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Uncommon Reactions to Commonly Used Anticoagulants

The usual side effects of warfarin, heparin, and clopidogrel are well-known to all practitioners who treat patients with these anticoagulants. However, several rare and rather unique reactions to these commonly prescribed drugs frequently have been overlooked.

Purple Toe Syndrome

Warfarin, and very rarely heparin, can cause a violaceous and often painful discoloration of the toes and sides of the feet. Occasionally the same findings are noted on the hands, and net-like skin changes appear on the abdomen (livedo reticularis). This occurs mainly in an older patient population, especially those with atherosclerosis. The pathogenesis of this syndrome is thought to be caused by bleeding into atheromatous plaques with resultant cholesterol embolization to the small arteries and arterioles of the feet. ^1,²

The diagnosis can be challenging, because several serious, and non-serious conditions can mimic this condition. Serious syndromes include those associated with hypoxemia or trauma, erythromelalgia, as well as cold-associated syndromes like Raynaud phenomenon, cryoglobulinemia, and frostbite. Syndromes of lesser severity are benign acrocyanosis and pernio. ³

New Treatment Strategies for Advanced Lung Cancer

The incidence and mortality rates of lung cancer in this country have declined substantially, especially for men ¹. Furthermore, important controversial questions regarding treatment have been resolved, and the discovery and use of certain biological agents have had a major impact on the natural history of this disease for a significant subset of patients.

Locally Advanced Intrathoracic Disease

Locally advanced NSCLC is considered inoperable when there is direct invasion of the mediastinum, major blood vessels, heart, vertebral body, or involvement of multi-station lymph nodes. In this setting randomized studies showed that the addition of chemotherapy to radiation improved overall survival, and that although more toxic, outcomes were better when treatment was concurrent rather than sequential ². In fact, five year survivals of 15-20% were possible for the percentage of patients with good initial performance status. Administration of a targeted agent like gefitinib (Iressa®) with or after chemoradiation has not improved survival, but cetuximab (Erbitux®) currently is being tested in this setting ³.

Advanced Metastatic NSCLC

Initial Therapy

Two drug combination chemotherapy (a “doublet”) using either cis- or carboplatin as the backbone, together with another chemotherapy agent, has become standard therapy for advanced disease. An important clinical trial compared four commonly used two-drug platinum-based regimens and found equal efficacy for all four ⁴. Several third generation chemotherapy agents, when combined with a platinum compound, have shown similar results. Although two drug regimens clearly are better than single agents, trials of triple agents did not produce prolongation of overall survival ¹, but instead just added more toxicity. Therefore, a platinum-based doublet remains the standard.

Update on Classic Gastrointestinal Carcinoid

Overview

Carcinoid tumors are rare neoplasms arising from neuroendocrine cells scattered diffusely throughout the aerodigestive tract. The most common sites are small intestine (42%), rectum (25%), appendix (12%), and stomach (8.9%)⁸. Occasionally these tumors are found in bronchi (bronchial carcinoids). They are virtually always malignant, and have the potential to metastasize to nodes, liver, or less commonly bone, lung, brain and other organs. Despite this metastatic potential, carcinoids typically are slow-growing, insidious, and have a low mitotic index. The majority is sporadic, but hereditary syndromes have been described as well ¹. The range for median survival of advanced disease is unusually wide, months to many years (some have survived for decades), indicating that typical carcinoids may have long periods of inactivity ².

Carcinoid tumors may be non-functional or functional. Functional tumors secrete a variety of hormones, the most important of which are serotonin, histamine, and tachykinins. These hormones are cleared by first pass through the liver; therefore, systemic hormone excess and the resultant carcinoid syndrome (flushing, cramps, diarrhea, wheezing) mainly occurs when hepatic metastases are present, because direct access to the circulation occurs. An exception may occur with extragastrointestinal and bronchial carcinoids which occasionally may present with carcinoid syndrome because they have direct circulatory access. Additionally, as a result of stimulation of fibroblast proliferation by excess serotonin, 20-30% of patients with carcinoid syndrome develop fibrosis of the tricuspid valve and/or pulmonic stenosis ¹.

A Close Look at Warfarin Mangement

Warfarin is prescribed to an estimated 2 million Americans, but a number of factors make this drug difficult to manage: delayed onset of action, narrow therapeutic margin, drug and dietary interactions, variations in patient sensitivity, and issues regarding how best to reverse its effect¹. Even with expert management, patients are within therapeutic range only 60% of the time² and 14% of patient time is spent with INRs higher than appropriate ⁸.

An increased INR is an independent predictor for major hemorrhage. A contemporary study of bleeding for patients on warfarin reported rates of 0.25, 1.1, and 6.2 per 100 patient years for fatal, major, and minor bleeds respectively ². Bleeding risk is highest during the first 90 days³. A major hemorrhage on warfarin potentially is a very serious event as confirmed by a meta-analysis that found a case fatality rate of 13.4%. The most serious is intracranial hemorrhage, which has an estimated 60% mortality ^1,4.

Pathophysiology and Treatment of Malignant Skeletal Disease

Bisphosphonates are the most commonly prescribed drugs for the treatment and prevention of osteoporosis. Long term studies lasting 7 to 10 years have demonstrated their safety and effectiveness¹, although patients need to be monitored for adverse events which occur in some individuals. This class of drugs targets the process of bone resorption by inhibiting osteoclast function. The first generation, etidronate and clodronate (Didronel®, Bonefos®) lack nitrogen, adhere to bone, and are metabolized by osteoclasts causing mitochondrial dysfunction and apoptosis. The second generation contains nitrogen, is internalized by osteoclasts and then inhibits an enzyme crucial for cellular vesicle transport, without which osteoclasts cannot form the tight sealing zones or ruffled borders at the bone surface required for bone resorption. These drugs include pamidronate, zoledronic acid, risendronate, and ibandronate (Aredia®, Zometa®, Actonel®, Boniva® respectively)⁵.

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