A Quest For the Relief of Atherosclerosis: Potential Role of Intrapulmonary Heparin--A Hypothesis

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

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.     

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.     

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.     

Fondaparinux in the treatment of acute coronary syndromes: evidence from OASIS 5 and 6

Anticoagulant therapy is widely used for the management of acute coronary syndromes. In order to optimize patient outcomes, anticoagulants should ideally combine high antithrombotic efficacy with a low risk of bleeding. Intravenous unfractionated heparin has been in clinical use for more than 50 years and reduces the risk of recurrent ischemic events in patients with acute coronary syndromes but at the cost of increased bleeding. Enoxaparin, compared with intravenous unfractionated heparin, further reduces the risk of ischemic events but also increases bleeding. Neither of these approaches has been shown to reduce mortality. The synthetic parenteral Factor Xa inhibitor, fondaparinux, is highly effective for the prevention and treatment of venous thromboembolic disease in medical and surgical patients. The Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS) 5 and 6 trials evaluated the efficacy and safety of fondaparinux in more than 32,000 patients with non-ST elevation acute coronary syndromes or ST elevation myocardial infarction. This clinical trial report discusses the findings of these two pivotal trials.     

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.     

Homeopathic remedies for the treatment of osteoarthritis: a systematic review

Osteoarthritis is a common rheumatic disease. Limitations of conventional medical management of this condition indicate a real need for safe and effective treatment of osteoarthritic patients. The authors review the clinical evidence for and against the effectiveness of homeopathic medicines in the treatment of patients with osteoarthritis. A systematic review of all randomised controlled clinical trials of homeopathic treatment of patients with this condition is presented. A comprehensive search yielded four trials which are discussed in detail. The authors conclude that the small number of randomised clinical trials conducted to date, although favouring homeopathic treatment, do not allow a firm conclusion as to the effectiveness of homeopathic remedies in the treatment of patients with osteoarthritis. The clinical evidence appears promising, however, and more research into this area seems warranted.     

Evaluation of the risk of venous thromboembolism in the medical patients

The venous thromboembolic risk seems to be demonstrated in medical patients since the incidence of symptomatic and asymptomatic deep vein thrombosis (DVT) without any prophylactic methods is respectively about 50 per cent in stroke, 25 per cent in acute myocardial infarction (AMI) and 15 per cent in internal medicine. A synthesis of clinical trials performed in medical patients shows that prophylactic doses of heparins (unfractionated heparin or low molecular weight heparins) reduce the incidence of DVT by 40 to 60 per cent compared with the lack of any antithrombotic agents but without any significant effect on total mortality. Other antithrombotic agents such as antiplatelet agents seem to reduce the incidence of DVT by about 40 per cent associated with a significant decrease in total mortality of stroke or AMI. But the recommendations made on the basis of these results have to be extremely cautious since the number of medical patients included in clinical trials is quite limited compared with the surgical area. Moreover, each of these recommendations is not sufficiently proven. Thus more clinical trials have to be carried out with a placebo control group in internal medicine and an aspirin control group for stroke and AMI.     

Retrospective database analysis of the prevention of venous thromboembolism with low-molecular-weight heparin in acutely III medical inpatients in community practice

BACKGROUND: Clinical trials have demonstrated that prophylaxis with low-molecular-weight heparin reduces the occurrence of venous thromboembolism (VTE) among acutely ill medical inpatients in the experimental setting. OBJECTIVE: The goal of this retrospective database analysis was to examine the outcomes of low-molecular-weight heparin thromboprophylaxis among acutely ill medical inpatients in community practice. METHODS: Using a large, geographically diverse, multihospital US database, we identified persons aged > or =40 years who had a hospital stay > or =6 days for an acute medical condition (including selected circulatory disorders, respiratory disorders, infectious diseases, or neoplasms) during calendar-year 2000. From these patients, those who received either enoxaparin thromboprophylaxis or no thromboprophylaxis were identified. Surgical patients, patients with nonthrombotic conditions requiring anticoagulant therapy, those transferred from or discharged to another acute care facility, and those medically ineligible for anticoagulation therapy were excluded. We compared the incidence of deep-vein thrombosis (DVT), pulmonary embolism (PE), all VTE (ie, DVT and/or PE), and death during the hospital stay in the 2 cohorts. RESULTS: A total of 162 patients receiving enoxaparin thromboprophylaxis and 3557 receiving no thromboprophylaxis were identified. The risk of VTE over the course of hospitalization was 1.9% with enoxaparin thromboprophylaxis versus 6.2% with no thromboprophylaxis (relative risk = 0.30; P=0.023 ); mortality was similar in the 2 groups (8.0% vs 7.3; P=NS ). CONCLUSIONS: Using hospital administrative data, we observed a 70% lower risk of VTE for hospitalized acutely ill medical patients receiving low-molecular-weight heparin thromboprophylaxis verus those receiving no thromboprophylaxis; these results are consistent with findings from clinical trials of low-molecular-weight heparin versus placebo. We conclude that the low-molecular-weight heparin enoxaparin is effective in reducing the risk of VTE in acutely ill medical inpatients in community practice.     

Clinical trials: deliberations on their essence and value

RATIONALE, AIM & OBJECTIVES: In the context of the evidence-based medicine (EBM) movement, the clinical trial has come to be hailed as the ultimate source of medical knowledge, and especially of clinical pharmacology. By subjecting the premises of this procedure to a thorough analysis, the author hopes to achieve a sound rating of its epistemological significance in the context of medical research. METHOD: Current claims on the basic importance of the evidence provided by standardized clinical trials are confronted with conflicting observations concerning their current application in medical practice. The stereotyped trials of present research in multiple sclerosis serve as an example to illustrate this point. RESULTS: Traditional assumptions concerning the validity of standardized clinical trials are based on an illusion of absolute objectivity and reliability. Apart from being subject to tough publish (conveniently)-or-perish and commercial influences, the results of clinical trials, especially drug trials, are of limited informative value in diverse respects, such as (i) clinical trials do not identify every possible drug reaction for every instance of a disease; (ii) their results never allow the prediction of the efficacy of a specific drug in any given individual; (iii) clinical trials have no inherent potential to provide concrete insights into the nature and cause(s) of a definite morbid condition; and (iv) extensions of clinical drug trials to ever-larger study groups indicate serious problems in basic theoretical respects. CONCLUSION: A clinical trial cannot indicate a certain prevention or cure for any particular instance of a disease, and the correctness of its individual predictions is always only contingent. This can be explained by the fact that the correspondence between the nature of each of all pathological conditions presented by the different members of a clinical trial population and by the individual patients being treated according to the results of the trial is never complete.     

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.     

Pulmonary embolism: an overview of treatment and nursing issues

Pulmonary embolism presents with a vague clinical picture. Pathophysiological effects vary from small pulmonary infarcts to life-threatening cardiogenic shock. Therefore, radiological investigation to confirm the diagnosis is required to institute appropriate treatment. This ranges from heparin therapy to surgical embolectomy. Care of this patient group requires vigilant nursing, because of not only the risk of further embolic episodes, but also the potential serious complications of treatment. Prevention of venous thromboembolism can be pharmacological or mechanical. The proactive role that nurses take in prevention of this potentially fatal disease process is often overlooked by the medical literature.     

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.     

Direct thrombin inhibitors

Cardiovascular disease is a leading cause of death and pathologic coagulation plays an integral role in the development, propagation, and intervention of cardiovascular disease. The 2 classic anticoagulants, heparin and vitamin K antagonists, though having served humanity for nearly a century, are both inconvenient and nonspecific. Through both direct and indirect roles, thrombin is essential to coagulation, and makes for a very attractive target in medical intervention of pathologic thrombosis. This article will review the nature of direct thrombin inhibitors, current indications, and ongoing trials.     

Prevention of venous thromboembolism in the hospitalized medical patient

Hospitalized acutely ill medical patients are at high risk for venous thromboembolism (VTE), and clinical trials clearly demonstrate that pharmacologic prophylaxis of VTE for up to 14 days significantly reduces the incidence of VTE in this population. Guidelines recommend use of low-molecular-weight heparin (LMWH) or unfractionated heparin (5,000 U three times daily) for VTE prophylaxis in hospitalized medical patients with risk factors for VTE; in patients with contraindications to anticoagulants, mechanical prophylaxis is recommended. All hospitalized medical patients should be assessed for their risk of VTE at admission and daily thereafter, and those with reduced mobility and one or more other VTE risk factors are candidates for aggressive VTE prophylaxis. Based on results from the recently reported EXCLAIM trial, extended postdischarge prophylaxis with LMWH for 28 days should be considered for hospitalized medical patients with reduced mobility who are older than age 75 or have a cancer diagnosis or a history of VTE.     

Evolving role of low-molecular-weight heparins in ST-elevation myocardial infarction

OBJECTIVE: To review the available literature on the efficacy and safety of low-molecular-weight heparin (LMWH) in the treatment of ST-elevation myocardial infarction (STEMI) in patients treated with fibrinolytic therapy or conservative medical management. DATA SOURCES: A MEDLINE search (1966-March 2004) using the key words myocardial infarction, STEMI, LMWH, enoxaparin, and dalteparin identified pertinent articles. The references of these articles were reviewed for additional pertinent references. STUDY SELECTION AND DATA EXTRACTION: All human trials of LMWH in STEMI were evaluated. All pertinent studies were included in the review. DATA SYNTHESIS: LMWH did not show a benefit in STEMI without fibrinolytic therapy. Enoxaparin is similar to intravenous unfractionated heparin (UFH) in combination with nonspecific fibrinolytic therapy with regard to invasive reperfusion markers and 30-day clinical outcomes. Enoxaparin decreases composite endpoints in combination with fibrin-specific fibrinolytic therapy compared with UFH, primarily through a reduction in the incidence of reinfarction at 30 days. Bleeding rates with LMWH in combination with fibrinolytic agents are not greater than those with UFH. CONCLUSIONS: Enoxaparin is a reasonable alternative to UFH in patients with STEMI treated with fibrin-specific fibrinolytic therapy. LMWH in patients managed with nonspecific fibrinolytic therapy or conservative medical treatment does not provide an advantage over standard management. Large clinical trials are ongoing which will provide more definitive recommendations.     

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.     

Chemotherapie beim Prostatakarzinom

For many years the benefit of chemotherapy in patients with prostate cancer was thought to be limited to palliation of late-stage disease, and thus this treatment option only became involved in patient care towards the end of the disease process, if at all. However, two landmark phase-III trials with docetaxel-based therapy (TAX 327 and Southwest Oncology Group, SWOG, 9916) have shown a survival benefit for patients with hormone refractory prostate cancer (HRPC) thus prompting a change in patterns of care. With raising interest for chemotherapeutic options and clinical trials for new drugs and new indications (neoadjuvant therapy, adjuvant therapy, increasing PSA levels after local treatment, and hormone sensitive cancer) under way our goal was to review within the context of a multidisciplinary team the available evidence and explore the standard for the medical treatment of prostate cancer outside of clinical trials. We are carefully evaluating the current treatment recommendations based on the available evidence and highlight potential future treatment options but also discuss important clinical topics (treatment until progression versus the advantage of chemo holidays, definition of particular patient subgroups and potential second line options) for which there are no clear cut answers to date. The role and importance of radiotherapy, biphosphonate treatment and the medical management of pain and side effects is also discussed. The multitude of treatment options for patients with advanced prostate cancer clearly asks for a close collaboration between urologists, medical oncologists and radiation therapists.     

Is there evidence to support the use of direct Factor Xa inhibitors in coronary artery disease?

As coronary artery disease (CAD) remains a leading cause of death in the world, the development of anti-coagulants to prevent CAD progressing to myocardial infarction and death is a high priority. A number of direct Factor Xa (FXa) inhibitors are being developed for use in CAD. Despite being developed to the stage of Phase II clinical trials, DX-9065a is no longer a priority with its developing company for further development, possibly because the Phase II trials did not show any major benefit of DX-9065a over heparin in subjects undergoing percutaneous coronary interventions (PCI) or with non-ST-elevation acute coronary syndromes (ACS). ZK-807834, otamixaban, apixaban, and rivaroxaban are all direct FXa inhibitors that have undergone preclinical and some clinical testing for use in CAD. In a large Phase II clinical trial of subjects with ACS, some doses of otamixaban had a better benefit/risk profile than the unfractionated heparin/eptifibatide combination. However, neither ZK-807834 nor otamixaban appear to be undergoing further clinical development at present. In ACS, placebo-controlled large Phase II clinical trials with apixaban and rivaroxaban have not shown clear cut benefits. Nevertheless, apixaban and rivaroxaban are presently in placebo-controlled Phase III clinical trials for ACS. Presently, there is no compelling evidence to support the use of direct FXa inhibitors in ACS.