Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-09-07
2001-07-10
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06258798
ABSTRACT:
INTRODUCTION
The invention relates to a method for treatment of unstable coronary artery disease, which is characterised by an early revascularisation together with administration of a low molecular weight heparin. Preferably the low molecular weight heparin is administered up to revaseularisation.
The methods are also useful for treatment of unstable angina and not worsening chest pain and for treatment of non-Q-wave myocardial infarction (mild heart attack).
BACKGROUND
Heparin is a sulphate-containing polysaccaride, which on a large scale is isolated from intestinal mucus from swine or lung from cattle. It is used as an anti-coagulant medicament. Low molecular weight heparin is obtained by depolymerisation of heparin, normally with a molecular weight of 2000 to 9000 Da. Low molecular weight heparins are clinically used as anti-thrombotic agents.
Fragmin® is a low molecular weight heparin, which has been on the market since 1985 and is manufactured by Pharmacia & Upjohn. It is an antithrombotic agent useful in the treatment and prophylaxis of thrombosis, containing dalteparin sodium with an average molecular weight of 5000 Da. Dalteparin sodium is produced through nitrous acid depolymerisation of sodium heparin from porcine intestinal mucosa. It is composed of strongly acidic sulphatcd polysaccaride chains with an average molecular weight of 4000-6000 and about 90% of the material within the range 2000-9000 Da.
Other low molecular weight heparins on the market are e.g. Klexane® (enoxaparin). Fraxiparine® (nadroparin), Clivarin® (reviparin) and Innohelp® (tinzaparin). Different uses within the therapeutic area have been suggested for low molecular weight heparin such as treatment of diabetic nephopathy and diabetic neuropathy (EP513513), treatment of chronical renal insufficiency (EP710483), inhibition of TNF-&agr; secretion (WO9219249) and treatment of inflammatory or immunological diseases (WO9418988). During the past tell years considerable progress has been made in the medical treatment of patients with acute myocardial infarction as well as unstable and stable angina pectoris. In this type of patients with coronary artery disease the risk of total occlusion and development of a larger myocardial infarction can be reduced by 50% by aspirin (1, 2, 3) and by another 65% by heparin infusion or weight-adjusted s.c. dalteparin, a low molecular weight heparin, for six days (1, 2, 4, 5), reducing the myocardial infarction rate to 1-2% during this period During the short-term dalteparin/heparin treatment, symptoms subside (2, 5) but a significant stenosis often remains in the artery because of the pre-existing atherosclerotic lesion and/or remaining thrombotic material (6-8). Still, after the acute treatment period the risk of a new myocardial infarction is around 10% after six weeks and 15% after six months, despite conventional treatment. Therefore, a long-term pharmaceutical and/or interventional policy is urgently needed in these patients to reduce the long-term event rate.
The FRISC study (5) demonstrated that treatment with a low molecular weight (l.m.w.) heparin (dalteparin, Fragmin®) influenced the risk of death/myocardial infarction. It was shown that Fragmin® 120 IU/kg/12 h for six days compared to placebo reduced myocardial infarction by 63%, recurrent angina and the need for urgent revascularisation by 50% during the initial six days. During the continued long-term treatment using 7,500 IU/24 h for forty days or corresponding placebo the absolute reduction in event rates was maintained.
However, early after the lowering of the dose at six days there were indications of reactivation of the disease.
Numerous studies have demonstrated that signs of ischemia at ambulatory monitoring or stress tests might identify patients at an increased risk of subsequent cardiac events (9-14).
Most of these studies were performed without the use of modern medication, such as aspirin, &bgr;-blockers, ACE-inhibitors and lipid lowering drugs. At the present time the utilisation and timing of revascularisation in these patients is variable and very little guidance can be obtained from the presently available scientific reports. Inadequate use of modern protective medication and invasive procedures might result in considerable consequences both for the patients and the costs of medical care. Therefore, it seemed essential to explore further the protective effects of prolonged intense antithrombotic medication. Of equal interest has been to elucidate whether a direct invasive approach with early coronary revascularisation had any advantages compared to a stepwise selective approach with invasive procedures only at recurring or incapacitating symptoms or ischemia in patients with unstable coronary artery disease, who received optimal protective medication.
ABBREVIATIONS AND DEFINITION OF TERMS
ACE
angiotensin converting enzyme
Angiography
Study of vessels
Anti-ischemic drugs
defined as &bgr;-blockers, nitrates (long- and short-acting),
calcium antagonists
ASA
aspirin, acetyl salicylic acid
BMI
body mass index
CABG
coronary artery bypass grafting
CAD
coronary artery disease
Lipid lowering drugs
defined as statins, fibrates and other lipid lowering
drugs
l.m.w. heparin
low molecular weight heparin
MI
myocardial infarction
Other cardiovascular drugs
defined as ACE-inhibitors, digitalis, diuretics drugs
p.o.
per oral
PTCA
percutaneous transluminal coronary angioplasty
p-value
Cochran-Mantel-Haenszel test
Revascularisation, Rev
restoration of blood supply by surgical intervention
e.g. balloons and/or by-pass
s.c.
subcutaneous
Non-invasive policy = stepwise selective approach with coronary angiography and coronary revascularisation only at recurring br incapacitating symptoms or severe ischemia at exercise test
Invasive policy = direct invasive approach with early coronary angiography and revascularisation
FIGS.
FIG. 1
Probability of death or MI during treatment up to 3 months
FIG. 2
Death, MI or revascularisation (comulative hazard)
FIG. 3
Death or MI (comulative hazard)
THE INVENTION
The invention relates to a method for treatment of unstable coronary artery disease, which is characterised by an early revascularisation together with administration of a low molecular weight heparin. Preferably the low molecular weight heparin is administered up to revascularisation.
Clinical benefit has been shown for treatment up to 60 days, but the revascularisation should be done as early as possible, and more preferably before 30 days.
The methods are also useful for treatment of unstable angina, for not worsening chest pain and for treatment of non-Q-wave myocardial infarction (mild heart attack).
The present study compared the efficacy of prolonged (three months) treatment with Fragmin with that of short term (five to seven days) treatment in patients with unstable coronary artery disease. During the first five to seven days, known as the open acute phase of this double blind randomized clinical trial, all 2,267 patients received 120 IU/kg/12h of
Fragmin. Durinig the prolonged (up to 90 days) double blind phase, 2,105 patients were randomized to treatment with either subcutaneous Fragmin at a dose of 5,000 or 7,500 IU twice daily or placebo.
From Day 1 to 150, the incidence of death and/or MI was statistically significant between the two treatment strategies in favour of the early invasive policy (p=0.031).
It has been found that prolonged treatment with Pharmacia & Upjohni's low molecular weight heparin, Fragmin® (dalteparin sodium injection) for up to 30 days demonstrates a 47 percent reduction in the incidence of death or heart attack in patients who suffered unstable coronary artery disease, which includes unstable angina (worsening chest pain, often when at rest) and non-Q-wave myocardial infarction (mild heart attack).
Results from the study below shows that after 30 days of treatment with Fragmin, the incidence of death/myocardial infarction in patients was 3.1 percent compared with 5.9 percent for patients who received placebo afte
Dinsmore & Shohl LLP
Fonda Kathleen K.
Pharmacia AB
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