Overview of Therapeutic Agents Used in Thrombotic Disorders

Sam Schulman

Victor J. Marder

In this section, the many recent developments in drug and device therapy for venous or arterial thromboembolism are presented together with reviews of the biochemistry, pharmacology, mechanism of action, and side effects of the various agents. Thrombolytic therapy has gone through many modifications regarding both agents and regimens over the past 40 years from the initial infusions of streptokinase or urokinase. An important reason for the many attempts to improve this kind of therapy has been the wish to reduce the risk of bleeding and to simplify the treatment. Conversely, the drive to improve treatment with antiplatelet agents during the past 30 years has mainly been related to a desire to improve efficacy. Among the anticoagulants, vitamin K antagonists (VKAs) and unfractionated or low molecular weight heparins have dominated the clinical stage until the last decade. Recently, an unprecedented number of new anticoagulants have been taken to phase II and III clinical trials, and the standard therapy is about to undergo a shift in paradigm. Finally, vena cava filters have been refined to enhance retrieval after they have served their purpose, and sophisticated catheters for local injection of thrombolytic agents in combination with mechanical clot disruption are for the first time investigated in randomized control trials.

This introduction to the section focuses on some therapeutic dilemmas that will continue to haunt the clinicians for the foreseeable time, despite improvements of the therapeutic agents.

ANTICOAGULANTS AND COMPLIANCE

The VKAs are very effective—as long as they are taken as ordered and the proportional time in therapeutic range (TTR) is high. Even in well-conducted randomized clinical trials, about 30% of the time is spent outside of the therapeutic range.¹, ² Many countries have difficulties keeping an average TTR above 50% due to their therapeutic traditions. The new orally available anticoagulant agents may improve the efficacy by reducing the risk of nontherapeutic levels related to drug-drug or drug-food interactions. Poor compliance from the patients will, however, continue to result in treatment failures. An attempt to solve this problem was seen with the development of a very long-acting, more negatively charged derivative of the pentasaccharide fondaparinux. Idraparinux, with a half-life of 80 hours, was designed to be injected once a week, but with the actual experiences from phase III clinical trials and a half-life after multiple injections of 60 days,³ it might have been suitable for even less frequent administration. This could have been a helpful solution for the poorly compliant patients employing relatively inexpensive support from medical staff.

The favorable results from treatment of deep vein thrombosis (DVT) in phase II,⁴ were replicated with the selected dose of 2.5 mg idraparinux also in phase III in patients with DVT.⁵ Nevertheless, the same dose was inferior regarding efficacy in the treatment of pulmonary embolism (PE),⁵ and, conversely, it caused an increased risk of bleeding, particularly intracranial bleeding, compared to warfarin in patients with atrial fibrillation⁶ (Table 104.1). The trial program of idraparinux has been discontinued, but the dilemma of how to best manage poor compliance will be highlighted with the introduction of new oral anticoagulants without the need for routine laboratory monitoring.

Furthermore, this lesson has taught us that results from trials in DVT cannot be directly extrapolated to other types of patients not only to those with atrial fibrillation but also to the very closely related condition PE. Although often thought of as one and the same disease, PE and DVT are probably best described as different expressions of a disease—with discrepancies regarding clinical picture, short-term prognosis in case of missed diagnosis,⁷ location of recurrence,⁸ and case fatality of recurrences.⁹

With respect to the issue of compliance, the use of the new, nonmonitored anticoagulants will require imaginative steps to ensure adherence. Otherwise, the promising results from clinical trials², ¹⁰ (EINSTEIN) will not be replicated in the realworld setting. The solutions may include clinical follow-up with unannounced point-of-care screening test, for example with activated partial thromboplastin time for oral thrombin inhibitors. It would be of interest to develop a test that identifies activation of coagulation over prolonged periods, corresponding to the HbA1c for diabetes. Another option is the use of “intelligent” drug packaging that records removal of tablets and alarms when a dose is missed.¹¹

Finally, in terms of new development of glycosaminoglycans—our oldest clinically used anticoagulant—the most recent agent currently in phase III trials is a hemisynthetic heparin with a molecular weight of only 2,000 to 3,000 Da (semuloparin, AVE5026), which makes it almost a pure factor Xa inhibitor.¹² Whether it can be adapted for oral administration, in view of its low molecular weight, is unclear, but previous attempts with longer glycosaminoglycans have only had limited success.¹³, ¹⁴ The glycosaminoglycans are reviewed in
detail regarding their pharmacology and mechanism of action in Chapter 105.

Table 104.1 Example of discrepant results with the same drugs (warfarin with therapeutic range, INR 2-3, vs. idraparinux 2.5 mg daily) for different indications

	Idraparinux (%)	Warfarin (%)	Hazard Ratio (95% CI)	Interpretation
Efficacy
DVT: Recurrence	3.7	3.7	1.01 (0.66-1.55)	Noninferior
PE: Recurrence	4.0	2.0	2.09 (1.22-3.57)	Inferior
Atrial fibrillation: Stroke, systemic embolism	0.9	1.3	0.71 (0.39-1.30)	Noninferior
Bleeding
DVT: Major	0.8	1.2	NA	Noninferior, P = 0.35
PE: Major	1.1	2.1	NA	Borderline superior, P = 0.05
Atrial fibrillation: Intracranial	1.1	0.4	2.58 (1.18-5.63)	Inferior
Death
DVT	2.3	2.0	NA	Noninferior, P = 0.61
PE	5.1	2.9	NA	Inferior, P = 0.006
Atrial fibrillation	3.2	2.9	NA	Noninferior, P = 0.49
CI, confidence interval; NA, not available.

DURATION OF ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM

For most of the indications for anticoagulant treatment, until now mainly with VKAs, the duration is minimally disputed. Thus, 1 to 3 months is considered sufficient after cardioversion for atrial fibrillation, 3 months after anterior myocardial infarction and/or left-ventricle thrombus, ablation therapy for atrial fibrillation with low risk for stroke, and (if at all) after bioprosthetic valve replacement or postoperative transient atrial fibrillation. Indefinite treatment duration is chosen for patients with mechanical heart valves or atrial fibrillation with risk factors for stroke. The situation is different for venous thromboembolism (VTE) for the following reasons: (a) the risk of recurrence seems to remain indefinitely, albeit with some decrease over time, (b) the balance between recurrence without treatment and bleeding with treatment is tight for many patients with suboptimal control of the anticoagulation, (c) the individual risk of recurrence varies widely depending on the presence or absence of a large number of known risk factors, and (d) despite more randomized trials than for any other indication no clear answer has emerged.

For a minority of patients—those with a distal DVT provoked by temporary risk factors such as surgery or trauma— 6 weeks of therapy seems sufficient.¹⁵, ¹⁶ At the other end of the spectrum are the patients with unprovoked and recurrent VTE, or thromboembolism associated with noncurable cancer or with serious thrombophilia (deficiency of antithrombin or combinations of defects). The vast majority of patients with VTE fall between these groups. Since several studies on the duration of treatment showed that the risk of recurrence after unprovoked VTE was 10% during the 1st year after stopping anticoagulation, irrespective of the treatment duration being 3, 6, 12, or 24 months, it has been suggested that the choice should be between 3 months and indefinite duration.¹⁷ This dichotomous decision should be influenced by the risk of bleeding and the quality of anticoagulant management provided.

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