Vena cava filters in hospitalised patients with chronic obstructive pulmonary disease and pulmonary embolism.

In view of the high case fatality rates of patients with chronic obstructive pulmonary disease (COPD) who have pulmonary embolism (PE) we speculated that such patients might benefit from vena cava filters. To test this hypothesis we assessed the database of the Nationwide Inpatient Sample. From 1998-2009, 440,370 patients were hospitalised with PE and COPD who were not in shock or ventilator-dependent and did not receive thrombolytic therapy or pulmonary embolectomy. In-hospital all-cause case fatality rate among those with filters was 5,890 of 68,800 (8.6%) (95% confidence interval [CI] = 8.4-8.8) compared with 38,960 of 371,570 (10.5%) (95% CI = 10.4-10.6) (p<0.0001) who did not receive filters. Case fatality rate was age-dependent. Only those who were older than aged 50 years had a lower in-hospital all-cause case fatality rate with filters. Among such patients, absolute risk reduction was 2.1% (95% CI = 1.9-2.3). The greatest reduction of case fatality rate with vena cava filters was shown in patients >aged 80 years, 11,720 of 81,600 (14.4%) compared with 1,570 of 17,220 (9.1%) (p<0.0001). In conclusion, a somewhat lower in-hospital all-cause case fatality rate was shown with vena filters in stable patients with PE >aged 50 years who also had COPD. The benefit was greatest in elderly patients. The benefit in terms of a decreased case fatality rate would seem to outweigh the risks of vena cava filters in such patients.

Effect of compression stockings on venous blood velocity and blood flow.

The effects of graduated compression stockings (GCS) on venous blood velocity have not been established. In healthy subjects, most investigations showed no effect on blood velocity, but mixed results have been reported. In this investigation we to test the hypothesis that popliteal blood velocity is increased by properly fitted GCS. Time average peak velocity in the popliteal vein, as well as time average mean velocity, vein diameter and mean volumetric flow were measured by pulsed wave Doppler ultrasound in 25 healthy male volunteers without compression stockings and repeated with fitted thigh-length compression stockings. Measurements were obtained while supine and while sitting at rest and during ankle exercise. Thigh-length GCS did not increase popliteal vein blood velocity, diameter, or volumetric blood flow while supine or sitting, with or without ankle exercise.

Noninvasive imaging of the coronary arteries.

A reliable noninvasive imaging method for significant coronary artery stenosis would have enormous implications related to cost of diagnosis and enhanced patient safety. Cardiac motion and calcified plaques, in the past, rendered a substantial number of computed tomographic (CT) images of the coronary arteries uninterpretation. The accuracy of multidetector CT for the detection of coronary stenosis appears to have progressively improved as the imaging equipment increased from 4-slice and 16-slice to 64-slice CT. With 64-slice CT, scanning of the entire coronary artery tree is possible in 10 to 13 s. Pooled data of results of a few investigations with 64-slice CT showed that the proportion of unevaluable segments is only 4%. The sensitivity of 64-slice CT for the detection of significant (>50% or = or >50%) coronary stenosis in a patient, based on pooled data, was 97% and specificity was 91%. Regarding detection of significant stenosis in any segment, the sensitivity, based on pooled data, was 91% with 64-slice CT and specificity was 96%. In a limited number of patients, sensitivity for detection of significant stenoses in proximal segments was 100%, in mid segments it was 94%, and in distal segments sensitivity it was 80%. Multi-detector CT provides the opportunity to quantify non-calcified coronary artery plaques, which may potentially be a strong predictor of cardiac events. It was also shown to be useful for the detection of stenosis in coronary artery bypass grafts.

Design and synthesis of 4-substituted benzamides as potent, selective, and orally bioavailable I(Ks) blockers.

Multiple delayed rectifier potassium currents, including I(Ks), are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent I(Ks) blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.

Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review.

PURPOSE: Evidence-based medicine guidelines based on venographic end points recommend in-hospital prophylaxis with low-molecular-weight heparin (LMWH) in patients having elective hip surgery. Emerging data suggest that out-of-hospital use may offer additional protection; however, uncertainty remains about the risk-benefit ratio. To provide clinicians with a practical pathway for translating clinical research into practice, we systematically reviewed trials comparing extended out-of-hospital LMWH prophylaxis versus placebo. DATA SOURCES: Studies were identified by 1) searching PubMed, MEDLINE, and the Cochrane Library Database for reports published from January 1976 to May 2001; 2) reviewing references from retrieved articles; 3) scanning abstracts from conference proceedings; and 4) contacting pharmaceutical companies and investigators of the original reports. STUDY SELECTION: Randomized, controlled trials comparing extended out-of-hospital prophylaxis with LMWH versus placebo in patients having elective hip arthroplasty. DATA EXTRACTION: Two reviewers extracted data independently. Reviewers evaluated study quality by using a validated four-item instrument. DATA SYNTHESIS: Six of seven original articles met the defined inclusion criteria. The included studies were double-blind trials that used proper randomization procedures. Compared with placebo, extended out-of-hospital prophylaxis decreased the frequency of all episodes of deep venous thrombosis (placebo rate, 150 of 666 patients [22.5%]; relative risk, 0.41 [95% CI, 0.32 to 0.54; P < 0.001]), proximal venous thrombosis (placebo rate, 76 of 678 patients [11.2%]; relative risk, 0.31 [CI, 0.20 to 0.47; P < 0.001]), and symptomatic venous thromboembolism (placebo rate, 36 of 862 patients [4.2%]; relative risk, 0.36 [CI, 0.20 to 0.67; P = 0.001]). Major bleeding was rare, occurring in only one patient in the placebo group. CONCLUSIONS: Extended LMWH prophylaxis showed consistent effectiveness and safety in the trials (regardless of study variations in clinical practice and length of hospital stay) for venographic deep venous thrombosis and symptomatic venous thromboembolism. The aggregate findings support the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty surgery.

Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review.

BACKGROUND: Perioperative and postoperative venous thrombosis are common in patients undergoing elective hip surgery. Prophylactic regimens include subcutaneous low-molecular-weight heparin 12 hours or more before or after surgery and oral anticoagulants. Recent clinical trials suggest that low-molecular-weight heparin initiated in closer proximity to surgery is more effective than the present clinical practice. We performed a systematic review of the literature to assess the efficacy and safety of low-molecular-weight heparin administered at different times in relation to surgery vs oral anticoagulant prophylaxis. METHODS: Reviewers (A.F.M. and S.M.M.) identified studies by searching MEDLINE, reviewing references from retrieved articles, scanning abstracts from conference proceedings, and contacting investigators and pharmaceutical companies. Randomized trials comparing low-molecular-weight heparin administered at different times relative to surgery with oral anticoagulants in patients undergoing elective hip arthroplasty, evaluated using contrast phlebography, were selected. Two reviewers (A.F.M. and S.M.M.) extracted data independently. RESULTS: The literature review identified 4 randomized trials meeting predefined inclusion criteria. The results indicate that low-molecular-weight heparin initiated in close proximity to surgery resulted in absolute risk reductions of 11% to 13% for deep vein thrombosis, corresponding to relative risk reductions of 43% to 55% compared with oral anticoagulants. Low-molecular-weight heparin initiated 12 hours before surgery or 12 to 24 hours postoperatively was not more effective than oral anticoagulants. Low-molecular-weight heparin initiated postoperatively in close proximity to surgery at half the usual dose was not associated with a clinically or statistically significant increase in major bleeding rates (P =.16). CONCLUSIONS: The timing of initiating low-molecular-weight heparin significantly influences antithrombotic effectiveness. The practice of delayed initiation of low-molecular-weight heparin prophylaxis results in suboptimal antithrombotic effectiveness without a substantive safety advantage.

Cost-effectiveness of currently accepted strategies for pulmonary embolism diagnosis.

Improvements in the methods of clinical trials combined with the use of objective tests to detect venous thrombosis have enhanced the clinician's ability to diagnose pulmonary embolism and venous thrombosis (venous thromboembolism). The authors updated a previous cost-effectiveness analysis of the commonly recommended strategies for pulmonary embolism diagnosis and management to reflect current clinical practice. Two criteria of effectiveness were used: correct identification of venous thromboembolism and correct identification of venous thromboembolism and correct identification of patients for whom treatment was unnecessary. The cost of each diagnostic alternative was defined as the direct cost of administering the diagnostic tests plus the treatment costs associated with a positive test result. A strategy based on the combined use ofventilation-perfusion lung scanning, serial ultrasonography, cardiorespiratory evaluation, and pulmonary angiography was the most cost-effective. This strategy also necessitated pulmonary angiography in the fewest number of patients. The safety of this strategy relates to two important biologic concepts: 1) local extension of submassive pulmonary embolism in the lung is not an important cause of morbidity or mortality in patients with adequate cardiorespiratory reserve, and 2) in most patients, proximal vein thrombi of the lower extremities are the source of recurrent pulmonary embolism.

Antithrombotic therapy in valvular heart disease.

Whether antithrombotic therapy in elderly patients differs from that in younger populations depends on whether the risk for such bleeding differs in the elderly. Regarding long-term therapy with warfarin derivatives, evidence shows that there is a difference. The anticoagulation response to warfarin is exaggerated with advancing age. This article discusses antithrombotic therapies for valvular heart disease, including bioprosthetic and mechanical prosthetic heart valves, aspirin and dipyridamole in combination with oral anticoagulant therapy, antiplatelet agents alone or in combination with very low dose warfarin, tilting disk valves, valve position, first-generation valves compared with modern valves, interruption of anticoagulant therapy, and miscellaneous indications for antithrombotic therapy.

Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.

1. Permanent therapy with oral anticoagulants offers the most consistent protection in patients with mechanical heart valves. 2. Antiplatelet agents alone do not consistently protect patients with mechanical prosthetic heart valves, including patients in sinus rhythm with St. Jude Medical valves in the aortic position. 3. Levels of oral anticoagulants that prolong the INR to 2.0 to 3.0 appear satisfactory for patients with St. Jude Medical bileaflet and Medtronic-Hall tilting disk mechanical valves in the aortic position, provided they are in sinus rhythm and the left atrium is not enlarged. Presumably, this is also true for the CarboMedics bileaflet valve, based on the observation of no clinically important difference in the rate of systemic embolism with this valve and the St. Jude Medical bileaflet valve. 4. Levels of oral anticoagulants that prolong the INR to 2.5 to 3.5 are satisfactory for tilting disk valves and bileaflet prosthetic valves in the mitral position. 5. Experience in patients with caged ball valves who had prothrombin time ratios reported in terms of the INR is sparse, because few such valves have been inserted in recent years. The number of surviving patients with caged ball valves continues to decrease. It has been suggested that the most advantageous level of the INR in patients with caged ball or caged disk valves should be as high as 4.0 to 4.9. However, others have shown a high rate of major hemorrhage with an INR that is even somewhat lower, 3.0-4.5. The problem is self-limited, however, because few such valves are being inserted. 6. In patients with mechanical heart valves, aspirin, in addition to oral anticoagulants, has been shown to diminish the frequency of thromboemboli. The risk of bleeding is somewhat increased if the INR is 2.0 to 3.0 or 2.5 to 3.5. However, if the INR is 3.0 to 4.5, the risk of bleeding becomes excessive with aspirin. There are no investigations in which aspirin 80 mg/d in combination with oral anticoagulants was evaluated. 7. Data are insufficient to recommend dipyridamole over low doses of aspirin in combination with warfarin. Whether dipyridamole plus aspirin is more effective than aspirin alone when used with warfarin is undetermined. 8. Patients with bioprosthetic valves in the mitral position as well as patients with bioprosthetic valves in the aortic position may be at risk for thromboemboli during the first 3 months after operation. 9. Among patients with bioprosthetic valves in the mitral position, oral anticoagulants at an INR of 2.0 to 2.3 were as effective as an INR of 2.5 to 4.0 and were associated with fewer bleeding complications during the first 3 months after operation.10. Aspirin may reduce the long-term frequency of thromboembolism in patients with bioprosthetic valves.

Clinical validity of a normal pulmonary angiogram in patients with suspected pulmonary embolism--a critical review.

AIM: To determine the validity of a normal pulmonary angiogram in the exclusion of pulmonary embolism (PE), based on the safety of withholding anticoagulant therapy in patients with a normal pulmonary angiogram. MATERIALS AND METHODS: A review of English reports published between 1965 and April 1999 was carried out. Eligible articles described prospective studies in patients with suspected PE and a normal pulmonary angiogram, who remained untreated and were followed-up for a minimum of 3 months. Articles were evaluated by two authors, using pre-defined criteria for strength of design. End points consisted of fatal and non-fatal recurrent thromboembolic events. A sensitivity analysis was performed, by removing one study at a time from the overall results and by comparing pre- and post-1990 publications. RESULTS: Among 1050 patients in eight articles included in the analysis, recurrent thromboembolic events were described in 18 patients (1.7% 95% CI: 1.0-2.7%). These were fatal in three patients (0.3% 95% CI: 0.02-0.7%). The recurrence rate of PE decreased from 2.9% (95% CI: 1.4-6.8%) before 1990 to 1.1% (95% CI: 0.5-2.2%) after 1990. CONCLUSION: It would appear that the ability to exclude PE by angiography has improved over the years, as indicated by recurrence rate of PE. The low recurrence rate of PE supports the validity of a normal pulmonary angiogram for the exclusion of PE.

Withholding treatment in patients with acute pulmonary embolism who have a high risk of bleeding and negative serial noninvasive leg tests.

PURPOSE: Patients who have nonmassive acute pulmonary embolism and a high risk of bleeding or contraindication to anticoagulants, such recent surgery or gastrointestinal bleeding, present a clinical dilemma. We sought to estimate whether such patients could be safely left untreated if serial compression ultrasound or serial impedance plethysmography were negative and cardiorespiratory reserve was adequate. SUBJECTS AND METHODS: The frequency of recurrent pulmonary embolism among patients with nonmassive acute pulmonary embolism and negative serial noninvasive leg tests who were not treated was estimated from two prospective studies of the noninvasive management of patients with suspected pulmonary embolism. One of the studies used serial impedance plethysmography of the lower extremities; the other used serial compression ultrasound. The prevalence of pulmonary embolism in patients with nondiagnostic ventilation/perfusion lung scans was determined from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). RESULTS: The estimated frequency of fatal recurrent pulmonary embolism was 1% [95% confidence interval (CI), 0% to 5%) among untreated patients with nonmassive pulmonary embolism who had negative serial impedance plethysmograms and 0% (95% CI, 0% to 4%) among those with negative serial compression ultrasonograms. The frequency of nonfatal recurrent pulmonary embolism among untreated patients was 3%, regardless of whether they had negative serial impedance plethysmograms or negative serial compression ultrasonograms. These results were comparable with the frequency of recurrent pulmonary embolism among patients treated with anticoagulants or with inferior vena cava filters. CONCLUSION: Withholding treatment of nonmassive acute pulmonary embolism, if serial impedance plethysmograms or serial venous ultrasonograms are negative and cardiopulmonary reserve is adequate, is a possible strategy for the management of patients with a high risk of bleeding or other contraindication to anticoagulants. This strategy may be associated with fewer adverse events than treatment with anticoagulants or an inferior vena cava filter. Prospective trials comparing alternative treatments are needed.

Biphenylsulfonamide endothelin receptor antagonists. 2. Discovery of 4'-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ET(A) antagonists.

The synthesis and structure-activity relationship (SAR) studies of a series of 4'-oxazolyl-N-(3,4-dimethyl-5-isoxazolyl)[1, 1'-biphenyl]-2-sulfonamide derivatives as endothelin-A (ET(A)) receptor antagonists are described. The data reveal a remarkable improvement in potency and metabolic stability when the 4'-position of the biphenylsulfonamide is substituted with an oxazole ring. Additional 2'-substitution of an acylaminomethyl group further increased the binding activity and provided one of the first subnanomolar ET(A)-selective antagonists in the biphenylsulfonamide series (17, ET(A) K(i) = 0.2 nM). Among the compounds described, 3 (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1, 1'-biphenyl]-2-sulfonamide; BMS-193884) had the optimum pharmacological profile and was therefore selected as a clinical candidate for studies in congestive heart failure.

Review of criteria appropriate for a very low probability of pulmonary embolism on ventilation-perfusion lung scans: a position paper.

The "low-probability" interpretation of ventilation-perfusion lung scans has been characterized as misleading or even dangerous because of the high prevalence of pulmonary embolism associated with such an interpretation. Since the completion of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, analyses of the PIOPED database have allowed identification of several abnormalities seen on ventilation-perfusion scans that have a positive predictive value (PPV) for pulmonary embolism of less than 10%. These include nonsegmental perfusion abnormalities (PPV = 8%), perfusion defects smaller than the corresponding areas of increased opacity at chest radiography (PPV = 8%), matched ventilation-perfusion abnormalities in two or three zones of a single lung (PPV = 3%), one to three small segmental perfusion defects (PPV = 1%), triple matched defects in the upper or middle lung zone (PPV = 4%), and the stripe sign (PPV = 7%). Use of these abnormalities as interpretative criteria constitutes "very low probability" interpretation and will reduce the number of low-probability interpretations of ventilation-perfusion lung scans, which may be considered nondiagnostic because of the unacceptably high rate of false-negative results. This will enhance the utility of the ventilation-perfusion lung scan for screening patients with suspected pulmonary embolism.

Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group.

BACKGROUND: Pulmonary embolism (PE) occurs in 50% or more of patients with proximal deep-vein thrombosis. Low-molecular-weight heparin treatment is effective and safe in patients with deep vein thrombosis and may also be so in patients with PE. Recent rigorous clinical trials have established objective criteria for determining a high probability of PE by perfusion lung scanning. OBJECTIVE: To compare low-molecular-weight heparin with intravenous heparin for the treatment of patients with objectively documented PE and underlying proximal deep vein thrombosis. METHODS: In a multicenter, double-blind, randomized trial, we compared fixed-dose subcutaneous low-molecular-weight heparin (tinzaparin sodium) given once daily with dose-adjusted intravenous heparin given by continuous infusion using objective documentation of clinical outcomes. Pulmonary embolism at study entry was documented by the presence of high-probability lung scan findings. RESULTS: Of 200 patients with high-probability lung scan findings at study entry, none of the 97 who received low-molecular-weight heparin had new episodes of venous thromboembolism compared with 7 (6.8%) of 103 patients who received intravenous heparin (95% confidence interval for the difference, 1.9%-11.7%; P = .01). Major bleeding associated with initial therapy occurred in 1 patient (1.0%) who was given low-molecular-weight heparin and in 2 patients (1.9%) given intravenous heparin (95% confidence interval for the difference, -2.4% to 4.3%). CONCLUSIONS: Low-molecular-weight heparin administered once daily subcutaneously was no less effective and probably more effective than use of dose-adjusted intravenous unfractionated heparin for preventing recurrent venous thromboembolism in patients with PE and associated proximal deep vein thrombosis. Our findings extend the use of low-molecular-weight heparin without anticoagulant monitoring to patients with submassive PE.

Fever in acute pulmonary embolism.

BACKGROUND: Although fever has been reported in several case series of acute pulmonary embolism (PE), the extent to which fever may be caused by PE, and not associated disease, has not been adequately sorted out. Clarification of the frequency and severity of fever in acute PE may assist in achieving an accurate clinical impression, and perhaps avoid an inadvertent exclusion of the diagnosis. PURPOSE: The purpose of this investigation is to evaluate the extent to which fever is caused by acute PE. METHODS: Patients participated in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). Temperature was evaluated among patients with angiographically proven PE. A determination of whether other causes of fever were present was based on a retrospective analysis of discharge summaries, PIOPED summaries, and a computerized list of all discharge diagnoses. RESULTS: Among patients with PE and no other source of fever, fever was present in 43 of 311 patients (14%). Fever in patients with pulmonary hemorrhage or infarction was not more frequent than among those with no pulmonary hemorrhage or infarction, 39 of 267 patients (15%) vs 4 of 44 patients (9%; not significant). Clinical evidence of deep venous thrombosis was often present in patients with PE and otherwise unexplained fever. CONCLUSION: Low-grade fever is not uncommon in PE, and high fever, although rare, may occur. Fever need not be accompanied by pulmonary hemorrhage or infarction.

Incidence of acute pulmonary embolism in a general hospital: relation to age, sex, and race.

PURPOSE: The purpose of this investigation is to determine the incidence of acute pulmonary embolism (PE) according to age, sex, and race in a tertiary care general hospital. BACKGROUND: Population-based investigations and autopsy studies have shown that acute PE occurs predominantly in middle-aged and elderly people. The incidence of PE according to age, race, and sex in a general hospital has been only sparsely studied. METHODS: Patients with PE diagnosed by a high-probability ventilation/perfusion lung scan or pulmonary angiography were identified in a tertiary care general hospital. The incidence of PE was determined according to age, sex, and race. RESULTS: The incidence of PE was 400 of 175,730 (0.23%; 95% CI, 0.21 to 0.25%). The incidence was linearly related to age (r = 0.94). Among patients >/= 50 years of age, the incidence of PE was higher among women (0.40% vs 0.29%; p < 0.01). The incidence was comparable among patients < 50 years of age. African Americans showed an incidence of 0.26%, and whites showed an incidence of 0. 21% (p < 0.05). CONCLUSION: Acute PE in a tertiary care hospital is more frequent than previously reported among short-term hospitals. Occasionally, young adults and adolescents had PE, although PE occurred primarily among middle-aged and elderly patients. Among patients >/= 50 years of age, the incidence of PE was higher among women. The incidence was not higher among women < 50 years of age, suggesting that childbirth and birth control pills had little impact. Only a trivial difference of the incidence of PE was observed among African Americans compared to whites.

The role of newer diagnostic techniques in the diagnosis of pulmonary embolism.

Among the evolving techniques for the diagnosis of acute pulmonary embolism, contrast enhanced spiral CT takes a particularly prominent role because it is available at most centers, it images the pulmonary embolism directly, and it is minimally invasive. It has not yet been fully evaluated, however. Magnetic resonance angiography also has appeal for similar reasons. Few patients have been studied, however. Magnetic resonance angiography for pulmonary embolism is still in the early testing phase. Transesophageal echocardiography can image pulmonary embolism in central pulmonary arteries, but preliminary tests suggest that it has a low negative predictive value and cannot be used to exclude pulmonary embolism. Finally, it seems that a rapid and sensitive technique for measuring d-dimer may now be available, which may assist in eliminating the diagnosis of acute pulmonary embolism in a significant percentage of patients in whom the diagnosis is suspected.