BRPI1000685A2 - use of clopidogrel with acetylsalicylic acid (wing) for the preparation of a medicament for use in the prevention of major vascular events - Google Patents

Abstract

USE OF CLOPIDOGREL WITH ACETYLSALICYLIC ACID (ASA) FOR THE PREPARATION OF A MEDICINE FOR USE IN THE PREVENTION OF LARGER VASCULAR EVENTS. The present invention relates to patients with a history of atrial fibrillation or who suffer from atrial fibrillation, unsuitable for the Vitamin K antagonist, adding clopidogrel to ASA reduced major vascular events, increased major bleeding and reduced stroke.

Description

Report of the Invention Patent for "USE OF CLOPIDOGREL WITH ACETILSALICYLIC ACID (ASA) FOR PREPARING A MEDICINAL PRODUCT FOR PREVENTION OF LARGEST VASCULAR EVENTS".

The present invention relates to the use of clopidogrel with acetylsalicylic acid (ASA) or pharmaceutically acceptable salts thereof for the preparation of a medicament for reducing at least one of the major vascular events in patients with a history of atrial fibrillation or suffering from atrial fibrillation. of atrial fibrillation.

Clopidogrel with the dextrorotatory chemical formula methyl (+) - (S) -a- (2-chlorophenyl) -4,5,6,7, tetrahydrothene [3,2-c] pyridinyl-5-acetate, is described in EP 0 281 459 B.

In the present descriptive report, the term "clopidogrel" shall be understood to mean free base clopidogrel or its pharmaceutically acceptable salts, such as hydrogen sulfate, hydrochloride, hydrobromide, besylate, napsilate, napadisilate, taurocholate, sulfosalicylate, cansilate or tosylate.

Clopidogrel is an ADP-induced platelet aggregation inhibitor indicated by recent myocardial infarction (MI) 1 recent stroke or established peripheral arterial disease (PAD).

ASA is an acetyl derivative of salicylic acid. It is helpful in relieving headache, muscle and joint pain. ASA is also effective in reducing fever, inflammation, and swelling and is thus used to treat rheumatoid arthritis, rheumatic fever, and moderate infection. ASA is also known to be a platelet aggregation inhibitor.

Co-administration of the two active ingredients is known for the treatment of diseases caused by platelet aggregation as described in EP 0 881 901 as in acute coronary syndrome.

The applicant surprisingly found that clopidogrel plus ASA significantly reduced major vascular events by 11% compared with ASA alone in the atrial fibrillation (AF) population.

Major vascular events include events such as stroke, non-CNS systemic embolism, MI, or vascular death.

Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of five times more stroke. It affects more than 1% of the population and is common in the elderly. In those older than 75 years, their prevalence is greater than 10%. One of the serious outcomes associated with AF is stroke, which occurs at an annual rate of 4.5% in AF patients. Approximately 15% of all strokes are attributable to AF, and in those older than 80 years, a quarter of strokes are attributable to AF. Approximately two thirds of strokes in AF patients are estimated to be cardioembolic. In a meta-analysis of AS1 versus anticoagulation therapy trials in FA1 there were a total of 514 cardiovascular events (stroke, non-CNS systemic embolism, MI [MI], or vascular death), of which 48% ( 248) were ischemic strokes.

In the present descriptive report, the term "AF population" should be understood as a population of patients suffering from AF or with at least two episodes of intermittent AF in the previous six months. The term "non-CNS systemic embolism" should be understood as a blood clot in the bloodstream but not in the brain, and the term "vascular death" is any death not clearly due to a non-vascular cause.

The invention also includes the use of clopidogrel with ASA for the preparation of medicament in the prevention of stroke.

Stroke is defined as the sudden onset of a neurological focal deficit lasting more than 24 hours and is classified as ischemic (including hemorrhagic transformation), hemorrhagic, or uncertain. Strokes are classified as ischemic, hemorrhagic or uncertain and the severity of stroke is assessed by the modified Rankin score at the time of hospital discharge or within 7 days of the event. Subdural hematoma is considered as an intracranial hemorrhage, but not classified as stroke.

The invention also includes the use of clopidogrel with ASA for the preparation of medicament in the prevention of MI.

MI is diagnosed according to standard guidelines.

The invention also includes the use of clopidogrel with ASA for the preparation of medicament in the prevention of non-CNS systemic embolism.

The invention also includes the use of clopidogrel with ASA for the preparation of medicament in the prevention of vascular death.

The invention also includes the use of clopidogrel with ASA for the preparation of medicament intended to reduce at least one major vascular event in patients already having protocol AF or at least two episodes of intermittent AF in the previous six months in other words showing a history of AF1 as well as evidence of high risk of vascular events, ie at least one of the following risk criteria may be present:

(a) are 75 years or older;

b) under treatment for systemic hypertension;

c) anterior stroke, transient ischemic attack or non-CNS systemic embolus;

d) Left ventricular dysfunction with left ventricular ejection fraction estimated by echocardiogram or angiogram (radionuclide or contrast) should be

<45%;

e) peripheral vascular disease (anterior peripheral arterial revascularization, limb and foot amputation, or the combination of current intermittent claudication and ankle and arm systolic blood pressure ratio <0.9);

(f) 55 to 74 years old and either of them;

f1) diabetes mellitus requiring drug therapy, or

f2) Documented previous MI or documented coronary artery disease.

These criteria were defined in clinical trials.

The invention also includes the use of clopidogrel with ASA for the preparation of medicament intended to reduce at least one major vascular event in patients with oral anticoagulation (OAC) contraindications or in patients who refuse to take OAC such as Vitamin K antagonists (VKA). ).

In this descriptive report "patients who cannot take OAC" should be understood as patients with contraindications to oral anticoagulation or in patients who refuse to take oral anticoagulation such as Vitamin K antagonists.

Dose-Adjusted Vitamin K (VKA) 1 a OAC antagonists and antiplatelet agents reduce the risk of stroke by 64% and 22%, respectively (Hart RG1 Pearce LA1 Aguilar Ml. Meta-analysis: Antitrombotic Therapy for present stroke in patients whe hae non vascular AF Ann Ann Intern Med 2007; 146: 857-67) and compared with ASA, VKA reduces stroke by 38% (95% Cl 18-52%) but more than doubles risk intracranial hemorrhage and increases the risk of extracranial major hemorrhage by 70%. This does not reduce total or vascular mortality. Based on these results, VKA and ASA are recommended for patients at higher and lower risk of stroke; respectively (Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, Lip GYH, Manning WJ. Antithrombotic therapy in atrial fibrillation. Chest 2008; 133,546S-592S). However, VKAs have a narrow window for therapeutic benefit, and require regular monitoring. VKA ratios are inadequate for a patient including multiple drug interactions, increased risk of bleeding, reduced compliance with International Normalized Ratio monitoring, and the patient's desire to prevent VKA therapy.

One of the most effective stroke treatments in AF in the class of anticoagulants such as VKA (coumarins, diketones such as fluidione, diphenadione or chlorindione and thioclomarol) is warfarin. Compared with ASA, it reduces stroke by 38%; however, it increases major hemorrhage by 70% and intracranial hemorrhage by> 100%. It is also difficult to use, requiring monitoring and lifestyle restrictions. Separate ASA is modestly effective, reducing stroke by 22%. Guidelines have recommended warfarin for patients at higher risk, but many do not take it. This is because a patient may be unsuitable for warfarin includes, risk of bleeding or inappropriate clinical evaluation. Many patients simply prefer not to take it.

The invention also relates to an article of manufacture comprising

a) a packaging material;

b) clopidogrel and ASA and

c) a label, medication guide, or packaging insert contained within the packaging material indicating that clopidogrel and ASA are indicated in patients who have a history of AF.

The invention also relates to a package comprising clopidogrel and a label or clopidogrel, ASA and a label, that label comprising a printed instruction informing a prospective user that clopidogrel and ASA are indicated in patients who have a AF history.

In some embodiments, the printed instruction informs a prospective user of one or more of the following:

a) clopidogrel and ASA are indicated in patients who are 75 years and older:

b) clopidogrel and ASA are indicated in patients undergoing treatment for systemic hypertension;

c) clopidogrel and ASA are indicated in patients suffering from anterior stroke, transient ischemic attack or non-CNS systemic embolus;

d) clopidogrel and ASA are indicated in patients with left ventricular dysfunction with left ventricular ejection fraction (EF) estimated by echocardiogram or angiogram (radionuclide or contrast) being <45%;

e) clopidogrel and ASA are indicated in patients with peripheral vascular disease (anterior peripheral arterial revascularization, limb and foot amputation, or the combination of intermittent claudication and ankle and arm systolic blood pressure ratio <0, 9);

f) clopidogrel and ASA are indicated in patients aged 55 to 74 years and either one; and diabetes mellitus requiring drug therapy, or documented previous MI or documented coronary artery disease.

The invention also relates to a label, medication guide, or package insert indicating that clopidogrel and ASA are indicated in patients who are not

can take OAC.

An effective, simple and safe alternative to this treatment may be of great clinical value. Both ASA and clopidogrel are antiplatelet agents that act through different mechanisms and are effective in preventing vascular events in high-risk patients.

To illustrate the invention, in a non-restrictive manner, a study was performed as described in Example 1. The primary study outcome showed major vascular events (stroke, non-CNS systemic embolism, MI, or vascular death). The most important secondary outcome showed stroke. Other secondary outcomes were the other components of the primary outcome (non-CNS systemic embolism, MI, or vascular death) and the composite of the primary outcome (stroke, non-CNS systemic embolism, MI, or vascular death), and major bleeding.

Major bleeding was any overt bleeding requiring transfusion of at least two units or meeting severe bleeding criteria that included any of the following: death, hemoglobin drop ≥ 50 gm / L, hypotension requiring inotropic agents, intraocular bleeding leading to substantial loss of vision, requirement for surgical intervention, symptomatic intracranial hemorrhage or transfusion requirement ≥ 4 units of blood. Minor bleeding was another bleeding associated with modification of drug study regimen.

For its therapeutic use, clopidogrel as well as ASA of this is generally introduced for pharmaceutical compositions. Such pharmaceutical compositions contain an effective dose of active ingredients or pharmaceutically acceptable salts thereof, and also at least one pharmaceutically acceptable excipient. The two active ingredients may be in the same pharmaceutical composition or in two separate pharmaceutical compositions.

Such excipients are chosen according to the pharmaceutical form and desired method of administration from the usual excipients which are known to those skilled in the art.

In such pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, clopidogrel, or a pharmaceutically acceptable salt thereof, may be administered in unit administration form. as a mixture with conventional pharmaceutical excipients, animals and humans in the cases mentioned below.

Suitable unit administration forms include oral administration forms, such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal forms, oral administration forms. inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants. For topical application, clopidogrel and pharmaceutically acceptable salts thereof may be used in gels, creams, ointments or lotions.

The daily oral dose of clopidogrel may be up to 300 mg taken as one or more consumptions.

The daily oral dose of ASA may be up to 100 mg taken in one or more intakes.

There may be specific cases in which higher or lower dosages do not deviate from the context of the invention. In accordance with standard practice, the appropriate dosage for each patient is determined by the physician in accordance with the method of administration, weight, pathology, body surface area, cardiac output, and patient response.

The present invention is illustrated by the data hereinafter with reference to the accompanying figures in which:

Figure 1 The upper figure represents a Kaplan Meier curve with the cumulative risk plotted schemes for the primary outcome (stroke, IM1 non-CNS systemic embolism, or vascular death).

figure 1; lower figure represents Kaplan Meier curve for stroke which is the major secondary endpoint.

Figure 2; represents subgroup analysis for primary outcome (upper) and stroke (lower).

Example 1

I. Patient Selection

Patients should have a history of protocol AF or should have at least two episodes of intermittent AF within the previous six months.

Patient recruitment was performed taking into account the following inclusion criteria:

Inclusion criteria:

To be eligible for trial patients, they must meet the following three conditions at the same time:

evidence of AF on a current electrocardiogram (ECG) or two ECGs recorded within two weeks, one part for 6 months prior to study protocol.

Evidence of high risk of vascular events: At least one of the following risk criteria must be present:

(a) are 75 years or older;

b) in treatment of systemic hypertension;

c) anterior stroke, transient ischemic attack or non-CNS systemic embolus;

d) left ventricular dysfunction with left ventricular ejection fraction estimated by echocardiogram or angiogram (radionuclide or contrast) being <45%; e) peripheral vascular disease (anterior peripheral arterial revascularization, limb and foot amputation, or the combination of current intermittent claudication and ankle and arm systolic blood pressure ratio <0.9);

(f) 55 to 74 years old and either of them;

f1) diabetes mellitus requiring drug therapy, or

f2) Documented previous MI or documented coronary artery disease.

They cannot take OAC.

Exclusion Criteria:

Patients were excluded if any of the following were present:

a.clopidogrel requirement

Oral requirement for anticoagulant

ç. previous intolerance to ASA or clopidogrel

d. Peptic ulcer disease documented six months earlier

and. anterior intracerebral hemorrhage

f. significant thrombocytopenia (platelet count <50 χ 10 ^ 9 / L)

g. psychosocial reason making study participation impractical

H. geographical reason making study participation impractical

i. progressive alcohol abuse

j. mitral stenosis

k. severe comorbid condition such that the patient is not expected to survive in 6 months

l. patient receiving an investigative pharmacological agent

m chronic therapy requirement for chronic non-COX-2 NSAID inhibitor (> 3 months) (non-steroidal anti-inflammatory drugs) unless desired to be recorded in the study.

II. Duration and treatment 7,554 AF patients at risk of stroke and unable to take CAB were randomized to receive 75 mg of clopidogrel or placebo once daily on top of ASA (75-100 mg recommended daily). The primary outcome was a composite of stroke, MI, systemic non-central nervous system embolism, or vascular death.

There were 7,554 patients who gave informed consent and were randomized between June 2003 and May 2006 to receive clopidogrel (3772) or placebo (3782). All patients initially received study medication and were followed until November 2008. There were 52 patients lost to follow-up (0.7%). All patients were included in the final analysis to the last follow-up point. The average duration of study follow-up for both groups was 3.6 years.

III. Results

The results that are obtained in this trial were analyzed by Kaplan Meier curves in relation to time of events, were compared by means of the registration grading test using bilateral significance tests. An Independent Data Safety Monitoring Board periodically reviewed the efficacy and safety data, and was guided by a modified Haybit-tie-Peto limit of four standard deviations in the first half. of the study and three in the second half of study termination consideration regarding efficacy. Relative risk (RR) was estimated using the Cox proportional effect regression model. The percentage reduction χ of a given event is calculated as follows:

χ = 1 - relative risk.

III.1. Success Results

A major vascular event occurred in 833 patients on clopidogrel (6.8% per year) and in 925 placebo patients (7.6% per year; RR 0.89; 95% Cl, 0.81-0, respectively). 98; ρ = 0.014). This reduction was due to a reduction in stroke and MI. Stroke occurred in 297 patients on clopidogrel (3.2% per year) and 409 patients on placebo (2.4% per year; RR 0.72, 95% Cl, 0.62-0.84; ρ <0.001 ). MI occurred in 116 patients on clopidogrel (0.9% per year) and 90 placebo patients (0.7% per year; RR 0.78, 95% Cl 0.59 - 1.03; ρ = 0.067). Annual rates of non-CNS systemic embolism were low and similar between groups.

There were similar numbers of vascular death with an additional clopidogrel death (600 vs. 601) with a rate of 4.7% per year in both groups (RR 1.00, 95% Cl, 0.89 -1.12; ρ = 0.77). There were 1,662 total deaths, including 164 fatal strokes, which are responsible for 10% of all deaths. Other major causes of death were non-vascular in 27%, arrhythmic in 21%, pumping failure in 19%, and a variety of other or unknown vascular causes in remnants. There were 70 fatal hemorrhages that were 4% of all deaths.

Table 1 represents baseline characteristics of patients. The average age was 72 years and 58% were men. The average CHADS2 index was 2.1. 83% of patients received ASA under baseline and 8.5% were on a VKA. The reasons identified for protocol in the study were specified as bleeding risk at 23%, no bleeding risk specified, but medical assessment that VKA was inadequate at 50% and patient preference at 26%.

The CHADS2 index is an algorithm to predict the risk of stroke in patients with AF. The index designates points for various risk factors as follows: congestive heart failure (1 point), hypertension (1 point), age> 75 years (1 point), diabetes (1 point), and previous stroke or transient ischemic attack (2 points). The index is calculated by adding together all the points for a given patient.

There were no statistically significant differences in any characteristics according to treatment distribution (p <0.05). Table 1: Baseline Characteristics

<table> table see original document page 13 </column> </row> <table> <table> table see original document page 14 </column> </row> <table>

Data is number (%) or mean (SD). Bpm = beats per minute; CABG = coronary artery bypass graft (saphenous vein); CAD = coronary artery disease; ECG = electrocardiographic; ACE = angiotensin converting enzyme; VKA = Vitamin K Antagonist.

** Patients with a CHADS2 index of 0 meet the study inclusion criteria and usually had peripheral vascular disease, age exactly 75 years, or coronary artery disease age 55-74 years. There is insufficient data to calculate the index in 5 patients.

III.2. Results referring to types of stroke and severity

Ischemic stroke was significantly reduced by 2.7% per year on ASA to 1.8% per year on clopidogrel with an ASA therapy foundation (p <0.001). There is a non-significant increase in the rate of clopidogrel-added hemorrhage from 0.2% to 0.2% per year. Strokes of all severities, as measured by the modified Rankin index, were reduced by clopidogrel with an ASA therapy foundation. Addition of clopidogrel prevented 47 non-disabling strokes (modified Rankin index 0-2), and 67 disabling or fatal strokes (modified Rankin 3-6). With clopidogrel, there is a net decrease of 21 fatal strokes, 27 rare fatal stroke of an ischemic or uncertain etiology, and 6 most fatal hemorrhagic strokes.

Table 2 represents the primary outcomes in the total population.

Non-disabling strokes were those with modified Rankin indices of 0-2. Disabling or fatal strokes were those with modified Rankin indices of 3-6. According to the modified Rankin scale: 0 = no symptoms; 1 = no significant disability; 2 = slight disability; 3 = moderate disability; 4 = moderately severe disability; 5 = severe disability; 6 = dead. Table 2

<table> table see original document page 16 </column> </row> <table> ΙΙΙ.3. Results referring to haemorrhage

Major bleeding occurred in 250 clopidogrel patients (1.9% per year) and 162 placebo patients (1.3%; RR 1.55, 95% Cl, 1.27-1.89; ρ <0.001) . There are an excess of 77 major bleeds from non-clopidogrel strokes, including an excess of 12 fatal non-stroke bleeds. The most common bleeding site was the gastrointestinal tract with an excess of 63 major bleeds under clopidogrel (132 versus 68). Patients with composite success of primary outcome or major hemorrhage under clopidogrel (966 versus 995) were rare (RR 0.97; 95% Cl 0.89-1.06; ρ = 0.24).

Table 3 represents the major bleeding in the total population. <table> table see original document page 18 </column> </row> <table>

Claims (14)

1. Use of clopidogrel and acetylsalicylic acid for the preparation of medicament intended to reduce at least one of the major vascular events in a patient with a history of atrial fibrillation. Use according to claim 1 for the preparation of medicament in the prevention of stroke. Use according to claim 1 or 2 for the preparation of medicament for the prevention of myocardial infarction. Use according to one of the preceding claims for the preparation of a medicament for the prevention of non-CNS systemic embolism. Use according to one of the preceding claims for the preparation of a medicament for preventing vascular death. Use according to one of the preceding claims, characterized in that the patient also exhibits at least one of the following risk factors: (a) they are 75 years or older; b) in treatment of systemic hypertension; c) anterior stroke, transient ischemic attack or non-CNS systemic embolism; d) left ventricular dysfunction with left ventricular ejection fraction estimated by echocardiogram or angiogram (radionuclide or contrast) being <45%; e) peripheral vascular disease (anterior peripheral arterial revascularization, limb and foot amputation, or the combination of current intermittent claudication and ankle and arm systolic blood pressure ratio <0.9); (f) 55 to 74 years old and either of them; f1) diabetes mellitus requiring drug therapy; or f2) documented anterior myocardial infarction or documented coronary artery disease. Use according to one of the preceding claims, characterized in that the patients are 75 years or older. Use according to one of the preceding claims, characterized in that the patient cannot take oral anticoagulant. Use according to claim 8, characterized in that the oral anticoagulant is the vitamin K antagonist. Use according to one of the preceding claims, characterized in that clopidogrel hydrogensulfate is used. An article of manufacture comprising: a) a packaging material; b) clopidogrel and acetylsalicylic acid; and c) a label or packaging insert contained within the packaging material indicating that clopidogrel and acetylsalicylic acid are indicated in patients who have a history of atrial fibrillation. An article according to claim 11, wherein the label, medication guide, or package insert indicates that clopidogrel and ASA are indicated in patients who exhibit at least one of the following risk factors: 75 years or older; b) in treatment of systemic hypertension; c) anterior stroke, transient ischemic attack or non-CNS systemic embolism; d) left ventricular dysfunction with left ventricular ejection fraction estimated by echocardiogram or angiogram (radionuclide or contrast) less than 45%; e) peripheral vascular disease (anterior peripheral arterial revascularization, limb and foot amputation, or the combination of current intermittent lameness and ankle and arm systolic blood pressure ratio <0.9); (f) 55 to 74 years old and either of them; f1) diabetes mellitus requiring drug therapy; or f2) documented anterior myocardial infarction or documented coronary artery disease. An article according to claim 11 wherein the label, medication guide, or package insert indicates that clopidogrel and ASA are indicated in patients who cannot take oral anticoagulant. 14. Packaging comprising clopidogrel and a label or clopiodogrel, acetylsalicylic acid and a label, the label comprising a printed instruction informing a prospective user that clopidogrel and acetylsalicylic acid are indicated in patients who have a history of atrial fibrillation.