A quest for the relief of atherosclerosis: potential role of intrapulmonary heparin--a hypothesis.

Recent progress in the treatment of coronary artery disease is reviewed from the standpoint of changes in lifestyle, surgical techniques to revascularize the myocardium and a variety of medical interventions. Among the medical modalities, heparin appears to have a greater potential than any other agent tested to neutralize the atherogenic process at most of its stages. This potential is supported by success in clinical trials of heparin administered by intravenous, subcutaneous, pulmonary, sublingual and topical routes. The suggested self-administration of low-dose heparin by inhalation appears to be well justified and easily adaptable to home therapy. The summarized evidence suggests the need for further clinical trials to test the use of heparin in the prophylaxis of atherosclerotic disease.     

Unintended bias, clinical trial results, and the heparin post hoc crossover fallacy

OBJECTIVE: To describe the unintended pitfalls in the interpretation of postrandomization events in clinical trials. DESIGN: Analysis of patients enrolled in clinical trials for new sepsis interventions with postrandomization exposure to heparin. PATIENTS: Retrospective review of patients enrolled in large phase III sepsis trials after treatment with experimental anticoagulant therapies. INTERVENTIONS: Nonrandomized exposure to heparin therapy administered for a variety of clinical indications after enrollment in large phase III sepsis trials. RESULTS: The effect of heparin on overall survival in septic patients in trials that randomized patients into treatment assignments other than heparin is difficult to quantitatively analyze because of unintended selection bias and allocation bias. Both forms of bias overestimate the potential therapeutic value of heparin. This post hoc analysis of the data is functionally a crossover study in which only surviving patients can cross over in one direction (toward the heparin treatment arm). CONCLUSION: Great caution should be exercised in the post hoc interpretation of the potential efficacy of nonrandomized treatments such as heparin therapy derived from phase III clinical data of other drugs for sepsis. The therapeutic value of heparin as a treatment modality in severe sepsis can best be determined in a formal, randomized, prospective clinical trial. This will obviate the unavoidable selection bias and allocation bias intrinsic to postrandomization events in clinical trials with a high early mortality rate such as severe sepsis and septic shock.     

Current and future antithrombotic agents in children

Thromboembolic complications are increasing in children, and the use of anticoagulation has seen a dramatic increase despite the lack of randomized clinical trials. The most widely used agents in children are heparin and warfarin, however these agents have limitations that are exaggerated in children. This has led to the use of newer agents with improved pharmacologic properties such as low-molecular-weight heparin, however, the use of novel agents such as direct thrombin inhibitors has been limited to case reports. These agents, however, have potential advantages over heparin, low-molecular-weight heparin and warfarin. Current clinical trials are in progress to define the proper dose of two such agents--argatroban (Argatroban, GlaxoSmithKline) and bivalirudin (Angiomax, The Medicines Company). The selective Factor Xa inhibitor fondaparinux (Arixtra, Sanofi-Synthelabo) has not been used in children; however, there are situations in which this agent may be advantageous. This review will discuss the currently available agents, with an emphasis on those that are novel and their potential uses in children.     

Low-molecular-weight heparin in outpatient treatment of DVT

Patients with a diagnosis of acute deep venous thrombosis have traditionally been hospitalized and treated with unfractionated heparin followed by oral anticoagulation therapy. Several clinical trials have shown that low-molecular-weight heparin is at least as safe and effective as unfractionated heparin in the treatment of uncomplicated deep venous thrombosis. The use of low-molecular-weight heparin in an outpatient program for the management of deep venous thrombosis provides a treatment alternative to hospitalization in selected patients. Use of low-molecular-weight heparin on an outpatient basis requires coordination of care, laboratory monitoring, and patient education and participation in treatment. Overlapping the initiation of warfarin permits long-term anticoagulation. Advantages include a decreased incidence of heparin-induced thrombocytopenia and fewer episodes of bleeding complications. Future clinical trials evaluating the safety and efficacy of low-molecular-weight heparin in the treatment of complicated deep venous thrombosis will further define appropriate indications for use and strategies for outpatient management.     

Low-molecular-weight Heparins for the Treatment of Venous Thromboembolism

Recent studies have indicated that certain low-molecular-weight heparins given subcutaneously may replace continuous intravenous unfractionated heparin for the treatment of venous thromboembolism. Low-molecular-weight heparins have a predictably high absorption rate when given subcutaneously and they do not require laboratory monitoring. These characteristics of low-molecular-weight heparin therapy raise the possibility of treating uncomplicated patients with deep venous thrombosis or pulmonary embolism in the outpatient setting. The advantages to the patient of avoiding in-hospital care and its associated hazards are obvious. Outpatient lowmolecular-weight heparin will likely prove to be highly cost-effective. At the present time, the findings associated with an individual low-molecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight heparins and each must be evaluated in separate clinical trials. Recent randomized clinical trials indicate that low-molecular-weight heparin may be safer and more effective than continuous intravenous unfractionated heparin in the treatment of proximal venous thrombosis. A decreased mortality rate, which was particularly striking in patients with metastatic carcinoma, was unexpected and requires confirmation in further prospective randomized trials.     

Role of heparin and low-molecular-weight heparins in the management of acute ischemic stroke

The numerous large-scale randomized clinical trials performed during the last decade on either unfractionated heparin, or low molecular weight heparin have not been able to demonstrate undisputed benefits in patients with acute ischemic stroke, compared with no treatment or aspirin. However, a large number of these trials, including the International Stroke Trial and Chinese Acute Stroke Trial, exhibit severe methodological limitations and need to be interpreted with caution. Knowledge of thromboembolism pathophysiology and clinical experience leads to the theory that heparins will prevent red thrombus formation, propagation and embolism. Heparins effectively prevent venous thrombosis and pulmonary embolism. More trials are needed to test heparins in patients whose cardiocerebrovascular lesions are better defined by newer neuroimaging techniques. The efficacy of heparins has not been adequately tested in patients with defined stroke subtypes and occlusive vascular lesions. Heparins should not be indiscriminately given to all patients with acute ischemic stroke. High-quality, randomized trials that adequately study heparin use in patients using modern technology for vascular lesions and stroke subtypes are lacking, and need to be performed.     

Clinical applications of bivalirudin in the cardiac catheterization laboratory

Heparin has been used in the catheterization laboratory to prevent ischemic complications of percutaneous coronary intervention (PCI). Bivalirudin, a direct thrombin inhibitor, is an anticoagulant that has several pharmacologic advantages over heparin, and it has been proposed that bivalirudin is superior to heparin in its ability to prevent bleeding complications of PCI. As such, there have been a variety of large prospective clinical trials comparing bivalirudin and heparin over the past 13 years. The results of these trials have prompted the general acceptance of bivalirudin as a safe alternative to heparin use during PCI, and bivalirudin has been given a class 1 recommendation by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for a variety of clinical indications. This article will review the data supporting the use of bivalirudin in the cardiac catheterization laboratory and describe several advantages of bivalirudin over traditional heparin use. We also include a discussion of the use of bivalirudin in conjunction with other medications that are frequently used in the catheterization laboratory. We end with an analysis of the economic differences between bivalirudin and heparin and the impact that financial factors may have on the choice of anticoagulant.     

Heparin and atherosclerosis: an investigative report on the treatment of atherosclerosis

Both animal and clinical evidence of the special role of long-term low-dose heparin as a preventative of atherosclerosis is presented. Some of the many beneficial effects of heparin aside from its anticoagulant capability are mentioned. Concern about hemorrhage and osteoporosis which can occur when taken in the usual anticoagulant doses does not apply to long-term administration of low-dose heparin. Taken by the intrapulmonary route using an ultrasonic nebulizer weekly or fortnightly, heparin is safe and assures patient compliance. Further clinical trials are strongly indicated.     

Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

ABSTRACT: BACKGROUND: Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications. METHOD: We performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans. RESULTS: The efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings. CONCLUSION: Local anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.     

Correlation between thrombus regression and recurrent venous thromboembolism. Examining venographic and clinical effects of low-molecular-weight heparins: a meta-analysis.

We analyzed the correlation between thrombus regression on control venography performed after discontinuation of heparin therapy and recurrent venous thromboembolism (VTE) detected during clinical follow-up in randomized trials comparing low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in patients with deep vein thrombosis (DVT). Data were abstracted from MEDLINE, conference abstracts and reference lists of previous reviews. Randomized, controlled trials comparing LMWH and UFH for the treatment of DVT using a combined venographic and clinical assessment and with at least 2 months of follow-up were selected. The proportions of patients with thrombus regression on control venography performed soon after discontinuation of heparin therapy and recurrent VTE at 2-6 months were independently collected by two researchers. Thirteen studies met the inclusion criteria. There was a strong inverse correlation between thrombus regression and recurrent VTE (r =- 0.70; P =0.008). The venographic effect varied between the different LMWHs (P = 0.013). A very strong correlation was found when the results were pooled by the type of LMWH used (r = - 0.84; P=0.037). No influence of the dose interval used on the venographic effect (P=0.156) or on recurrent VTE (P=0.218) was shown. The lack of thrombus regression in venography, performed soon after heparin discontinuation, was correlated with clinical recurrence. Non-invasive imaging techniques should be relevant to identify non-responders and to assess the optimal duration of initial heparin treatment in daily clinical practice.     

Synthesis: certainties/uncertainties in the prevention of venous thrombosis in medical patients

In medical patients there are numerous and variable risk factors for deep vein thrombosis. Placebo-controlled clinical trials are rare. The efficacy of standard heparin or low molecular weight heparin for the prevention of deep vein thrombosis is clearly demonstrated for patients with recent myocardial infarction, ischaemic stroke with hemiplegia or severe pulmonary sepsis with lung failure. Pharmacological prophylaxis is probably also efficient in patients with a severe acute disease and a certain history of deep vein thrombosis. For all other medical and especially for bedridden elderly patients, use of low molecular weight heparin might decrease the incidence of deep vein thrombosis but might not modify the overall mortality. In these situations, placebo-controlled clinical trials are needed for best evaluation of the benefit-risk ratio.     

The use of low molecular weight heparin in the initial management of patients with deep vein thrombosis

Low molecular weight heparins (LMWH) have been found to be a safe and effective treatment for the prevention of venous thromboembolism. Recent clinical trials have further investigated the use of this class of drugs in the initial treatment of venous thromboembolism. The interest surrounding this new group of anticoagulants is sparked by the reduction in intensive resources required to safely administer this medication in comparison to the traditional treatment with heparin. Low molecular weight heparins do not require laboratory monitoring and can be given once or twice a day by subcutaneous injection, thereby allowing safe administration in the home. The potential cost savings incurred is timely in light of cost containment needs surrounding the current health care climate.     

Extended duration of thromboprophylaxis in acutely ill medical patients: optimizing therapy?

Summary. Patients who are hospitalized for an acute medical illness are at risk of venous thromboembolism (VTE). Current evidence-based guidelines recommend prophylaxis with unfractionated heparin or low-molecular-weight heparin in acutely ill medical patients who are admitted to hospital with congestive heart failure, severe respiratory disease, or who are bedridden with an additional VTE risk factor. The need for thromboprophylaxis is therefore clear in this patient population; however, the optimal duration of prophylaxis in these patients is less clear. In patients undergoing orthopedic or cancer surgery, extended-duration prophylaxis has been shown to be superior to placebo. To date, however, no large-scale clinical trials have assessed the benefits of extended-duration prophylaxis in acutely ill medical patients. This review therefore focuses on the VTE risk profile of acutely ill medical patients, examines the currently available literature for evidence of a potential benefit of extended-duration prophylaxis in these patients, and provides a rationale for the testing of such a hypothesis in a randomized clinical trial.     

Fludrocortisone for the treatment of heparin-induced hyperkalemia

OBJECTIVE: To report the use of fludrocortisone for heparin-induced hyperkalemia and to briefly review the available literature relating to heparin-induced hyperkalemia. CASE SUMMARY: A 34-year-old African-American man was admitted to the hospital for pneumococcal pneumonia and sepsis. His hospital course was complicated by the development of acute respiratory distress syndrome, severe sepsis, acute renal failure, placement of a tracheostomy, and recurrent nasopharyngeal bleeding. The patient also developed a subclavian vein thrombosis with extension to the cephalic and basilic veins secondary to placement of a pulmonary artery catheter; anticoagulation with heparin was required. On day 9 of heparin therapy, the patient developed symptomatic hyperkalemia refractory to conventional therapies. Oral fludrocortisone 0.1 mg/d was initiated with resolution of the hyperkalemia within 24 hours despite the continued administration of heparin. DATA SOURCES: A MEDLINE (1966-October 1999) search was performed to identify case reports and clinical trials discussing heparin-induced hyperkalemia or the use of fludrocortisone for hyperkalemia. DISCUSSION: Heparin has the potential to induce hyperkalemia by several mechanisms, including decreased aldosterone synthesis, reduction in number and affinity of aldosterone II receptors, and atrophy of the renal zona glomerulosa. Fludrocortisone promotes potassium excretion by its direct actions on the renal distal tubules. In this patient, fludrocortisone resulted in a significant and rapid decrease in serum potassium even with continued heparin administration and acute renal failure. CONCLUSIONS: This case suggests that fludrocortisone is a reasonable alternative therapy for patients with hyperkalemia secondary to heparin therapy when the continued administration of heparin is necessary.     

Prevention of venous thromboembolism in the cancer surgery patient

Cancer patients, especially those undergoing surgery for cancer, are at extremely high risk for developing venous thromboembolism (VTE), even with appropriate thromboprophylaxis. Anticoagulant prophylaxis in cancer surgery patients has reduced the incidence of VTE events by approximately one-half in placebo-controlled trials, and extended prophylaxis (for up to 1 month) has also significantly reduced out-of-hospital VTE events in clinical trials in this population. Clinical trials show no difference between low-molecular-weight heparin (LMWH) and unfractionated heparin in VTE prophylaxis efficacy or bleeding risk in this population, although the incidence of heparin-induced thrombocytopenia is lower with LMWH. The risk-benefit profile of low-dose anticoagulant prophylaxis appears to be favorable even in many cancer patients undergoing neurosurgery, for whom pharmacologic VTE prophylaxis has been controversial because of bleeding risks.     

Nebulised heparin: a new approach to the treatment of acute lung injury?

The administration of heparin by nebulisation has been proposed for the 'local' treatment of pulmonary coagulation disturbances in acute lung injury (ALI). Alveolar and lung micro-vascular fibrin accumulation and breakdown inhibition indeed play a central role in the development and clinical course of this disease. Preclinical studies provide some evidence of the beneficial effects of heparin inhalation in several animal models of ALI. Clinical investigations are sparse, and trials such as the one presented by Dixon and colleagues in a recent issue of Critical Care are welcome as they provide insight into the possible clinical use of nebulised heparin in this situation. This phase 1 trial involved 16 patients with early ALI, and showed the feasibility of the approach. In addition, non-significant changes in respiratory functions and systemic anticoagulant effects were documented with the four doses tested. The study of Dixon and colleagues adds to data that helps pave the way towards a possible clinical use of heparin by nebulisation in ALI. It remains to be clarified in which clinical situations, at what time points and with which dosages the best chances exist for a beneficial effect on the prognosis of these patients.     

The use of low-molecular-weight heparin in acute coronary syndromes

The initiating event in unstable angina (USA) and non-Q-wave myocardial infarction (NQMI) is the rupture of an atherosclerotic plaque resulting in local thrombosis. The current standard treatment is the administration of aspirin and heparin. The introduction of low-molecular-weight heparin (LMWH) offers a potential alternative therapy. Clinical trials have begun to examine the efficacy and safety of using LMWH in the management of acute coronary syndromes. Two pivotal studies have evaluated the effects of LMWH preparations on patients with USA or NQMI: The ESSENCE and the TIMI 11B trials. These studies suggest that LMWH plus aspirin is more effective and safer than unfractionated heparin in preventing myocardial infarction, recurrent angina, or death. Because of these differences, the American College of Cardiology and the American Heart Association have updated their guidelines for the treatment of USA and NQMI.     

Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery

The periprocedural management of patients receiving chronic therapy with oral anticoagulants (OACs), including vitamin K antagonists (VKAs) such as warfarin and direct OACs (DOACs), is a common clinical problem. The optimal perioperative management of patients receiving chronic OAC therapy is anchored on four key principles: (i) risk stratification of patient‐related and procedure‐related risks of thrombosis and bleeding; (ii) the clinical consequences of a thrombotic or bleeding event; (iii) discontinuation and reinitiation of OAC therapy on the basis of the pharmacokinetic properties of each agent; and (iv) whether aggressive management such as the use of periprocedural heparin bridging has advantages for the prevention of postoperative thromboembolism at the cost of a possible increase in bleeding risk. Recent data from randomized trials in patients receiving VKAs undergoing pacemaker/defibrillator implantation or using heparin bridging therapy for elective procedures or surgeries can now inform best practice. There are also emerging data on periprocedural outcomes in the DOAC trials for patients with non‐valvular atrial fibrillation. This review summarizes the evidence for the periprocedural management of patients receiving chronic OAC therapy, focusing on recent randomized trials and large outcome studies, to address three key clinical scenarios: (i) can OAC therapy be safely continued for minor procedures or surgeries; (ii) if therapy with VKAs (especially warfarin) needs to be temporarily interrupted for an elective procedure/surgery, is heparin bridging necessary; and (iii) what is the optimal periprocedural management of the DOACs? In answering these questions, we aim to provide updated clinical guidance for the periprocedural management of patients receiving VKA or DOAC therapy, including the use of heparin bridging.     

Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children: A systematic review

BackgroundAround the world, guidelines and clinical practice for the prevention of complications associated with central venous catheters (CVC) vary greatly. To prevent occlusion, most institutions recommend the use of heparin when the CVC is not in use. However, there is debate regarding the need for heparin and evidence to suggest normal saline may be as effective. The use of heparin is not without risk, may be unnecessary and is also associated with increased costs.ObjectivesTo assess the clinical effects (benefits and harms) of heparin versus normal saline to prevent occlusion in long-term central venous catheters in infants, children and adolescents.DesignA Cochrane systematic review of randomised controlled trials was undertaken.Data sourcesThe Cochrane Vascular Group Specialised Register (including MEDLINE, CINAHL, EMBASE and AMED) and the Cochrane Register of Studies were searched. Hand searching of relevant journals and reference lists of retrieved articles was also undertaken.Review MethodsData were extracted and appraisal undertaken. We included studies that compared the efficacy of normal saline with heparin to prevent occlusion. We excluded temporary CVCs and peripherally inserted central catheters. Rate ratios per 1000 catheter days were calculated for two outcomes, occlusion of the CVC, and CVC-associated blood stream infection.ResultsThree trials with a total of 245 participants were included in this review. The three trials directly compared the use of normal saline and heparin. However, between studies, all used different protocols with various concentrations of heparin and frequency of flushes. The quality of the evidence ranged from low to very low. The estimated rate ratio for CVC occlusion per 1000 catheter days between the normal saline and heparin group was 0.75 (95% CI 0.10 to 5.51, two studies, 229 participants, very low quality evidence). The estimated rate ratio for CVC-associated blood stream infection was 1.48 (95% CI 0.24 to 9.37, two studies, 231 participants; low quality evidence).ConclusionsIt remains unclear whether heparin is necessary for CVC maintenance. More well-designed studies are required to understand this relatively simple, but clinically important question. Ultimately, if this evidence were available, the development of evidenced-based clinical practice guidelines and consistency of practice would be facilitated.     

In vitro inhibition of Plasmodium falciparum rosette formation by Curdlan sulfate

Spontaneous binding of infected erythrocytes to uninfected erythrocytes to form rosettes is a property of some strains of Plasmodium falciparum that is linked to severe complications of malaria. Curdlan sulfate (CRDS) is a sulfated glycoconjugate compound that is chemically similar to known rosette-inhibiting drugs such as heparin. CRDS has previously been shown to have antimalarial activity in vitro and is safe for clinical use. Here we show that CRDS at therapeutic levels (10 to 100 microg/ml) significantly reduces rosette formation in vitro in seven P. falciparum laboratory strains and in a group of 18 African clinical isolates. The strong ability to inhibit rosetting suggests that CRDS has the potential to reduce the severe complications and mortality rates from P. falciparum malaria among African children. Our data support further clinical trials of CRDS.