines that advise against this combination in older patients with AF and stable coronary disease. They stress that careful monitoring in the early phase of therapy is needed to reduce bleeding during this risk-prone period and interventions are needed to reduce falls since these patients have higher rates of intracranial hemorrhage. They emphasize that “because elderly patients are slower to normalize an elevated INR, more aggressive management of excessive anticoagulation in this group seems prudent” and “further research of age-related vasculopathies that predispose to intracerebral hemorrhage is needed.” Based on their findings, the authors conclude that “published rates of major hemorrhage derived from younger noninception cohorts underestimate the bleeding that occurs in clinical practice” and “higher rates of bleeding and short-term tolerability likely contribute to the reported underutilization of warfarin among elderly patients with AF.” They stress that the aging of the population makes stroke prevention in AF a pressing health concern.

[1] Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115(21):2689-2696

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Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes

This study [1] is a meta-analysis of 42 of 116 potentially relevant trials that compared rosiglitazone, a thiazolidinedone drug used to lower blood glucose in patients with type 2 diabetes, with placebo or active comparators to evaluate its effect on cardiovascular outcomes.

In these trials, patients were randomly assigned to regimens that included rosiglitazone (n=15,565) and comparator groups (n=12,282) with regimens that did not include rosiglitazone. The trials included five of the studies submitted to the FDA advisory board hearing that recommended approval of the drug; 35 studies identified in the Glaxo-Smith clinical-trial registry; and two large, recently published trials, the Diabetes Reduction Assessment with Ramipiril and Rosiglitazone Medication (DREAM) trial and the A Diabetes Outcome Prevention Trial (ADOPT). The inclusion criteria for this meta-analysis were: 1) A study duration of more than 24 weeks; 2) use of a randomized control group not receiving rosiglitazone; and 3) availability of outcome data for myocardial infarction and death from cardiovascular causes. For both study groups, baseline characteristics included relatively young patients (mean <57 years of age), a moderate predominance of men, and poor diabetes control with a mean baseline glycated hemoglobin level of ≈ 8.2%.

In the rosiglitazone group, there were 86 myocardial infarctions as compared with 72 in the control group and 39 deaths as compared with 22 in the control group. The rosiglitazone group, as compared with the control group, had a summary odds ratio for myocardial infarction of 1.43 (95% confidence interval [CI], 1.03–1.98; P=0.03) and an odds ratio of 1.64 (95% CI, 0.98–2.74; P=0.06) for cardiovascular events. In an analysis that was not prespecified, the effects of rosiglitazone on death from any cause resulted in an odds ratio of 1.18 (95% CI, 0.89–1.55; P=0.24).

Based on their data, the authors concluded that “… as compared with placebo or with other antidiabetic regimens, treatment with rosiglitazone was associated with a significant increase in the risk of myocardial infraction and with an increase in the risk of death from cardiovascular causes that was of borderline significance.” While they note a number of limitations to their analysis including the lack of patient-level source data, they emphasize the need for additional further analysis from larger controlled trials to address the potential public health impact of cardiovascular risks found in their study. The authors speculate that potential contributing factors to the increase in myocardial infarction and death with rosiglitazone might be related to the adverse effect of the drug on serum lipids, e.g. increase in LDL cholesterol, and the known susceptibility of some patients who take rosiglitazone and other thiazolidinediones that precipitates congestive heart failure. They point out that other PPAR agonists have been reported to increase cardiovascular events and “the biologic effects of the protein targets for most of the genes influenced by PPAR agonists remain largely unknown,” which led them to question whether the risks they found in their meta-analysis represent a “class effect” of thiazolidinediones. Given their findings, the authors also questioned “the appropriateness of the current regulatory pathways for the development of drugs to treat diabetes.” They warn that “until more precise estimates of the cardiovascular risk of this treatment can be delineated in patients with diabetes, patients and providers should carefully consider the potential risks of rosiglitazone in the treatment of type 2 diabetes.”

[1] Nissen SE, Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356(24):2457-2471
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Characteristics, management, and outcomes of 5,557 patients Age ≥90 years with acute coronary syndromes

In order to address the uncertainty concerning the risks and benefits of current treatment guidelines for elderly (≥90 years) patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) who are often underrepresented in clinical registries and clinical trials, this study [1] used data from CRUSADE (Can Rapid risk stratification of unstable angina patients Suppress Adverse outcomes with Early implementation of the American College of Cardiology/American Heart Association) to investigate treatment and outcomes in this population.

A total of 51,827 patients ages ≥75 enrolled in CRUSADE from January 1, 2001, through June 30, 2005. Of this population 5557 patients were 90 years of age or older and 112 were 100 years of age or older. Baseline characteristics, treatment patterns, and in-hospital outcomes for this older elderly population (≥90 years) were compared with a cohort of 46,270 patients who were 75–89 years of age. Although both groups had similar baseline characteristics, the ≥90 year group tended to be women who were less likely to have traditional coronary artery disease risk factors including diabetes, recent smoking, obesity and a family history of premature coronary artery disease. While there were no differences in low-density lipoprotein cholesterol levels, the older elderly group had slightly higher high-density lipoprotein cholesterol levels and lower triglycerides than the younger elderly cohort group (75–89 years). Moreover, while the incidence of previous myocardial infarction was similar between groups, the older elderly were less likely to have undergone previous percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG).

During the first 24 hours after admission, older elderly patients without contraindications were less likely to receive guideline-recommended acute therapies including heparin (75.1% vs 82.4%), glycoprotein (Gp) IIb/IIIa inhibitors (12.0% vs 29.2%), and statins (30.4% vs 45.7%; all P<0.001). There was a significant difference in the number of eligible older elderly patients who underwent cardiac catherization within the first 48 hours after presentation as compared with the younger cohort (10.8% vs 36.3%; P<0.001). Similarly, the use of revascularization occurred less frequently in the older elderly population, as compared with the younger cohort (12.6% vs 40.1%; P<0.001). The older elderly were also more likely to die during hospitalization as compared with their younger cohort (12.0% vs 7.8%; P<0.001) and more likely to experience adverse cardiovascular events (26.8% vs 21.3%; P<0.001). This difference persisted even after adjustment for baseline patient and hospital characteristics. For both age groups, an increasing use of therapies with potential for increasing bleeding (aspirin, acute clopidogrel, acute heparin, catherization within 48 hours with or without Gp IIb/IIIa inhibitors) was associated with increased bleeding and a direct, graded reduction in risk-adjusted in-hospital mortality.

Based on these findings, the authors concluded that “the older elderly were more likely to have documented contraindications to acute treatments, less likely to receive such care independent of contraindications, and were more likely to die in-hospital.” They also point out that even though there was a graded relationship between the number of therapies delivered and bleeding complications, “increasing adherence to guideline-recommended therapies was associated with lower in-hospital mortality in both cohorts.” The authors acknowledge several limitations to the study that included exclusion of older adults who present with atypical symptoms or with ACS in context of another major medical illness; possible unmeasured confounding; lack of reported information on key variables related to the elderly, e.g. function and cognitive status, financial status or patient preferences); inability to account for undocumented contraindications to recommend therapies or for patients transferred to another hospital; and limitation of the assessment to in-hospital outcomes. Nevertheless, the authors point out that “these findings reinforce the importance of optimizing care patterns for even the oldest patients with NSTE-ACS while examining novel approaches to reduce the risk of bleeding for this rapidly expanding patient population.”

[1] Skolnick AH, Alexander KP, Chen AY, et al. Characteristics, management, and outcomes of 5,557 patients Age ≥90 years with acute coronary syndromes. Results from the CRUSADE Initiative. J Am Coll Cardiol 2007;49(17):1790-1797

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Use of selective serotonin-reuptake inhibitors in preganancy and the risk of birth defects

This study [1] uses data from the National Birth Defects Prevention Study (NBDPS), an ongoing multisite, case-controlled study of environmental and genetic risk factors for more than 30 categories of major birth defects, to assess the relationship between the maternal use of selective serotonin-reuptake inhibitors (SSRIs) in early pregnancy and the incidence of selected birth defects.

A total of 9622 case infants with major birth defects from surveillance systems in eight US States and 4092 control infants randomly selected from the same geographic area who were born from 1997 through 2002 comprised the study population. Twenty six categories and subcategories of birth defects met the criterion of having representation by at least 200 interviews with case mothers. SSRI use was defined as treatment with any SSRI from 1 month before to 3 months after conception.

A total of 408 (3.0%) case and control mothers reported using an SSRI at some point during pregnancy, 230 (2.4%) of the case mothers (2.4%) and 86 (2.1%) of the control mothers. As compared with the case mothers, the mothers of the control cases were significantly more likely to be younger (<35 years of age), to have more years of education (<12 years), and to have a higher family income whereas the case mothers in comparison were more likely to smoke, have diabetes and hypertension, and to be obese. In general, no significant associations were found between maternal use of SSRIs in early pregnancy and congenital heart defects or most categories or subcategories of birth defects. An association was found for maternal SSRI use for anencephaly (214 infants, nine exposed; adjusted odds ratio [OR], 2.4%; 95% confidence interval [CI], 1.1–5.1), craniosynostosis (432 infants, 24 exposed; adjusted OR, 2.5%; 95% CI, 1.5–4.0), and omphalocele (181 infants, 11 exposed; adjusted OR, 2.8; 95% CI, 1.3–5.7). Of note, post hoc analysis of potential effect modification by seven variables demonstrated significant effect modification by obesity between SSRI use and craniosynostosis (P=0.05, by the Breslow-Day test). Further analysis demonstrated that among women who did not use SSRIs, obese women were more likely than nonobese women to have infants with conotruncal heart defects (adjusted OR, 1.3; 95% CI, 1.0–1.6) and septal heart defects (adjusted OR, 1.3; 95% CI, 1.1–1.5) and this relationship was strengthened among women reporting SSRI use. SSRI use in nonobsese women was associated with craniosynostosis (adjusted OR, 2.0; 95% CI, 1.1–3.7), but the risk was greater among obese women reporting SSRI use (adjusted OR, 5.9; 95% CI, 2.4–4.3).

The authors summarized their findings by stating  “we found no significant associations between the use of SSRIs in early pregnancy and the risks of the majority of birth defects assessed in this study, including congenital heart defects,” but noted that they “observed associations between SSRI use and the occurrence of anencephaly, craniosynostosis, and omphalocele, defects that had not been previously associated with maternal SSRI use in pregnancy.” Alwan et al point out that to their knowledge, the effect modification by prepregnancy obesity that was found post for the association between SSRI and the occurrence of birth defects has not been reported previously. They note several important limitations to the study: 1) The effect of maternal SSRI use could not be separated from the effect of depression itself. 2) Dose-response relationships could not be conducted because dosage data were unavailable. 3) In terms of SSRI use, mothers were prompted by brand names of the three most common SSRIs, which could have resulted in underreporting of SSRIs. 4) Recall bias could have been introduced because of material reporting. 5) Selection bias could have occurred since participation was less than 100%. The authors caution that even though SSRI was present in a small number of cases of certain defects, the absolute risks associated with SSRI use appeared small in relation to the baseline risks of birth defects that exist in every pregnancy. They also point out that discontinuation of antidepressant treatment in pregnant women with serious depressive illness may have adverse effects on the mother and her baby and emphasize that “thorough assessment of the potential risks and benefits of SSRI use is necessary to allow women of reproductive age to make informed decisions about such therapy.”

[1] Alwan S, Reefhuis J, Rasmussen SA, et al. Use of selective serotonin-reuptake inhibitors in preganancy and the risk of birth defects. N Eng J Med 2007;356(26):2684-2692

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See also: Pregnancy and the Heart: First-Trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects

First-Trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects

Controversy exists about the risk of birth defects after antenatal exposure to selective serotonin-reuptake inhibitors (SSRIs). To elucidate the risk, Louik et al used data from the Stone Epidemiology Center Birth Defects Study to assess the relationship between first-trimester maternal use of SSRIs and the risk of birth defects in infants with and without birth defects [1].

A total of 9,849 infants with malformations and 5,860 control infants comprised the study population. For defects previously found to be associated with SSRI use, the study included 42 comparisons. In general, use of SSRIs was not found to be associated with significantly increased risks of craniosynostosis (115 subjects, two exposed to SSRIs; odd ratio [OR], 0.8; 95% confidence interval [CI], 0.2–3.5) omphalocele (127 subjects, three exposed; OR, 1.4%; 95% CI, 0.4–4.5), or heart defects overall (3,724 subjects, 100 exposed; OR 1.2%; 95% CI, 0.9–1.6). However, associations between the use of individual SSRIs and specific defects demonstrated significant associations between the use of sertraline and omphalocele (OR, 5.7; 95% CI, 1.6–20.7; three exposed subjects) and septal defects (OR, 2.0; 95% CI, 1.2–4.0; 13 exposed subjects) and between the use of paroxetine and right ventricular outflow tract obstruction defects (OR, 3.3; 95% CI, 1.3–8.8; six exposed subjects). For other SSRIs or non-SSRI antidepressants, the risks were not appreciably or significantly increased for other defects. Additional exploratory analysis using 66 comparisons indicated possible associations of paroxetine and sertraline with other specific defects.

The authors concluded that their analysis “did not confirm previously reported associations between overall use of SSRIs and craniosynostosis, omphalocele, or heart defects as a group,” although they did point out that a significant association was found between sertraline use and omphalocele, but noted that the finding was based on only three exposed subjects. Louik et al cautioned that previously unreported associations of the use of certain SSRIs identified in this study warrant careful interpretation. They note that “despite the large size of [their] study overall, [they] had limited numbers to evaluate associations between rare outcomes and rare exposures,” but they point out that certain associations, e.g. sertraline in relation to anal atresia and limb-reduction defects and paroxetine in relation to neural-tube defects and club foot, warrant further exploration. They point out several issues to consider including the fact that recall bias might have been a confounder since mothers of children with defects may recall and report exposures more completely than the mothers with children with no defects; and observational studies, by their nature, may include confounding by uncontrolled factors, e.g., the effect of depression itself, unrelated to drug treatment. Louik et al caution that while their study suggests that specific SSRIs may increase the risk of specific birth defects, additional studies with sufficient power are needed in the future to address these clinical questions.

[1] Louik C, Werler MM, Diaz SH, et al. First-Trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356(26):2675-2683

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Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure

The purpose of this study [1] was to evaluate the relationship of B-type natriuretic peptide (BNP) levels to in-hospital mortality in acute decompensated heart failure (HF) using data from the Acute Decompensated Heart Failure National Registry (ADHERE). This registry collects data on hospitalization from initial presentation until discharge, transfer, or in-hospital death.

From April 2003 through December 2004, 48,629 (63%) of 77,467 patient episodes were identified in 191 hospitals that had BNP assessment within 24 hours of presentation. Patients were grouped by BNP quartiles (Q): Q1 (<430 pg/ml); Q2 (430 to 839 pg/ml); Q3 (840 to 1,729 pg/ml); and Q4 (≥1,730 pg/ml). The analysis included the overall cohort as well as 19,544 patients with reduced (left ventricular ejection fraction [LVEF] (<40%) and 18,164 patients with preserved (LVEF ≥40%) systolic function.

Patients in the BNP Q1, as compared with patients in Q4, were slightly younger (mean age 71.5 vs. 73.9 years), more likely to be women (55% vs. 49%) and less likely to have a history of HF (71% vs. 82%) and more likely to have a history of diabetes (50% vs. 40%), a lower creatinine (1.2 mg/di vs. 1.7 mg/di) and higher LVEF (50% vs. 28%). For the overall cohort, in-hospital mortality risk was 3.6% (1,760 of 48,629). A near-linear relationship was found between BNP and in-hospital mortality (Q1, 1.9%; Q2, 2.8%; Q3, 3.8%; Q4, 6.0%; P<0.0001). BNP quartiles were highly predictive of mortality even after adjustment for age, gender, systolic blood pressure, blood urea, nitrogen, creatinine, sodium, pulse, and dyspnea at rest, Q4 vs. Q1 (adjusted odds ratio 2.23: 95% confidence interval 1.91–2.62, P< 0.0001). In the patients with reduced and preserved systolic function, BNP quartiles independently predicted mortality. Additionally, BNP quartile groups also predicted a number of other clinical outcomes, e.g. the need for mechanical ventilation, length of stay, time in the intensive care unit, and percent hospitalization in the intensive care unit.

The authors conclude that their analysis, using ADHERE data, “demonstrates that the risk of in-hospital mortality can be reliably estimated using BNP obtained on hospital admission.” They point out that this study is the first to show this relationship with in-hospital mortality among this patient population. This study also represents “the largest analysis to date of the predictive capability of a biomarker in patients hospitalized with cardiovascular disease.” The authors note that “current HF guidelines recommend consideration of BNP testing solely for diagnostic purposes, and only in patients where the initial diagnosis is uncertain.” They suggest that their findings lend support to routine assessment of BNP or NT-proBBP levels in order to provide short and long-term prognostic information in patients presenting with acute decompensated HF. The authors pointed out a number of limitations to the study, e.g. results included various commercially available BNP assays rather than results from a single central core laboratory; findings may not apply to patients who receive care in settings substantially different from ADHERE settings; actual risk for patients may be influenced by factors others than those measured in this analysis; no data were available concerning patient status following hospital discharge; and the study cohort may contain multiple admissions for the same patient because ADHERE does not contain specific patient identifiers. The authors suggest that “in light of the demonstration of incremental prognostic information, the BNP assay may be considered for inclusion as part of the assessment of patients presenting with acute decompensated HF.”

[1] Fonarow GC, Peacock WF, Phillips CO, et al. Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure. J Am Coll Cardiol 2007;49(19):1943-1950 

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See also: The Medical Management of Heart Failure: N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure (see p1397)

Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery

This retrospective cohort study [1] uses data from the National Surgical Quality Improvement Program (NSQIP) to examine the prevalence of preoperative anemia and polycythemia and their effects on 30-day post-operative outcomes in elderly patients who underwent major noncardiac surgery.

The NSQIP is a Veterans Health Administration (VHA) initiative that collects data from 132 VHA hospitals nationwide with the goal of improving the quality of surgical care through prospective collection of clinical data on major surgeries and reporting of comparative risk-adjusted postoperative outcomes. Between 1997 and 2004, a total of 326,124 surgery cases for veterans ≥65 years of age were identified. Of this total, 310,311 were included in the study. The primary outcome measure was death within 30 days of the index surgery. A secondary outcome was a composite end point of death or cardiac events (cardiac arrest or Q-wave myocardial infarction) within 30 days of the index surgery. Using preoperative hematocrit levels, the study population was stratified into standard categories of anemia (hematocrit <39.0%), normal hematocrit (39%–53.9%), and polycythemia (hematocrit ≥54%).

This categorization resulted in 42.8% of the population with preoperative anemia, 56.9% with normal preoperative hematocrit values and 0.2% with polycythemia. Increases in 30-day postoperative cardiac event and mortality risks were estimated in relation to each hematocrit point deviation from the normal category. For patients with progressively lower or higher hematocrit values than the reference category, mortality and cardiac event rates increased monotonically with higher rates at both extremes of the hematocrit spectrum. A 1.6% (95% confidence interval, 1.1%–2.2%) increase in the risk of 30-day postoperative mortality was found for every percentage point of hematocrit deviation from the normal range (39.0%–53.9%). The adjusted risk of 30-day postoperative mortality and cardiac morbidity rose when hematocrit levels decreased to less than 39% or went beyond 51%.
The authors concluded that their “results suggest that in elderly patients, even minimal degrees of anemia or polycythemia are associated with a significant increase in the risk of 30-day postoperative mortality and cardiac event.” They note that this increase was seen in the majority of the 14 subgroups analyzed. The notable exceptions were seen in the female populations and those patients who underwent emergent surgery. They speculate that for women this exception may be related to fact that women are known to have different cutoffs for a normal hermatocrit range than men and the limited sample size might have failed to detect a significant relationship between hematocrit and postoperative mortality. The exception for patients with emergent surgery may be related to an overshadowing effect by the severity of the underlying disease and/or the preoperative hematocrit value might not reflect the actual value at the time of the emergency surgery. The authors point out that “[their] results constitute the first large study to associate borderline polycythemia with increased postoperative mortality, starting at the previously considered normal hematocrit values of 51% and greater.” Several study limitations were noted that included: 1) Approximately 21% of the preoperative hematocrit values were obtained more than 4 weeks prior to surgery and, thus, may not accurately reflect hematocrit levels at the time of surgery. 2) Due to the smaller sample size, conclusions for patients with polycythemia may not be as robust as those found for patients with anemia. 3) The casual relationship between low or high hematocrit values and risk of postoperative adverse events could not be determined. They authors emphasize that “among older men undergoing elective surgery, the lowest risk of adverse outcomes was in those with preoperative hematocrit values between 39.0% and 50.9%” and suggest that “future studies should determine if treatment of preoperative anemia and polycythemia improve the postoperative outcomes of this vulnerable population.”

[1] Wu, W-C, Schifftner TL, Henderson WG, et al. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery. JAMA 2007;297(22):2481-2488

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Comparison of effects of ezetimibi/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels

This study [1] examines the anti-inflammatory and lipid-modifying effects of ezetimibe/simvastatin combination therapy on low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (CRP) as compared with simvastatin or atorvastatin monotherapy across the marketed doses in a large cohort of patients with primary hypercholesterolemia.

In order to compare ezetimibe/simvastatin with simvastatin monotherapy, data were combined from 3 similar prospective, randomized, multicenter, double-blind, placebo-controlled,10-arm, parallel-group 12-week trials. Patients in these trials with primary hypercholesterolemia (plasma low-density lipoprotein [LDL] cholesterol concentration of ≥145 to ≤250 mg/dl and triglygerides levels ≤350 mg/dl) were randomized to receive placebo; ezetimmibe 10 mg; ezetimibe 10 mg in addition to simvastatin 10, 20, 40 or 80 mg; or simvastatin 10, 20, 40 or 80 mg. In order to compare ezetimibe/simvastatin with atorvastatin, data were used from a phase III, multicenter, double-blind, randomized, active-controlled, eight-arm parallel-group study in which patients were randomized equally according to LDL cholesterol levels at the second visit 2 (≥130 and <160 mg/dl, ≥160 and <190 and ≥190 mg/dl) to receive ezetimibe/simvastatin 10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80 mg for 6 weeks.

Overall, at baseline the treatment groups were similar in terms of patient demographics, CRP levels, and lipid parameters within and between studies with the exception that atorvastatin study patients had slightly higher median triglyceride levels in comparison to the simvastatin study patients. There were also larger proportions of patients with diabetes and metabolic syndrome in the atorvastatin vs. simvastatin studies. When averaged across doses, significantly greater reductions were found with ezetimibe/simvastatin as compared with simvastatin alone in LDL cholesterol (52.5% vs. 38.0% respectively) and CRP levels (31.0% vs. 14.3% respectively). Similarly, at each individual simvastatin dose, co-administration with ezetimibe produced significant further CRP reductions as compared with simvastatin alone. When pooled across doses and in each milligram-equivalent dose comparison, ezetimibe/simvastatin was significantly more effective at lowering LDL cholesterol than atorvastatin (53.4% vs. 45.3% respectively). When averaged across doses and at each milligram-equivalent statin dose comparison, a similar magnitude of reductions in CRP was found with ezetimibe/simvastatin and atorvastatin.

The authors summarized their findings as follows: 1) “The present analysis showed that, when averaged across the dose range and at each milligram-equivalent statin dose, ezetimibe/simvastatin produced significantly greater reductions in LDL cholesterol relative to simvastatin and atorvastatin monotherapy in patients with hypercholesterolemia.” 2) “The superior LDL cholesterol-lowering efficacy of ezetimibe/simvastatin was consistently observed within all prespecified patient subgroups, including age, gender, race, and BMI, and was independent of baseline presence of diabetes, CHD, and metabolic syndrome.” 3) “…ezetimibe/simvastatin produced significantly greater CRP reductions relative to simvastatin monotherapy and similar CRP reductions compared with atorvastatin monotherapy.” They concluded that “the lipid-modulating and anti-inflammatory effects of ezetimibe/simvastatin provide additional benefits not realized by statin monotherapy alone.”

[1] Pearson T, Ballantyne C, Sisk C, et al. Comparison of effects of ezetimibi/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels. Am J Cardiol 2007;99(12):1706-1713

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