Lawrence V. Hofmann

Catheter-directed Therapy for the Treatment of Massive Pulmonary Embolism: Systematic Review and Meta-analysis of Modern Techniques

PURPOSE Systemic thrombolysis for the treatment of acute pulmonary embolism (PE) carries an estimated 20% risk of major hemorrhage, including a 3%-5% risk of hemorrhagic stroke. The authors used evidence-based methods to evaluate the safety and effectiveness of modern catheter-directed therapy (CDT) as an alternative treatment for massive PE. MATERIALS AND METHODS The systematic review was initiated by electronic literature searches (MEDLINE, EMBASE) for studies published from January 1990 through September 2008. Inclusion criteria were applied to select patients with acute massive PE treated with modern CDT. Modern techniques were defined as the use of low-profile devices (< or =10 F), mechanical fragmentation and/or aspiration of emboli including rheolytic thrombectomy, and intraclot thrombolytic injection if a local drug was infused. Relevant non-English language articles were translated into English. Paired reviewers assessed study quality and abstracted data. Meta-analysis was performed by using random effects models to calculate pooled estimates for complications and clinical success rates across studies. Clinical success was defined as stabilization of hemodynamics, resolution of hypoxia, and survival to hospital discharge. RESULTS Five hundred ninety-four patients from 35 studies (six prospective, 29 retrospective) met the criteria for inclusion. The pooled clinical success rate from CDT was 86.5% (95% confidence interval [CI]: 82.1%, 90.2%). Pooled risks of minor and major procedural complications were 7.9% (95% CI: 5.0%, 11.3%) and 2.4% (95% CI: 1.9%, 4.3%), respectively. Data on the use of systemic thrombolysis before CDT were available in 571 patients; 546 of those patients (95%) were treated with CDT as the first adjunct to heparin without previous intravenous thrombolysis. CONCLUSIONS Modern CDT is a relatively safe and effective treatment for acute massive PE. At experienced centers, CDT should be considered as a first-line treatment for patients with massive PE.

Positive contrast visualization of iron oxide‐labeled stem cells using inversion‐recovery with ON‐resonant water suppression (IRON)

In proton magnetic resonance imaging (MRI) metallic substances lead to magnetic field distortions that often result in signal voids in the adjacent anatomic structures. Thus, metallic objects and superparamagnetic iron oxide (SPIO)‐labeled cells appear as hypointense artifacts that obscure the underlying anatomy. The ability to illuminate these structures with positive contrast would enhance noninvasive MR tracking of cellular therapeutics. Therefore, an MRI methodology that selectively highlights areas of metallic objects has been developed. Inversion‐recovery with ON‐resonant water suppression (IRON) employs inversion of the magnetization in conjunction with a spectrally‐selective on‐resonant saturation prepulse. If imaging is performed after these prepulses, positive signal is obtained from off‐resonant protons in close proximity to the metallic objects. The first successful use of IRON to produce positive contrast in areas of metallic spheres and SPIO‐labeled stem cells in vitro and in vivo is presented. Magn Reson Med 58:1072–1077, 2007.

Management of Venous Thromboembolism: A Systematic Review for a Practice Guideline

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism, is a prevalent disease treated by internists. The incidence of VTE is about 7 per 10000 person-years among community residents (1, 2). The condition recurs in about 20% of patients after 5 years, but the rate varies depending on the presence of risk factors (3, 4). A community-wide study from the 1980s reported an incidence rate of pulmonary embolism, with or without DVT, of 2.3 per 10000 (5). Pulmonary embolism limits the short- and long-term survival of patients with VTE (6). Postthrombotic syndrome, another prevalent complication of DVT, may result in life-long morbidity with limb pain and edema (4). Treatment of VTE, with anticoagulants and thrombolytic therapies, is associated with its own risks. Given the prevalence of this condition and its associated morbidity, we reviewed the evidence on optimal treatment of VTE. We sought to summarize the evidence to inform the guidelines developed by the American Academy of Family Physicians and the American College of Physicians for management of patients with VTE. The foundation of this background paper was a previous systematic review of diagnosis and management of VTE (7). For this paper, we addressed the following questions: 1) Is heparin or low-molecular-weight heparin (LMWH) safer and more efficacious for initial treatment of VTE? 2) Is outpatient treatment of VTE safe and effective when compared with inpatient treatment? 3) Is LMWH cost-effective compared with heparin? 4) Does catheter-directed thrombolysis reduce VTE recurrences and the incidence of postthrombotic syndrome? 5) Does use of compression stockings reduce the incidence of postthrombotic syndrome? 6) Do vena cava filters alter the incidence of pulmonary embolism and recurrent DVT? 7) What is the optimal duration of therapy with vitamin K antagonists for VTE? 8) Does evidence support use of LMWH instead of vitamin K antagonists? 9) What is the best therapy for pregnant women with VTE? Methods The methods used in our systematic review are completely described in a detailed evidence report (7). The methods specific to this article are briefly described in the following section. Data Sources To identify relevant articles, we searched literature-indexing systems, including MEDLINE, MICROMEDEX, the Cochrane Controlled Trials Register, and the Cochrane Database of Systematic Reviews, beginning in the 1950s. We also examined reference lists from material identified through the electronic searching and from discussion with experts, and we reviewed recent tables of contents of the pertinent journals. For our previous report, we searched for citations through March 2002. For the current review, we extended the search through June 2006. Data Selection Our criteria for article inclusion are listed in Appendix 1. Two team members independently reviewed the titles and abstracts and excluded those that did not meet the eligibility criteria. For primary literature, the article must have been in English, addressed one of the chosen questions, not involved prevention only, included original human data, and not have been a single-patient case report. For our review of systematic reviews, we used these criteria but also stipulated that the article have included a systematic review, meta-analysis, or cost-effectiveness analysis. Data published only in abstract form were excluded. Each question had additional eligibility criteria. If both reviewers agreed about eligibility, we reviewed the article. In our previous review, we evaluated 64 systematic reviews and 148 primary studies. Of these, 16 systematic reviews and 32 primary studies were relevant to our questions about management of VTE. In our additional searching, we identified another 3 systematic reviews and 13 primary studies on the questions that were in the previous review. We also reviewed 515 additional abstracts to identify 46 primary studies on 5 additional questions covered in this review. Seven studies, previously included for question 7 above, were eliminated; they were published before 1995 and were inconsistent in their use of objective tests for diagnosing VTE. Data Extraction and Quality Assessment A single reviewer abstracted data, and a co-investigator did a secondary review to verify accuracy. We summarized data in evidence tables and assessed the quality of the article by using validated instruments, where appropriate (8). Two authors graded evidence according to the Strength of Recommendation Taxonomy (SORT) developed by a consortium of editors of U.S. family medicine and primary care journals (9). As shown in Table 1, level 1 indicates good-quality patient-oriented evidence, level 2 indicates limited-quality patient-oriented evidence, and level 3 indicates when there is other evidence. Table 1. Assessing Quality of Evidence* Data Synthesis and Analysis We pooled risk ratios across studies about duration of oral anticoagulation and generated CIs around the risk ratios with a random-effects model using the method of DerSimonian and Laird; the estimate of heterogeneity was taken from the Mantel-Haenszel model (Stata 9.0, StataCorp., College Station, Texas). The I2 statistic was calculated as 100%(Qdegrees of freedom)/Q, where Q is the measure of heterogeneity (10). Because the I2 statistic suggested heterogeneity between trials, we do not report pooled results. Role of the Funding Sources The initial systematic review was funded through a contract with the Agency for Healthcare Research and Quality. Members of the American College of Physicians/American Academy of Family Physicians guidelines committee for management of VTE reviewed drafts of this manuscript. Data Synthesis Is Heparin or LMWH Safer and More Efficacious for Initial Treatment of VTE? Numerous trials have compared the safety and efficacy of LWMHs to those of unfractionated heparin in the treatment of VTE. We report on 17 systematic reviews of these trials, published between 1994 and 2003, which reviewed rates of recurrent VTE, major bleeding, or death (1127). Five included only trials of patients with an isolated DVT, 1 review focused on patients with pulmonary embolism with or without concomitant DVT (23), and 1 evaluated the adequacy of dosing of unfractionated heparin (24). Thirteen LMWHs were compared with unfractionated heparin, almost always given intravenously. The LMWHs most often included were enoxaparin (13 reviews), dalteparin (12 reviews), nadroparin (11 reviews), tinzaparin (10 reviews), reviparin (9 reviews), and CY222 (8 reviews). The quality of the systematic reviews was generally good, although only 5 evaluated the quality of trials (14, 17, 23, 26, 28). Description of the search strategies and methods of combining results were weaker in the earlier reviews. Five reviews were descriptive and did not pool results (11, 18, 19, 22, 24). As expected, many of the same articles were included in multiple reviews. The reviews fell into 3 clusters depending on which trials they included. Table 2 summarizes the pooled trial results by these clusters. The cluster containing the most recent trials, cluster C, has odds ratios closer to 1.0 than the cluster containing only the earliest trials. Appendix Table 1 describes the individual trials within each review). Table 2. Systematic Reviews Comparing Low-Molecular-Weight Heparin with Unfractionated Heparin (n= 10)* Appendix Table 1. Individual Studies Included in Systematic Reviews The 5 descriptive reviews had discordant results (11, 18, 19, 22, 24). Among the 11 reviews that pooled trial results (with many trials in common), none showed heparin to be superior to LMWH in preventing recurrent DVT. In addition, patients treated with LMWH had fewer episodes of major bleeding than those treated with unfractionated heparin. All but 1 of 10 reviews showed that LMWH significantly reduced mortality during the 3 to 6 months of follow-up compared with unfractionated heparin (23). Only 4 reviews reported summary results separately for patients with pulmonary embolism; these reviews concluded that LMWH was as effective as unfractionated heparin in this population (16, 18, 23, 29). In summary, evidence is ample that LMWH is superior to unfractionated heparin for the treatment of DVT, particularly for reducing mortality and the risk for major bleeding during initial therapy. The magnitude of benefit from LMWH, while significant in many of these reviews, appears to be lower than was estimated in the earliest reviews. Additional trials are needed to examine the efficacy of LMWH for the treatment of pulmonary embolism, but reviews of existing trials indicate that LMWH is at least as effective as unfractionated heparin for these patients as well. This is level 1 evidence. Is Outpatient Treatment of VTE Safe and Effective When Compared with Inpatient Treatment? Thirteen studies compared the outcomes of patients with VTE treated with LMWH administered at home with outcomes of those treated with unfractionated heparin in the hospital (3042). Four of these were randomized trials (3032, 42); 9 were cohort studies. An additional 5 studies, including 2 randomized trials (43, 44), compared outcomes and costs for patients receiving LMWH at home with those for patients receiving LWMH in the hospital (4347). The studies used subcutaneous enoxaparin, nadroparin, tinzaparin, or dalteparin at varying dosages, and then an oral anticoagulant during follow-up. At least 8 studies allowed a brief inpatient admission for stabilization of patients randomly assigned to the outpatient group. Three studies permitted enrollment of patients with concomitant pulmonary embolism (38, 41, 47), while 1 prospective cohort study required stable patients with pulmonary embolism (45). The remaining studies excluded these patients. Inclusion criteria were restrictiveinvestigators screened far more patients than they enrolled. Most studies excluded patients with previous VTE, thrombophilic c

Reporting Standards for Endovascular Treatment of Lower Extremity Deep Vein Thrombosis

Suresh Vedantham, MD, Clement J. Grassi, MD, Hector Ferral, MD, Nilesh H. Patel, MD, Patricia E. Thorpe, MD, Vittorio P. Antonacci, MD, Bertrand M. Janne d’Othée, MD, Lawrence V. Hofmann, MD, John F. Cardella, MD, Sanjoy Kundu, MD, Curtis A. Lewis, MD, MBA, Marc S. Schwartzberg, MD, Robert J. Min, MD, and David Sacks, MD, for the Technology Assessment Committee of the Society of Interventional Radiology

Safety and Efficacy of Percutaneous Fiducial Marker Implantation for Image-guided Radiation Therapy

PURPOSE To evaluate the safety and technical success rate of percutaneous fiducial marker implantation in preparation for image-guided radiation therapy. MATERIALS AND METHODS From January 2003 to January 2008, we retrospectively reviewed 139 percutaneous fiducial marker implantations in 132 patients. Of the 139 implantations, 44 were in the lung, 61 were in the pancreas, and 34 were in the liver. Procedure-related major and minor complications were documented. Technical success was defined as implantation enabling adequate treatment planning and computed tomographic simulation. RESULTS The major and minor complication rates were 5% and 17.3%, respectively. Pneumothorax after lung implantation was the most common complication. Pneumothoraces were seen in 20 of the 44 lung implantations (45%); a chest tube was required in only seven of the 44 lung transplantations (16%). Of the 139 implantations, 133 were successful; in six implantations (4.3%) the fiducial markers migrated and required additional procedures or alternate methods of implantation. CONCLUSIONS Percutaneous implantation of fiducial marker is a safe and effective procedure with risks that are similar to those of conventional percutaneous organ biopsy.

Comparison of Urokinase, Alteplase, and Reteplase for Catheter-directed Thrombolysis of Deep Venous Thrombosis

PURPOSE To compare the efficacy, safety, and costs associated with catheter-directed thrombolysis with urokinase (UK) and the recombinant agents alteplase (tissue plasminogen activator [TPA]) and reteplase (recombinant plasminogen activator [RPA]) in the treatment of symptomatic deep vein thrombosis (DVT). MATERIALS AND METHODS The authors conducted a retrospective analysis on 74 patients (82 limbs) who underwent treatment for DVT. Thrombosed extremities were treated with either urokinase with therapeutic heparin dosing (UK group; 38 limbs), alteplase with subtherapeutic heparin dosing (TPA group; 32 limbs), or reteplase with subtherapeutic heparin dosing (RPA group; 12 limbs). Infusion times, dosages, drug costs, success rates, and complications were compared among the groups. RESULTS Gender, age, disease location, duration of symptoms, and use of additional interventional therapies did not differ statistically among the three cohorts. Median hourly infused doses, total doses, infusion times, drug costs, and success rates per limb were: UK, 11.3 (10(4)) U/hour, 4.361 million U, 40.6 hours, US dollars 6577, 97.4%; TPA, 0.57 mg/hour, 21.6 mg, 30.8 hours, US dollars 488, 96.9%; RPA, 0.74 U/hour, 21.4 U, 24.3 hours, US dollars 1787, 100.0%. Major and overall complication rates were: UK, 5.3% and 10.5%; TPA, 3.1% and 12.5%; RPA, 8.3% and 16.7%. Infusion times, success rates, and complications were not statistically different among the three groups. Alteplase and reteplase were significantly less expensive than urokinase (P <.001 and P <.01, respectively). CONCLUSION Catheter-directed thrombolysis for the treatment of DVT is safe and effective, regardless of the agent used. However, the new recombinant agents are significantly less expensive than urokinase.

Computed Tomography-Guided Percutaneous Needle Biopsy of Pulmonary Nodules: Impact of Nodule Size on Diagnostic Accuracy

PURPOSE This study was undertaken to compare the diagnostic accuracy and complication rate of computed tomography (CT)-guided percutaneous lung biopsies of lung nodules<or=1.5 cm versus >1.5 cm in diameter. PATIENTS AND METHODS A total of 139 patients (age range, 18-89 years; mean, 62.5 years) underwent CT-guided percutaneous fine-needle aspiration biopsy or 20-gauge core biopsy using an automated biopsy gun. In 37 patients, the lung nodule measured <or=1.5 cm (mean, 1.1 cm), and in 102 patients, the lung nodule was >1.5 cm (mean, 2.8 cm). Diagnostic accuracy was determined by cytopathology results. Major and minor complications were documented. RESULTS Overall diagnostic accuracy, pneumothorax rate, and thoracostomy tube insertion rates were 67.6%, 34.5%, and 5%, respectively. Of the 98 patients with malignancy, 77 patients (78.6%) had a definite diagnostic biopsy. Overall, nodules>1.5 cm were statistically more likely to result in a diagnostic specimen (73.5%) than nodules<or=1.5 cm (51.4%; P=.012). Similarly, diagnostic accuracy for malignancy was higher in nodules>1.5 cm than in those<or=1.5 cm (81.3% vs. 69.6%); however, this was not statistically significant. There was no correlation between nodule size and the incidence of complications. CONCLUSION Overall, diagnostic accuracy of CT-guided percutaneous lung biopsy of lung nodules<or=1.5 cm is slightly lower than that of nodules>1.5 cm. However, the diagnostic accuracy for malignancy is high in both groups, with a low risk of complications.

Catheter-Directed Embolectomy, Fragmentation, and Thrombolysis for the Treatment of Massive Pulmonary Embolism After Failure of Systemic Thrombolysis

PURPOSES The standard medical management for patients in extremis from massive pulmonary embolism (PE) is systemic thrombolysis, but the utility of this treatment relative to catheter-directed intervention (CDI) is unknown. We evaluated the effectiveness of CDI as part of a treatment algorithm for life-threatening PE. METHODS A retrospective review was performed on 70 consecutive patients with suspected acute PE over a 10-year period (from 1997 to 2006) who had been referred for pulmonary angiography and/or intervention. The criteria for study inclusion were patients who received CDI due to angiographically confirmed massive PE and hemodynamic shock (shock index, > or = 0.9). CDI involved suction embolectomy and fragmentation with or without catheter thrombolysis. RESULTS Twelve patients were treated with CDI. There were seven men and five women (mean age, 56 years; age range, 21 to 80 years). Seven patients (58%) were referred for CDI after failing systemic infusion with 100 mg of tissue plasminogen activator, and five patients (42%) had contraindications to systemic thrombolysis. Catheter-directed fragmentation and embolectomy were performed in all patients (100%). Additionally, catheter-guided thrombolysis was performed in eight patients (67%). Technical success was achieved in 12 of 12 cases (100%). There were no major procedural complications (0%). Significant hemodynamic improvement (shock index, < 0.9) was observed in 10 of 12 cases (83%). The remaining two patients (17%) died secondary to cardiac arrest within 24 h. Ten of 12 patients (83%) survived and remained stable until hospital discharge (mean duration, 20 days; range, 3 to 51 days). CONCLUSION In the setting of hemodynamic shock from massive PE, CDI is potentially a life-saving treatment for patients who have not responded to or cannot tolerate systemic thrombolysis.

MR-trackable intramyocardial injection catheter

There is growing interest in delivering cellular agents to infarcted myocardium to prevent postinfarction left ventricular remodeling. MRI can be effectively used to differentiate infarcted from healthy myocardium. MR‐guided delivery of cellular agents/therapeutics is appealing because the therapeutics can be precisely targeted to the desired location within the infarct. In this study, a steerable intramyocardial injection catheter that can be actively tracked under MRI was developed and tested. The components of the catheter were arranged to form a loopless RF antenna receiver coil that enabled active tracking. Feasibility studies were performed in canine and porcine myocardial infarction models. Myocardial delayed‐enhancement (MDE) imaging identified the infarcted myocardium, and real‐time MRI was used to guide left ventricular catheterization from a carotid artery approach. The distal 35 cm of the catheter was seen under MRI with a bright signal at the distal tip of the catheter. The catheter was steered into position, the distal tip was apposed against the infarct, the needle was advanced, and a bolus of MR contrast agent and tissue marker dye was injected intramyocardially, as confirmed by imaging and postmortem histology. A pilot study involving intramyocardial delivery of magnetically labeled stem cells demonstrated the utility of the active injection catheter system. Magn Reson Med 51:1163–1172, 2004.

Incorporating Cone-beam CT into the Treatment Planning for Yttrium-90 Radioembolization

PURPOSE To prepare for yttrium-90 ((90)Y) microsphere radioembolization therapy, digital subtraction angiography (DSA) and technetium- 99m-labeled macroaggregated albumin ((99m)Tc MAA) scintigraphy are used for treatment planning and detection of potential nontarget embolization. The present study was performed to determine if cone-beam computed tomography (CBCT) affects treatment planning as an adjunct to these conventional imaging modalities. MATERIALS AND METHODS From March 2007 to August 2008, 42 consecutive patients (21 men, 21 women; mean age, 59 years; range, 21-75 y) who underwent radioembolization were evaluated by CBCT in addition to DSA and (99m)Tc MAA scintigraphy during treatment planning, and their records were retrospectively reviewed. The contrast-enhanced territories shown by CBCT with selective intraarterial contrast agent administration were used to predict intrahepatic and possible extrahepatic distribution of microspheres. RESULTS In 22 of 42 cases (52%), extrahepatic enhancement or incomplete tumor perfusion seen on CBCT affected the treatment plan. In 14 patients (33%), the findings were evident exclusively on CBCT and not detected by DSA. When comparing CBCT versus (99m)Tc MAA scintigraphy, CBCT showed eight cases of extrahepatic enhancement (19%) that were not evident on (99m)Tc MAA imaging. CBCT findings directed the additional embolization of vessels or repositioning of the catheter for better contrast agent and microsphere distribution. One case of gastric ulcer from nontarget embolization caused by reader error was observed. CONCLUSIONS CBCT can provide additional information about tumor and tissue perfusion not currently detectable by DSA or (99m)Tc MAA imaging, which should optimize (90)Y microsphere delivery and reduce nontarget embolization.