N-acetylcysteine in the prevention of contrast-induced nephropathy: publication bias perpetuated by meta-analyses.

BACKGROUND: The use of N-acetylcysteine for the prevention of contrast-induced nephropathy has been the subject of numerous clinical trials and meta-analyses. We sought to examine the possibility of a publication bias and whether meta-analyses have magnified any potential publication bias. METHODS: We performed a Medline search and a manual search to identify published manuscripts. We also manually searched contemporaneous major cardiology scientific meetings to identify abstracts. We included only randomized controlled clinical trials. We pooled the results of abstracts and manuscripts separately and combined, calculating an odds ratio (OR). We analyzed meta-analyses according to the proportions of manuscripts and abstracts that they included and compared their calculated ORs to the OR of all available contemporaneous data. Our analysis spanned the time from the publication of the first manuscript on this topic through June 2006. RESULTS: Throughout the study period, the published manuscripts presented a treatment-effect estimate that was more optimistic than that found in unpublished abstracts. There was a temporal trend in that the estimate of treatment effect was greatest with early publications, which diminished as additional data became available. The profile of the journal (as assessed by impact factor) in which a manuscript was published was not related to the quality of the manuscript. However, studies reaching a positive conclusion were published in journals with higher impact factors compared with studies reaching negative conclusions. Meta-analyses included a substantially greater proportion of published manuscripts versus unpublished abstracts and provided more optimistic assessments of treatment effect than would have been derived had all available data been assessed. CONCLUSIONS: There was a significant publication bias that persisted throughout the life cycle of this clinical question. The bias was further amplified by meta-analyses.

Markers of cardiac collagen turnover are similar in patients with mild and more severe symptoms of heart failure.

Cardiac fibrosis plays an important role in the pathophysiology of heart failure. The authors sought to determine whether biomarkers of cardiac fibrosis for milder clinical degrees of heart failure are comparable to those of more advanced disease. Procollagen types I and III amino-terminal peptides (PINP and PIIINP) and type I collagen telopeptide (ICTP) were compared between aldosterone-antagonistnaive patients with heart failure and New York Heart Association class I or II (n=22/23) and class III or IV (n=42/3) symptoms. Median (interquartile) range concentrations of PINP (63.3 [44.2-88.8] vs 48.6 [37.8-74.9] microg/L), ICTP (7.0 [5.4-16.8] vs 6.5 [4.7-12.7] microg/L), and PIIINP (4.7 [3.2-7.0] vs 4.7 [2.9-7.3] microg/L) were comparable between patients with mild and moderate to severe disease, respectively. These data suggest that patients with mild heart failure may have similar degrees of cardiac fibrosis to patients with more severe disease and support the examination of antifibrotic therapy, including aldosterone antagonists, in milder degrees of heart failure.

Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial.

BACKGROUND: We were concerned that a fixed rather than a weight-based dosing regimen of dalteparin sodium to prevent venous thromboembolism (VTE) might result in decreased efficacy in obese patients and decreased safety in elderly patients. METHODS: We retrospectively performed subgroup analyses using the database from the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients (PREVENT) Trial, a study of 3706 hospitalized, medically ill patients randomized to receive either dalteparin sodium, 5000 U/d, or placebo. The primary end point was a composite of symptomatic VTE, fatal pulmonary embolism, sudden death, or asymptomatic proximal deep venous thrombosis by day 21. Obesity was defined as a body mass index (calculated as weight in kilograms divided by the square of height in meters) of 30 or greater for men and 28.6 or greater for women. RESULTS: Overall, 1118 patients (30.4%) were obese and 1226 (33.3%) were 75 years or older. In obese patients, the primary end point occurred in 2.8% of the dalteparin and in 4.3% of the placebo groups (relative risk, 0.64; 95% confidence interval [CI], 0.32-1.28). In patients 75 years or older, the primary end point was reported in 4.2% of the dalteparin and in 8.0% of the placebo groups (relative risk, 0.52; 95% CI, 0.31-0.87). The dalteparin effect for the primary end point (odds ratio, 0.51; 95% CI, 0.32-0.82) was not attenuated when adjusted for age, sex, obesity, history of VTE, and varicose veins. Dalteparin was not associated with an increase in major hemorrhage by day 21 in obese (0% vs 0.7% placebo; P>.99) and in elderly (1.1% vs 0.7%; P=.12) patients. CONCLUSION: Our findings suggest that a fixed low dose of dalteparin sodium of 5000 U/d is effective and safe in preventing VTE in obese and elderly hospitalized medical patients.

Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.

BACKGROUND: Considerable variability exists in the use of pharmacological thromboprophylaxis among acutely ill medical patients, partly because clinically relevant end points have not been fully assessed in this population. We undertook an international, multicenter, randomized, double-blind, placebo-controlled trial using clinically important outcomes to assess the efficacy and safety of dalteparin in the prevention of venous thromboembolism in such patients. METHODS AND RESULTS: Patients (n=3706) were randomly assigned to receive either subcutaneous dalteparin 5000 IU daily or placebo for 14 days and were followed up for 90 days. The primary end point was venous thromboembolism, defined as the combination of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, and asymptomatic proximal deep vein thrombosis detected by compression ultrasound at day 21 and sudden death by day 21. The incidence of venous thromboembolism was reduced from 4.96% (73 of 1473 patients) in the placebo group to 2.77% (42 of 1518 patients) in the dalteparin group, an absolute risk reduction of 2.19% or a relative risk reduction of 45% (relative risk, 0.55; 95% CI, 0.38 to 0.80; P=0.0015). The observed benefit was maintained at 90 days. The overall incidence of major bleeding was low but higher in the dalteparin group (9 patients; 0.49%) compared with the placebo group (3 patients; 0.16%). CONCLUSIONS: Dalteparin 5000 IU once daily halved the rate of venous thromboembolism with a low risk of bleeding.

Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients.

The clinical importance of asymptomatic proximal and distal deep vein thrombosis (DVT) remains uncertain and controversial. The aim of this retrospective, post-hoc analysis was to examine mortality and risk factors for development of proximal DVT in hospitalized patients with acute medical illness who were recruited into a randomized, prospective clinical trial of thromboprophylaxis with dalteparin (PREVENT). We analyzed 1738 patients who had not sustained a symptomatic venous thromboembolic event by Day 21 and who had a complete compression ultrasound of the proximal and distal leg veins on Day 21. We examined the 90-day mortality rates in patients with asymptomatic proximal DVT (Group I, N=80), asymptomatic distal DVT (Group II, N=118) or no DVT (Group III, N=1540). The 90-day mortality rates were 13.75%, 3.39%, and 1.92% for Groups I-III, respectively. The difference in mortality between Group I and Group III was significant (hazard ratio 7.63, 95% CI=3.8-15.3; p <0.0001), whereas the difference between Groups II and III did not reach significance (hazard ratio 1.36, 95% CI=0.41-4.45). The association of asymptomatic proximal DVT with increased mortality remained highly significant after adjusting for differences in baseline demographics and clinical variables. Risk factors significantly associated with the development of proximal DVT included advanced age (p=0.0005), prior DVT (p=0.001), and varicose veins (p=0.04). In conclusion, the high mortality rate in patients with asymptomatic proximal DVT underscores its clinical relevance and supports targeting of asymptomatic proximal DVT as an appropriate endpoint in clinical trials of thromboprophylaxis.

Risks of noncardiac surgery after coronary stenting.

An increased risk of major complications for noncardiac surgery after coronary stenting has been suggested. We retrospectively reviewed all cases of coronary stents from 1999 to 2003 with subsequent surgery to assess major adverse cardiovascular events (MACEs), including myocardial infarction, stent thrombosis, major bleeding, and death. Among the 56 patients identified, 8 developed MACEs; 38% underwent surgery < or =14 days after stenting, and 62% underwent surgery 15 to 42 days after stenting. No patient developed MACEs if surgery occurred >42 days after stenting. Among patients who developed MACEs, 77% of surgeries were elective, 19% were urgent, and only 4% were emergency. Noncardiac surgery 6 weeks after coronary stenting is associated with a high risk of MACEs.

Left atrial appendage closure with amplatzer septal occluder in patients with atrial fibrillation: CT-based morphologic considerations.

OBJECTIVES: This study analyzed left atrial appendage (LAA) dimensions measured by computed tomography (CT) scan to define optimal selection of Amplatzer septal occluders for LAA closure. BACKGROUND: Patients with atrial fibrillation and contraindications to anticoagulation have limited options for LAA closure until approval of dedicated closure devices. Off-label use of available cardiac devices represents one option. METHODS: All consecutive patients undergoing LAA occlusion with an Amplatzer device who had undergone CT scanning were included. Numerous dimensions of the LAA were measured in order to optimally select a device that would simultaneously provide good anchoring and good sealing of the LAA. RESULTS: Of 11 eligible patients, 8 had successful Amplatzer deployment. In all successful cases, the putative "left atrial" disc was well matched to the "landing zone" of the LAA, proving good anchoring. The proximal (putative "right atrial") disc was sized to cover the LAA orifice. The failed cases shed light on procedural variables. CONCLUSIONS: LAA occlusion with an Amplatzer device is a viable option for patients with atrial fibrillation and contraindications to anticoagulation. Careful attention to LAA dimensions as measured on CT scan assists in optimizing device selection.

A comparative trial of controlled-onset, extended-release verapamil, enalapril, and losartan on blood pressure and heart rate changes.

BACKGROUND: The excess morning risk of myocardial infarction and stroke may be attributable to the rapid rise in blood pressure (BP) and heart rate in the hours after awakening. The aim of this randomized, double-blinded, placebo-controlled, multicenter study was to compare once-daily, controlled-onset, extended-release (COER-24) verapamil to enalapril and losartan on BP and heart rate during the postawakening morning phase as well as throughout the 24-h period. METHODS: A total of 406 patients were randomized to an 8-week forced-titration period with one of the following: 1) COER-24 verapamil 240 mg/day titrated to 360 mg/day; 2) enalapril 10 mg/day titrated to 20 mg/day, 3) losartan 50 mg/day titrated to 100 mg/day, or 4) placebo. Office BP and heart rate and ambulatory 24-h BP monitoring was performed at baseline, 4 weeks, and 8 weeks. RESULTS: Each active treatment, as compared with placebo, lowered BP both during the morning hours as well as the entire 24-h period. COER-24 verapamil was more effective in lowering morning systolic (-16.6 mm Hg) and diastolic (-11.9 mm Hg) BP than either enalapril or losartan (P < .001). For the entire 24-h period, the effects of COER-24 verapamil (-11.6/-8.4 mm Hg) were comparable to enalapril (- 13.4/-8.3 mm Hg; P = NS). Losartan achieved a similar 24-h effect on systolic pressure (-9.3 mm Hg) but was less effective on diastolic pressure (-5.4 mm Hg; P = .004 v COER-verapamil). Unlike losartan or enalapril, COER-24 verapamil was the only treatment to lower the heart rate over both the 24-h period (-4.6 beats/min; P < .001) and during waking hours (-4.6 beats/min; P < .001). A blunted rate of rise in BP, heart rate, and rate-pressure product occurred during the postawakening period with COER-verapamil (P = .03) but not with either of the other treatment arms. Lastly, the decline in BP at night was similar for COER-verapamil and losartan and greater with enalapril (P = .014) CONCLUSIONS: COER-24 verapamil produces changes in BP and pulse that more closely match the normal circadian hemodynamic rhythms than either do enalapril or losartan.

Effect of stents in reducing restenosis in small coronary arteries: a meta-analysis.

The ability of stents to reduce restenosis was established in larger coronary arteries. Clinical trials of stenting in smaller vessels have yielded conflicting results due in part to their sample sizes. The aim of this meta-analysis was to increase the statistical power by pooling data from these clinical trials. Trials were identified from Medline search, review of recent cardiology meetings' abstracts, and manual review of bibliographies. Studies were included if they were prospective randomized controlled trials. Endpoints examined included a dichotomized definition of angiographic restenosis, target lesion revascularization (TLR), target vessel revascularization (TVR), or any repeat revascularization. Pooling of data was performed by calculating a Mantel-Haenszel odds ratio (OR). The analysis included 2,598 patients enrolled in eight clinical trials. Stenting significantly reduced restenosis (OR = 0.62; 95% CI = 0.61-0.63). Concordantly, stenting reduced TLR (OR = 0.49), TVR (OR = 0.90), and any revascularization (OR = 0.48). This meta-analysis supports the hypothesis that stenting reduces restenosis in small coronary arteries as well as in larger coronary arteries. The apparent discordant result of individual clinical trials was due in part to underpowering related to small sample sizes.

A meta-analysis of percutaneous vascular closure devices after diagnostic catheterization and percutaneous coronary intervention.

BACKGROUND: While each of the available femoral arterial sealing devices claims equivalent safety to manual compression following invasive cardiac procedures, these claims are based on small, underpowered studies. Our aim was to increase the ability to detect a clinically meaningful difference by performing a meta-analysis. METHODS: We identified studies via Medline and manual searches and selected studies that were prospective, randomized clinical trials for inclusion. Pooling of data was performed by calculation of the Mantel-Haenszel odds ratio (OR) and the variance of the OR was estimated using the method of Robins, Greenland and Breslow. RESULTS: Sixteen studies enrolling 5,048 patients were included in the analysis. The pooled OR was 0.89 (95% confidence interval, 0.86-0.91), indicating a significant decrease in risk by devices. Excluding hematomas from the endpoint resulted in a concordant result. Angio-Seal was associated with a significant reduction in risk (OR, 0.51) and Perclose had a neutral result (OR, 1.0), whereas Vasoseal had an increased risk of complications (OR, 1.18). CONCLUSION: Overall, sealing devices may be associated with a reduction in risk of complications following invasive coronary procedures, but significant differences may exist among individual devices. These potential differences need to be explored in randomized, controlled clinical trials.

Thromboprophylaxis in immobilized medical patients.

Venous thromboembolism accounts for a large number of preventable deaths. The majority of these events occur in medical patients, but medical thromboprophylaxis remains underutilised in this population. The purpose of this review is to examine the results of recent clinical trials of low molecular weight heparins in the prevention of venous thromboembolic disease in medical patients. The available data make a compelling case in favor of widespread use of low molecular weight heparin in medical patients.

Assessment of a novel software tool in the selection of aortic valve prosthesis size for transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) can be complicated by significant paravalvular leak (PVL). Optimal selection of TAVR prosthesis size can minimize the risk of clinically significant PVL. The aim of this study was to assess the utility of a proprietary software package, HeartNavigator (Philips), in selecting TAVR prosthesis to minimize PVL. METHODS: All consecutive TAVR patients were considered for inclusion. HeartNavigator assessment was compared to three conventional (average, area-based, and circumference- based) computed tomography (CT) scan measurements of annulus diameter. The primary endpoint was clinically important (≥2+) aortic insufficiency (AI). RESULTS: Fifty-six patients were suitable for analysis. The incidence of clinically important AI was 25%. The overall predictive value was identical for HeartNavigator (80.4%) and the three conventional CT parameters. Each method correctly identified a majority of patients destined for AI. Although HeartNavigator accurately identified a numerically greater portion of patients with AI (64.3%), this was not significantly different from the conventional CT parameters. CONCLUSIONS: As compared to conventional CT-based measurements, HeartNavigator offers an accurate method for selecting TAVR prostheses, comparable to conventional CT measurements.

Outcome of heart transplantation in patients with sarcoid cardiomyopathy.

BACKGROUND: Cardiac transplantation has been utilized increasingly in patients with sarcoid cardiomyopathy. We sought to review outcomes in patients with sarcoidosis who had heart transplants and compared their outcomes with those of transplanted patients without sarcoidosis. METHODS: We retrospectively reviewed the United Network for Organ Sharing (UNOS) database to assess the survival of patients with sarcoidosis who were treated by heart transplantation. RESULTS: Over an 18-year period, 65 patients (40 men and 25 women) with sarcoidosis underwent orthotopic heart transplantation. There were 4 operative deaths and 12 late deaths at a mean follow-up of 40 months. One-year post-transplant survival was significantly better for sarcoid patients receiving orthotopic transplantation compared with contemporaneous patients receiving transplantation for all other diagnoses (87.7% vs 84.5%, p = 0.030). CONCLUSIONS: Patients with sarcoidosis undergoing orthotopic heart transplant had better short- and intermediate-term survival than the majority of heart transplant recipients. The diagnosis of sarcoidosis should not disqualify potential transplant candidates.

Thromboprophylaxis with dalteparin in medical patients: which patients benefit?

It is unclear whether thromboprophylaxis produces a consistent risk reduction in different subgroups of medical patients at risk from venous thromboembolism. We performed a retrospective, post hoc analysis of 3706 patients enrolled in the PREVENT study. Patients were at least 40 years old with an acute medical condition requiring hospitalization for at least 4 days and had no more than 3 days of immobilization prior to enrolment. Patients received either subcutaneous dalteparin (5000 IU) or placebo once daily. The primary end point was the composite of symptomatic deep vein thrombosis (DVT), pulmonary embolism, asymptomatic proximal DVT, or sudden death. Primary diagnosis subgroups were acute congestive heart failure, acute respiratory failure, infectious disease, rheumatological disorders, or inflammatory bowel disease. All patients, except those with congestive heart or respiratory failure, had at least one additional risk factor for venous thromboembolism. A risk reduction was shown in patients receiving dalteparin versus placebo. The relative risk (RR) was 0.73 in patients with congestive heart failure, 0.72 for respiratory failure, 0.46 for infectious disease, and 0.97 for rheumatological disorders. The RR was 0.52 in patients aged > or = 75 years, 0.64 in obese patients, 0.34 for patients with varicose veins, and 0.71 in patients with chronic heart failure. No subgroup had a significantly different response from any other. Importantly, multivariate analysis showed that all patient groups benefited from thromboprophylaxis with dalteparin. Our findings, therefore, support the broad application of thromboprophylaxis in acutely ill hospitalized medical patients.

Rationale and design of a clinical trial of a low-molecular-weight heparin in preventing clinically important venous thromboembolism in medical patients: the prospective evaluation of dalteparin efficacy for prevention of venous thromboembolism in immobilized patients trial (the PREVENT study).

The utility of low-molecular-weight heparin (LMWH) in the prophylaxis of venous thromboembolic disease has been examined using the surrogate endpoint of venographically identified thrombi. The largest portion of these thrombi were asymptomatic calf-vein thrombi. The clinical relevance of this observation is a matter of debate. The present study is designed to evaluate the impact of an LMWH on clinically important endpoints. The current study is a randomized, prospective, double-blinded, multicenter, multinational, controlled clinical trial comparing dalteparin with placebo in moderately high-risk hospitalized medical patients. A total of 3300 patients will be randomized to receive either 5,000 IU per day of dalteparin or placebo for 14 days. Patients will undergo appropriate evaluation for any symptomatic episodes and all patients will undergo a bilateral compression ultrasound (CUS) on day 21 to search for asymptomatic proximal thrombi. The primary endpoint is the combination of objectively confirmed symptomatic deep vein thrombi (DVT), fatal or non-fatal pulmonary emboli, all proximal DVT, and sudden death. This study will be the first study to examine clinically important endpoints in evaluating the effect of a LMWH in hospitalized medical patients. This study also is the first study to use CUS rather than venography in concordance with contemporary medical practice. This trial is thus designed to address this important question in a clinically relevant manner.