The Effect of Serum LDL Lowering on Aspirin Resistance

NCT ID: NCT00466154

Last Updated: 2013-02-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-07-31
• Study Completion Date: 2007-01-31

Brief Summary

Aspirin resistance is the persistent platelet activation, demonstrated by platelet function tests (1).

The hypothesis is that:LDL lowering by statin in patients with aspirin resistance can improve the effect of aspirin due to the potential decreasing of cholesterol content in the platelet membranes.

Patients and methods:Forty hypercholesterolemic patients with aspirin resistance after 5 days of treatment with aspirin and high LDL and triglycerides<300 mg/dL, will be enrolled.

Ten healthy volunteers will be the control group.

Detailed Description

The patients will be treated by aspirin loading dose of 500mg and then 100 mg/day for other 4 days. For patients that will be entrolled in the regular working hours, platelet aggregation test and cholesterol content in platelet membranes will be done at baseline.

Blood tests for lipids, liver (ALT,AST,GGT,Alkaline phosphatase and bilirubin) and renal function tests (blood urea nitrogen and creatinine), complete blood count, general urine test and serum homocysteine will be done on the second day.

On the fifth day optical platelet aggregation test, cholesterol content in platelet membranes, platelet function in the PFA-100 system and soluble p-selectin in the plasma will be done If the patient has aspirin resistance (platelet aggregation 20% with epinephrine or 70% with ADP), LDL will be lowered in the plasma of 20 patients by hypolipidemic drugs (statin alone or combined with ezetimibe). Other 20 patients will continue to be treated by aspirin alone.

One month later, blood tests for lipids, liver (ALT,AST,GGT,Alkaline phosphatase and bilirubin) and renal function tests (blood urea nitrogen and creatinine), complete blood count, general urine test and serum homocysteine will be done for the second time and platelet activity will be tested again for all patients.

Platelet separation:

For platelet studies, venous blood (30 ml) will be collected through siliconized syringes into acid citrate dextrose solution(1.4% citric acid, 2.5% sodium citrate, and 2% dextrose) at a ratio of 9:1 (v:v) for washed platelets (WP)preparation.WP will be prepared by centrifugation at 240g for 20 min. The platelet bellet will be washed twice in 5 mmol Hepes buffer, pH 7.4 (140 mmol NaCl, 2 mmol KCL, 1 mmol MgCl2, 5 mmol Hepes, 12 mmol NaHCO3 and 5.5 mmol of glucose). For the preparation of WP suspension, 15 uL of acetic acid (1mmol) will be added to 1 ml of platelet suspension throughout WP preparation in order to ensure acidic conditions which are required for platelet resuspension. This procedure will reduce the medium pH to 6.5 and it does not influence the aggregation response of the WP.

Platelet aggregation:

Collagen (Nycomed, germany) will be used as the aggregating agent at a concentration of 4 ug/ml (this concentration can cause up to 60% aggregation amplitude in WP). Platelet aggregation will be perfomed at 37ºC in aggregometer using hepes as a reference system. Results will be expressed as the extent of maximal aggregation (% of maximal amplitude) and also as the slope of the aggregation curve (cm/min).

Cholesterol content in platelet membranes:

Platelets will be washed three times with Hepes buffer, and then sonicated twice for 20 seconds at 80 watt. Platelet lipids will be extracted with hexane:isopropanolol (3:2, v:v). The cholesterol content will be measured in the dried hexane phase by the method of Chiamori et al (12). Platelet protein will be determined using the method of Lowry (13).

Conditions

Aspirin Resistance; Hypercholesterolemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

Aspirin

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Hypercholesterolemic low-moderate risk patients without hypolipidemic drugs for at least one month.

2. Age ≥18 years on stable AHA step 1 diet.

3. For primary prevention, LDL > 130 mg/dL and for secondary prevention LDL>70 and <100mg/dL. .

4. CPK, ALT and AST < 1.5 x upper limit of normal at baseline.

Exclusion Criteria

1. Women currently receiving cyclical hormones.

2. Treatment with hypolipidemic drugs during the last month.

3. Oral corticosteroids, NSAID, COX-1 inhibitors and other antiplatelet drugs.

4. Women with childbearing potential unless on safe contraception.

5. Psychiatric disease with defect in judgement.

6. Severe renal or hepatic diease.

7. Uncontrolled hypo- or hyperthyroidism.

8. Contraindication for ezetimibe or statin treatment.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Ziv Hospital

OTHER_GOV

Sponsor Role: lead

Principal Investigators

Osamah Hussein, MD

Role: PRINCIPAL_INVESTIGATOR

Internal Medicine Department A, Ziv Medical Center

Locations

Internal Medicine Department A ,Ziv Goverment Hospital

Safed, , Israel

Countries

Israel

References

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Reference Type: BACKGROUND

PMID: 15738456 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 11492985 (View on PubMed)

Bruno A, McConnell JP, Mansbach HH 3rd, Cohen SN, Tietjen GE, Bang NU. Aspirin and urinary 11-dehydrothromboxane B(2) in African American stroke patients. Stroke. 2002 Jan;33(1):57-60. doi: 10.1161/hs0102.102010.

Reference Type: BACKGROUND

PMID: 11779889 (View on PubMed)

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

PMID: 15757620 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 9860782 (View on PubMed)

Patrono C. Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb Haemost. 2003 Aug;1(8):1710-3. doi: 10.1046/j.1538-7836.2003.00284.x. No abstract available.

Reference Type: BACKGROUND

PMID: 12911581 (View on PubMed)

Cipollone F, Ciabattoni G, Patrignani P, Pasquale M, Di Gregorio D, Bucciarelli T, Davi G, Cuccurullo F, Patrono C. Oxidant stress and aspirin-insensitive thromboxane biosynthesis in severe unstable angina. Circulation. 2000 Aug 29;102(9):1007-13. doi: 10.1161/01.cir.102.9.1007.

Reference Type: BACKGROUND

PMID: 10961965 (View on PubMed)

Surya II, Akkerman JW. The influence of lipoproteins on blood platelets. Am Heart J. 1993 Jan;125(1):272-5. doi: 10.1016/0002-8703(93)90096-r. No abstract available.

Reference Type: BACKGROUND

PMID: 8380241 (View on PubMed)

Ardlie NG, Selley ML, Simons LA. Platelet activation by oxidatively modified low density lipoproteins. Atherosclerosis. 1989 Apr;76(2-3):117-24. doi: 10.1016/0021-9150(89)90094-4.

Reference Type: BACKGROUND

PMID: 2730708 (View on PubMed)

Osamah H, Mira R, Sorina S, Shlomo K, Michael A. Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets. Br J Clin Pharmacol. 1997 Jul;44(1):77-83. doi: 10.1046/j.1365-2125.1997.00625.x.

Reference Type: BACKGROUND

PMID: 9241100 (View on PubMed)

CHIAMORI N, HENRY RJ. Study of the ferric chloride method for determination of total cholesterol and cholesterol esters. Am J Clin Pathol. 1959 Apr;31(4):305-9. doi: 10.1093/ajcp/31.4.305. No abstract available.

Reference Type: BACKGROUND

PMID: 13637038 (View on PubMed)

LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265-75. No abstract available.

Reference Type: BACKGROUND

PMID: 14907713 (View on PubMed)

Other Identifiers

HP 5-173 S

Identifier Type: -

Identifier Source: org_study_id