M. Patricia Massicotte

The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: Executive summary

Institutional Affiliations Co-chairs Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, Georgia Institute of Technology and Morehouse School of Medicine; Pamboukian SV: University of Alabama at Birmingham, Birmingham, Alabama; Teuteberg JJ: University of Pittsburgh, Pittsburgh, Pennsylvania Task force chairs Birks E: University of Louisville, Louisville, Kentucky; Lietz K: Loyola University, Chicago, Maywood, Illinois; Moore SA: Massachusetts General Hospital, Boston, Massachusetts; Morgan JA: Henry Ford Hospital, Detroit, Michigan Contributing writers Arabia F: Mayo Clinic Arizona, Phoenix, Arizona; Bauman ME: University of Alberta, Alberta, Canada; Buchholz HW: University of Alberta, Stollery Children’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Deng M: University of California at Los Angeles, Los Angeles, California; Dickstein ML: Columbia University, New York, New York; El-Banayosy A: Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; Elliot T: Inova Fairfax, Falls Church, Virginia; Goldstein DJ: Montefiore Medical Center, New York, New York; Grady KL: Northwestern University, Chicago, Illinois; Jones K: Alfred Hospital, Melbourne, Australia; Hryniewicz K: Minneapolis Heart Institute, Minneapolis, Minnesota; John R: University of Minnesota, Minneapolis, Minnesota; Kaan A: St. Paul’s Hospital, Vancouver, British Columbia, Canada; Kusne S: Mayo Clinic Arizona, Phoenix, Arizona; Loebe M: Methodist Hospital, Houston, Texas; Massicotte P: University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada; Moazami N: Minneapolis Heart Institute, Minneapolis, Minnesota; Mohacsi P: University Hospital, Bern, Switzerland; Mooney M: Sentara Norfolk, Virginia Beach, Virginia; Nelson T: Mayo Clinic Arizona, Phoenix, Arizona; Pagani F: University of Michigan, Ann Arbor, Michigan; Perry W: Integris Baptist Health Care, Oklahoma City, Oklahoma; Potapov EV: Deutsches Herzzentrum Berlin, Berlin, Germany; Rame JE: University of Pennsylvania, Philadelphia, Pennsylvania; Russell SD: Johns Hopkins, Baltimore, Maryland; Sorensen EN: University of Maryland, Baltimore, Maryland; Sun B: Minneapolis Heart Institute, Minneapolis, Minnesota; Strueber M: Hannover Medical School, Hanover, Germany Independent reviewers Mangi AA: Yale University School of Medicine, New Haven, Connecticut; Petty MG: University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota; Rogers J: Duke University Medical Center, Durham, North Carolina

Central venous catheter related thrombosis in children: Analysis of the Canadian Registry of Venous Thromboembolic Complications

BACKGROUND Central venous lines (CVLs) are frequently associated with deep venous thrombosis (DVT) in children; however, little is known about the epidemiologic characteristics or outcome of CVL-related DVT. METHODS The Canadian Childhood Thrombophilia Registry monitored 244 consecutive patients with objectively diagnosed CVL-related DVT for a median duration of 24 months (range 3 months to 7 years). RESULTS The incidence of CVL-related DVT was 3.5 per 10,000 hospital admissions. CVL-related DVTs were more frequent in the upper venous system. Ultrasonography or echocardiography were the most commonly used diagnostic tests (n = 183 patients). Venograms were performed on 82 (34%) patients. A variety of therapies were used. Thirty-nine children had pulmonary emboli, but most were not investigated for pulmonary emboli. Nine (3.7%) children died as a consequence of their thromboembolic disease. Recurrent DVT occurred in 16 (6.5%) children, and postphlebitic syndrome occurred in 23 (9.5%) children. CONCLUSION Currently no uniform guidelines exist for the prevention and management of CVL-related DVT in children. The frequency and clinical consequences of CVL-related DVTs justify controlled trials of primary prophylaxis in children requiring central venous access.

Comparison of 5-mg and 10-mg Loading Doses in Initiation of Warfarin Therapy

Warfarin levels are monitored by measuring the prothrombin time, which responds to reductions in levels of three vitamin K-dependent clotting factors: factors II, VII, and X [1, 2]. During the first 48 hours of treatment, the anticoagulant effect of warfarin is caused mainly by a reduction in the activity of factor VII, which has a half-life of 6 hours. In contrast, the antithrombotic effect of warfarin (which is thought to be caused primarily by a reduction in the activity of factor II) is delayed for as long as 60 hours [3, 4]. Therefore, during the first 48 hours of therapy, the anticoagulant and antithrombotic effects of warfarin may be dissociated. In addition, because the half-life of the vitamin K-dependent anticoagulant protein, protein C, is similar to that of factor VII [5], the early anticoagulant effect of warfarin (which results from reduction of factor VII) could be counteracted by a procoagulant effect (which results from reduction of protein C) [6]. Warfarin treatment is often initiated with a 10-mg loading dose and then reduced to a level that maintains the international normalized ratio (INR) within the therapeutic range. An alternative approach is to start warfarin therapy at a dose of 5 mg, which is the average dose required to maintain an INR of 2.0 to 3.0. Although a 10-mg loading dose produces a more rapid increase in the prothrombin time, this effect is caused largely by a decrease in factor VII levels and therefore may not produce a more rapid antithrombotic effect. The 10-mg loading dose has three potential short-comings. First, if heparin is discontinued as soon as the INR reaches the therapeutic range, thrombus extension may occur. This is because the antithrombotic effect of warfarin may not yet have manifested. Second, elderly or vitamin K-deficient patients may be exposed to an unnecessary risk for bleeding [7-12]. Third, protein C levels can be excessively decreased before the full antithrombotic effect of warfarin has been completely expressed through the reduction of factor II. On the basis of these considerations, we did a study to compare the relative effects of 5- and 10-mg loading doses of warfarin on four surrogate laboratory markers of efficacy and safety. Methods Patients with no contraindications to warfarin who required anticoagulation (target INR, 2.0 to 3.0) were invited to participate in the trial between June and November 1994 at The Hamilton Civic Hospitals (Ontario, Canada). Enrollment was targeted at 50 patients. All patients gave written, informed consent, and the study was approved by the local internal review board. Patients were assigned by random number table to receive warfarin at an initial dose of 5 or 10 mg. Subsequent doses were determined on the basis of nomograms that were developed before the study began through an iterative process. Because the study used laboratory outcomes, patients and health care professionals were not blinded to treatment assignments. Patients were followed for a maximum of 108 hours, during which time they received five doses of warfarin. Blood samples were taken before warfarin therapy was initiated, 12 hours after the first dose of warfarin, and at 24-hour intervals for 5 days. Blood was collected into vacuum-sealed containers that contained 0.102 mol of buffered sodium citrate per liter. To obtain platelet-free plasma, the sample was double centrifuged at 1700 g and frozen at 70C for batch assays [13]. The prothrombin time was measured using Thromborel S (International Sensitivity Index 1.06, Behring Diagnostics, Kanata, Ontario, Canada) and reported as an INR [14]. Heparin does not increase the prothrombin time in patients receiving both warfarin and heparin if this thromboplastin reagent is used. Factors II, VII, IX, and X were assayed by using the one-stage clotting method [15]. Protein C levels were measured by using a functional clotting assay (Dade International, Mississauga, Ontario, Canada) [16]. Treatment of supratherapeutic INRs with vitamin K was left to the discretion of the attending physician. The outcome measures were the time required to achieve an INR of 2.0 to 3.0, the proportion of INR values greater than 3.0, the time course for reductions in levels of factors II and X, and the time course for reduction in protein C levels. Additional data included levels of factors VII and IX. Results Fifty-one consecutive patients were enrolled in the trial. Two were excluded after one dose of warfarin: One died, and one required cardiac catheterization. Twenty-five patients were randomly assigned to receive a 10-mg loading dose of warfarin; 24 were assigned to receive a 5-mg loading dose. The two groups did not differ in age; weight; or frequency of acute thromboembolism, cancer, or surgery during or immediately before the study period. Forty-eight patients received concomitant heparin therapy for all or part of the study period. Beginning on study day 2, the dose of warfarin was adjusted using a nomogram. Warfarin doses in the two groups were similar except on days 1 and 2. The 10-mg group achieved an INR greater than 2.0 statistically significantly sooner than did the 5-mg group (Table 1). At 36 hours, 11 of 25 patients (44% [CI, 34% to 54%]) in the 10-mg group had INRs of 2.0 or greater compared with 2 of 24 patients (8% [CI, 3% to 14%]) in the 5-mg group (P = 0.005). At 60 hours, 9 of 25 patients in the 10-mg group (36% [CI, 17% to 54%]) had INRs greater than 3.0 compared with none of 23 patients in the 5-mg group (P = 0.002). Five patients (4 in the 10-mg group and 1 in the 5-mg group) received vitamin K. These patients had INRs of 4.8 to 9.3 and received 0.5 to 2.0 mg of vitamin K subcutaneously. No patient bled. Table 1. International Normalized Ratios for Patients Assigned to Receive a 5- or 10-mg Loading Dose of Warfarin* Levels of factors II and X declined slowly, and no substantial differences were seen between the 5-and 10-mg groups. In contrast, levels of factor VII and protein C decreased more rapidly and were statistically significantly lower in the 10-mg group than in the 5-mg group at 36 and 60 hours (Figure 1). Figure 1. Plasma levels of coagulation factors in patients receiving a 10-mg (striped bars) or 5-mg (white bars) loading dose of warfarin for each of six time points assessed. top middle bottom Discussion We compared the relative effects of 5- and 10-mg loading doses of warfarin. The time course of reduction in levels of factor II was used as a surrogate end point for clinical efficacy, and excessive elevation of the prothrombin time and unopposed reduction in protein C levels were used as surrogate end points for safety. Patients who received a 10-mg loading dose of warfarin achieved INRs greater than 2.0 more rapidly than did patients who received a 5-mg loading dose. However, because this change in the INR was entirely caused by the early reduction of factor VII levels in the 10-mg group, it may not reflect an antithrombotic effect of warfarin, which is thought to result from a reduction in factor II levels. Two separate experimental observations in rabbits support this idea: The first is the early report of a 5-day delay in achieving an antithrombotic effect with warfarin, although the prothrombin time was first prolonged into the therapeutic range and the level of factor VII was markedly reduced after 2 days of treatment [17]. This observation provides the rationale for overlapping heparin and warfarin therapy for 5 days during the initiation of anticoagulant therapy [17, 18]. The second is the finding that the antithrombotic effect of warfarin is abrogated by the infusion of factor II and (to a lesser extent) factor X [18]. In our study, the rate of reduction in levels of factor II and factor X activity were similar in the 5- and 10-mg groups. On the other hand, the 10-mg loading dose was associated with a significantly more rapid decrease in protein C activity (which decreased before levels of factors X and II were substantially reduced) than that seen in the 5-mg group and an excessive prolongation of the INR. The combination of markedly reduced protein C levels and near-normal levels of factors II and X over the first 2 days of warfarin therapy could produce a hypercoagulable state, and excessive prolongation of the INR could create a higher risk for bleeding. Our study is limited because we used surrogate markers for efficacy and safety. A much larger trial using clinical outcome measures is needed to determine whether the surrogate markers that we used are clinically relevant. Nevertheless, our findings suggest that both regimens result in a therapeutic INR in most patients by day 5 of treatment. From Hamilton Civic Hospital, McMaster University, and The Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada.

Prospective Trial of a Pediatric Ventricular Assist Device

BACKGROUND Options for mechanical circulatory support as a bridge to heart transplantation in children with severe heart failure are limited. METHODS We conducted a prospective, single-group trial of a ventricular assist device designed specifically for children as a bridge to heart transplantation. Patients 16 years of age or younger were divided into two cohorts according to body-surface area (cohort 1, <0.7 m(2); cohort 2, 0.7 to <1.5 m(2)), with 24 patients in each group. Survival in the two cohorts receiving mechanical support (with data censored at the time of transplantation or weaning from the device owing to recovery) was compared with survival in two propensity-score-matched historical control groups (one for each cohort) undergoing extracorporeal membrane oxygenation (ECMO). RESULTS For participants in cohort 1, the median survival time had not been reached at 174 days, whereas in the matched ECMO group, the median survival was 13 days (P<0.001 by the log-rank test). For participants in cohort 2 and the matched ECMO group, the median survival was 144 days and 10 days, respectively (P<0.001 by the log-rank test). Serious adverse events in cohort 1 and cohort 2 included major bleeding (in 42% and 50% of patients, respectively), infection (in 63% and 50%), and stroke (in 29% and 29%). CONCLUSIONS Our trial showed that survival rates were significantly higher with the ventricular assist device than with ECMO. Serious adverse events, including infection, stroke, and bleeding, occurred in a majority of study participants. (Funded by Berlin Heart and the Food and Drug Administration Office of Orphan Product Development; ClinicalTrials.gov number, NCT00583661.).

Berlin Heart EXCOR Pediatric Ventricular Assist Device for Bridge to Heart Transplantation in US Children

Background— Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection. Methods and Results— This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early (<2 months) and late mortality. Of 204 children supported with the EXCOR, the median duration of support was 40 days (range, 1–435 days). Survival at 12 months was 75%, including 64% who reached transplantation, 6% who recovered, and 5% who were alive on the device. Multivariable analysis identified lower weight, biventricular assist device support, and elevated bilirubin as risk factors for early mortality and bilirubin extremes and renal dysfunction as risk factors for late mortality. Neurological dysfunction occurred in 29% and was the leading cause of death. Conclusions— Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.

The use of low molecular weight heparin in pediatric patients: a prospective cohort study.

OBJECTIVE Low molecular weight heparins (LMWHs) offer several advantages over standard anticoagulant therapy (unfractionated heparin/warfarin) including predictable pharmacokinetics, minimal monitoring, and subcutaneous administration. Our objective was to determine the safety and efficacy of LMWHs in children. METHODS A prospective cohort of children treated with the LMWH enoxaparin (Rhone Poulenc Rorer) was monitored at the Hospital for Sick Children, Toronto, Canada, from March 1994 until July 1997. RESULTS There were 146 courses of LMWH administered for treatment and 31 courses for prophylaxis of thromboembolic events (TEs). Clinical resolution of TEs occurred in 94% of children receiving therapeutic doses of LMWH, and 96% of children receiving prophylactic doses of LMWH had no symptoms of recurrent or new TEs. Major bleeding occurred in 5% of children receiving therapeutic doses. Recurrent or new TEs occurred in 1% and 3% of children receiving therapeutic and prophylactic doses of LMWH, respectively. CONCLUSION LMWH appears to be efficacious and safe for both management and prophylaxis of TEs. The results of this cohort study justify a randomized controlled trial comparing LMWH with standard therapy for the management of TEs in children.

A Novel and Rapid Whole-Blood Assay for D-Dimer in Patients With Clinically Suspected Deep Vein Thrombosis

BACKGROUND The clinical utility of using a novel whole blood assay for D-dimer (SimpliRED), alone or in combination with impedance plethysmography (IPG), was investigated in a two-center, prospective cohort study of 214 consecutive patients with clinically suspected deep vein thrombosis (DVT). METHODS AND RESULTS All patients underwent the SimpliRED D-dimer assay, contrast venography, and IPG. According to the results of venography, 43 patients had proximal DVT (popliteal and/or more proximal veins), 10 had isolated calf DVT, and 161 had DVT ruled out. The D-dimer had a sensitivity of 93% for proximal DVT and of 70% for calf DVT, an overall specificity of 77%, and a negative predictive value of 98% for proximal DVT. The sensitivity and specificity of IPG for proximal DVT were 67% and 96%, respectively. When analyzed in combination with the IPG results, it was determined that (1) the combination of a negative D-dimer and a normal IPG had a negative predictive value of 97% for all DVT and of 99% for proximal DVT and occurred in 58% of patients (likelihood ratio, 0.1) and (2) the combination of a positive D-dimer and an abnormal IPG had a positive predictive value of 93% for any DVT and of 90% for proximal DVT and occurred in 14% of patients (likelihood ratio, 42.6). When the D-dimer and IPG results were discordant, it was not possible to exclude or diagnose DVT reliably; discordant results occurred in 28% of patients. CONCLUSIONS The SimpliRED D-dimer assay, which can be performed and interpreted at the bedside within 5 minutes, has great potential in patients with clinically suspected DVT, especially for ruling out DVT, and is complementary to IPG. The assay should be evaluated in large clinical management studies.

Bridging children of all sizes to cardiac transplantation: The initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device

BACKGROUND Beginning in 2000 and accelerating in 2004, the Berlin Heart EXCOR (Berlin Heart Inc Woodlands, TX) became the first pediatric-specific ventricular assist device (VAD) applied throughout North America for children of all sizes. This retrospective study analyzed the initial Berlin Heart EXCOR pediatric experience as a bridge to transplantation. METHODS Between June 2000 and May 2007, 97 EXCOR VADs were implanted in North America at 29 different institutions. The analysis is limited to 73 patients (75%) from 17 institutions, for which retrospective data were available. RESULTS Median age and weight at VAD implant were 2.1 years (range, 12 days-17.8 years) and 11 kg (range, 3-87.6 kg), respectively. The primary diagnoses were dilated cardiomyopathy in 42 (58%), congenital heart disease in 19 (26%), myocarditis in 7 (10%), and other cardiomyopathies in 5 (7%). Pre-implant clinical condition was critical cardiogenic shock in 38 (52%), progressive decline in 33 (45%), or other in 2 (3%). Extracorporeal membrane oxygenation was used as a bridge to EXCOR in 22 patients (30%). Device selection was left VAD (LVAD) in 42 (57%) and biventricular assist devices (BiVAD) in 31 (43%). The EXCOR bridged 51 patients (70%) to transplant and 5 (7%) to recovery. Mortality on the EXCOR was 23% (n = 17) overall, including 35% (11 of 31) in BiVAD vs 14% (6 of 42) in LVAD patients (p = 0.003). Multivariate analysis showed younger age and BiVAD support were significant risk factors for death while on the EXCOR. CONCLUSIONS This limited but large preliminary North American experience with the Berlin Heart EXCOR VAD as a bridge to cardiac transplantation for children of all ages and sizes points to the feasibility of this approach. The prospective investigational device evaluation trial presently underway will further characterize the safety and efficacy of the EXCOR as a bridge to pediatric cardiac transplantation.

Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease A Scientific Statement From the American Heart Association

Thrombosis has long been recognized as a potentially life-threatening complication in children with congenital heart disease (CHD), children with acquired heart disease, and in adults with CHD. High-risk groups include patients with shunt- dependent single ventricles (shunt thrombosis, 8%–12%; 4%

Guidelines for antithrombotic therapy in pediatric patients

Because of the relatively low incidence of TEs in children, the diagnostic and therapeutic approaches used are largely extrapolated from guidelines for adults. Features that differ in children compared with adults include underlying disorders, high incidence of CVL-related DVT in the upper venous system, and response to SH, warfarin, and thrombolytic agents. There is a paucity of information on the risk/benefit ratio of the therapeutic interventions and long-term outcome. Clinical trials are urgently needed to clarify optimal management for pediatric patients with TEs.