US Food and Drug Administration approval of generic versions of complex biologics: implications for the practicing physician using low molecular weight heparins (original) (raw)
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JAMA, 2003
molecular-weight heparins (LMWHs) possess several potential pharmacological advantages over unfractionated heparin as an antithrombotic agent. Objective To systematically summarize the clinical data on the efficacy and safety of LMWHs compared with unfractionated heparin across the spectrum of acute coronary syndromes (ACSs), and as an adjunct to percutaneous coronary intervention (PCI). Data Sources We searched MEDLINE for articles from 1990 to 2002 using the index terms heparin, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight heparin, myocardial infarction, unstable angina, coronary angiography, coronary angioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. Additional data sources included bibliographies of articles identified on MEDLINE, inquiry of experts and pharmaceutical companies, and data presented at recent national and international cardiology conferences. Study Selection We selected for review randomized trials comparing LMWHs against either unfractionated heparin or placebo for treatment of ACS, as well as trials and registries examining clinical outcomes, pharmacokinetics, and/or phamacodynamics of LMWHs in the setting of PCI. Of 39 studies identified, 31 fulfilled criteria for analysis. Data Extraction Data quality was determined by publication in the peer-reviewed literature or presentation at an official cardiology society-sponsored meeting. Data Synthesis The LMWHs are recommended by the American Heart Association and the American College of Cardiology for treatment of unstable angina/non-ST-elevation myocardial infarction. Clinical trials have demonstrated similar safety with LMWHs compared with unfractionated heparin in the setting of PCI and in conjunction with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an antithrombotic agent for the treatment of ST-elevation myocardial infarction. Conclusions The LMWHs could potentially replace unfractionated heparin as the antithrombotic agent of choice across the spectrum of ACSs. In addition, they show promise as a safe and efficacious antithrombotic agent for PCI. However, further study is warranted to define the benefit of LMWHs in certain high-risk subgroups before their use can be universally recommended.
Arquivos Brasileiros de Cardiologia, 2001
Acute coronary syndromes comprise clinical entities with variable prognoses, such as non-Q-wave acute myocardial infarction and unstable angina 1-4 . The unification of different manifestations of myocardial ischemia under a single term, even though questionable, reflects their similar pathophysiology. Erosion, fissure, or rupture of a relatively small atherosclerotic plaque 5-7 , which usually obstructs less than 50% of the arterial lumen 8-10 , promotes platelet activation and thrombin generation, forming a thrombus 11,12 .
Low molecular weight heparin biosimilars: how much similarity for how much clinical benefit?
Targeted oncology, 2012
The development of biosimilar versions of low molecular weight heparins (LMWHs) raises real medical concerns. To illustrate this, we have chosen as an example the specific clinical setting of antithrombotic management of acute coronary syndromes (ACS). In this indication, the LMWH enoxaparin has consistently shown its superiority in terms of efficacy when compared to unfractionated heparin (UFH) and in a number of direct or indirect comparisons to other LMWHs. For this reason, enoxaparin has become the gold standard for anticoagulation in cardiology, recommended by practice guidelines and extensively used in everyday practice. We are concerned by the fact that some patients might be treated with a biosimilar copy of enoxaparin, on the basis of simplified criteria that are not specific enough to differentiate between different available LMWHs and are thus unable to differentiate between enoxaparin and a biosimilar. In the absence of evidence from clinical trials, especially in ACS, w...
Low molecular weight heparins versus unfractionated heparin for acute coronary syndromes
Cochrane Database of Systematic Reviews, 2003
Characteristics of included studies Study ESSENCE 1997 Methods Design: Prospective, randomized, double-blind, parallel-group, multicenter trial Randomisation: not described. Blinding: double dummy trial, dummy heparin results, similar appearance of drug. Number excluded: not reported. Withdrawals: 367 (11.6%) all well documented and evenly balanced. Baseline characteristics: no imbalance demonstrated; adjusted analyses performed. Participants Location: 176 hospitals in 10 countries (North America, South America and Europe). Participants: 3171 patients 18 years of age or older. Unstable angina: Recent onset of angina at rest lasting at least 10 minutes and occurring within 24h before randomization. In addition, had to have one of the following three: ECG changes, previous MI or revascularization procedure, or invasive/noninvasive testing suggestive of ischemic heart disease. Non-Q wave MI: not included Exclusion criteria: left bundle branch block, pacemaker, persistent ST segment elevation, angina with established precipitating cause, contra-indications to anticoagulation, creatinine clearance < 30 ml/min. Interventions Intervention: ASA 100-325 mg/d, enoxaparin 100 anti-factor Xa units/kg sc bid, placebo bolus and infusion. Control: ASA 100-325 mg/d, UFH 5000 IU iv then drip to keep PTT between 55-85 seconds. Timing: Trial therapy was administered for a minimum of 48h to a maximum of 8 days. Co-interventions: not permitted; patients excluded if treating MD deviated from protocol. Other co-interventions (e.g., oxygen, beta-blockers, nitroglycerine, etc) not well described. Outcomes Acute Coronary Events: Recurrent angina, MI, death all reported. Urgent revascularization: reported End Point Definition: Triple end point for all cardiovascular events (angina, MI, death). Complication: Major bleeding, minor bleeding, and thrombocytopenia. Timing of assessment: Outcomes at 48h, 14 days, and 30 days. Notes Enoxaparin. We used the outcomes reported at 14 days for the pooled results. Correspondence with Pharmaceutical Company. Allocation concealment B Study FRAXIS 1999 Methods Prospective, randomized, double-blind, parallel-group, multicenter trial. Participants Patients 18 years of age or older with non-Q-wave MI or recent onset of rest angina lasting longer than 5 minutes or severe exertional angina and occurring within 48h before randomization. In addition, had to have ECG signs compatible with the clinical diagnosis or in cases of preexisting and documented LBBB, known CAD. If Q waves were present, a previous ECG tracing must confirm the long standing diagnosis. Interventions Group I: ASA 325 mg/d, UFH 5000 IU iv then infusion titrated to PTT x 6 days. Group II: ASA 325 mg/d, nadroparin iv 86 AXa IU/kg then sc 86 AXa IU/kg bid x 6 days. Group III: ASA 325 mg/d, nadroparin iv 86 AXa IU/kg then sc 86 AXa IU/kg bid x 14 days. 11 Low molecular weight heparins versus unfractionated heparin for acute coronary syndromes (Review)
Low-Molecular-Weight Heparins: Are they all the Same?
British Journal of Haematology, 2003
The low-molecular-weight heparin products dalteparin, enoxaparin and tinzaparin are very similar but not identical. The methods used to chemically prepare these commercially available products differ, and a number of studies have shown distinct differences in their in vitro and in vivo pharmacology. Unfortunately, only a few studies have directly compared different low-molecular heparins and these studies have been restricted to therapy for venous thromboembolism. The comparison studies that have been published have shown comparable clinical efficacy in the treatment and prevention of venous thromboembolism. In the absence of any direct comparison studies, the relative efficacy of different products in the treatment of patients with acute coronary syndrome remains controversial. For most indications, there are more studies in the literature that provide evidence supporting the use of enoxaparin. Aside from the treatment of venous thromboembolism, therapeutic interchange of different low-molecular-weight heparin products requires the assumption that the products are equivalent, and it also requires certain assumptions in order to calculate an equivalent dose.
Emergence of Low-Molecular-Weight Heparins in Cardiology
Pharmacotherapy, 1999
Drug therapy for the management of acute coronary syndromes is rapidly expanding. Over the past few years, a number of new antithrombotic agents have been introduced, including low-molecular-weight heparins. The epidemiology and pathophysiology of acute coronary syndromes are discussed, with a historical perspective on the use of antithrombotic therapy.
The New England Journal of Medicine, 1997
Background Antithrombotic therapy with heparin plus aspirin reduces the rate of ischemic events in patients with unstable coronary artery disease. Lowmolecular-weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, and does not require monitoring. Methods In a double-blind, placebo-controlled study, we randomly assigned 3171 patients with angina at rest or non-Q-wave myocardial infarction to receive either 1 mg of enoxaparin (low-molecular-weight heparin) per kilogram of body weight, administered subcutaneously twice daily, or continuous intravenous unfractionated heparin. Therapy was continued for a minimum of 48 hours to a maximum of 8 days, and we collected data on important coronary end points over a period of 30 days. Results At 14 days the risk of death, myocardial infarction, or recurrent angina was significantly lower in the patients assigned to enoxaparin than in those assigned to unfractionated heparin (16.6 percent vs. 19.8 percent, P ϭ 0.019). At 30 days, the risk of this composite end point remained significantly lower in the enoxaparin group (19.8 percent vs. 23.3 percent, P ϭ 0.016). The need for revascularization procedures at 30 days was also significantly less frequent in the patients assigned to enoxaparin (27.0 percent vs. 32.2 percent, P ϭ 0.001). The 30-day incidence of major bleeding complications was 6.5 percent in the enoxaparin group and 7.0 percent in the unfractionated-heparin group, but the incidence of bleeding overall was significantly higher in the enoxaparin group (18.4 percent vs. 14.2 percent, P ϭ 0.001), primarily because of ecchymoses at injection sites. Conclusions Antithrombotic therapy with enoxaparin plus aspirin was more effective than unfractionated heparin plus aspirin in reducing the incidence of ischemic events in patients with unstable angina or non-Q-wave myocardial infarction in the early phase. This benefit of enoxaparin was achieved with an increase in minor but not in major bleeding. (N Engl