Luan an tom tat (eng) nghiên cứu hiệu quả liều nạp clopidogrel 600mg trên độ ngưng tập tiểu cầu và kết quả can thiệp động mạch vành qua da trong cấp cứu nhồi máu cơ tim cấp có ST chênh lên

AND TRAINING DEFENSE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES --- BUI THI MIEN STUDY EFFICACY OF 600MG LOADING DOSE OF CLOPIDOGREL ON PLATELET AGGREGATION AND OUT

AND TRAINING DEFENSE

108 INSTITUTE OF CLINICAL MEDICAL AND

PHARMACEUTICAL SCIENCES

-

BUI THI MIEN

STUDY EFFICACY OF 600MG LOADING DOSE OF CLOPIDOGREL ON PLATELET AGGREGATION AND OUTCOMES OF PERCUTANEOUS CORONARY INTERVENTION IN ST SEGMENT ELEVATION

108 INSTITUTE OF CLINICAL MEDICAL AND

1 Prof Dr Nguyen Quang Tuan

2 Assoc Prof Dr Be Hong Thu

The dissertation can be found at:

1 National Library of Vietnam

2 Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences

BACKGROUND

Several studies have evaluated the efficacy of 300mg loading

dose of clopidogrel before percutaneous coronary intervention or

through fibrinolytics When comparing normal dose of clopidogrel

(300 mg) with doubled dose of clopidogrel (600 mg), many studies

show that 600mg loading dose of clopidogrel works faster, and

inhibits ST aggregation more strongly and improves effectiveness of

clinically percutaneous coronary intervention In order to reduce

waiting time, the 600 mg loading dose of clopidogrel inhibits TC

faster and more strongly Within 2 hours after administration of

600mg loading dose of clopidogrel, the TC is almost completely

inhibited, which reduces the risk of thrombotic occlusion stenting

and side effects similarly to the 300mg loading dose of clopidogrel

To evaluate the efficacy of 600mg loading dose of clopidogrel before

percutaneous coronary intervention in patients with ST segment

elevation myocardial perfusion, the study on efficacy of 600mg

loading dose of clopidogrel on platelet aggregation and outcomes of

percutaneous coronary intervention in ST segment elevation

myocardial infarction" was carried out for two purposes:

1 Compare the efficacy of 600mg and 300mg loading

doses of clopidogrel on platelet aggregation in ST segment

elevation myocardial infarction patients with percutaneous

coronary intervention

2 Evaluate the efficacy of percutaneous coronary

intervention using 600mg loading dose of clopidogrel

clinically, subclinically and some undesirable effects

Symptoms of myocardial ischaemia

Significant fluctuations of new ST-T or new possibility of occurrence or completely new left bundle branch block

Occurrence of Q wave on ECG

The most recent imaging proof of alive cardiac muscles or new occurrence of dyskinesia

Determination of coronary thrombosis through angiography or autopsy

1.1.2 Treatment of ST segment elevation myocardial infarction

1.1.5.1 General initial treatment

Patients should be lying motionlessly on beds If patients are over anxious, tranquilizers should be given Oxygen therapy is indicated with SaO2 <90% or PaO2 <90% Nitroglycerin is sublingual, can be repeated every 5 minutes Then vein catheter is set

up Fast-absorbing aspirins should be given orally or through vein catheter with a starting dose of 300 mg Then treatment is continued with 75-325 mg / day 300mg or 600mg loading doses of clopidogrel

or 60mg prasugrel dose or 90mg ticagrelor dose is administrated twice per day Anticoagulant: heparin is injected into veins with dose

of 65-70 IU/kg body weight, then 15-18 IU/kg body weight/hour is maintained Sympathetic beta blockers: reduce mortality rate and necrosis myocardial infarction ACE inhibitors: may be given within the first 24 hours if blood pressure is not low and there are no other contraindications

1.1.5.2 Reperfusion

The most important goal in treating acute myocardial infarction is re-perfusion (re-circulating clotting) as soon as possible First phase coronary intervention is the immediate intervention applied upon admission without using defibrinogenating agents

1.2 CLOPIDOGREL

1.2.1 Mechanism of clopidogrel actions

Clopidogrel inhibits non-recovery TC selection through ADP, mediated by the P2Y12 receptor located on the TC surface

1.2.2 Absorption and distribution

Cmax of 3 mg/L appears 1 hour after repeated dosing

1.2.3 Metabolism and excretion

The half-life excretion of carboxylic acid metabolites is 7 to 8 hours after single dose administration 50% is excreted in urine and about 46% is excreted in faeces

1.2.4 Usage

The drug is taken orally, can be taken at the same time with meals or not

1.2.5 Undesired effects of clopidogrel

Blood clots, bleeding, gastrointestinal disorders, skin and subcutaneous tissue disorders

2014

2.1.1 Criteria for selecting patients

All patients aged ≥ 18 hospitalized at Vietnam National Heart Institute from December 2011 and January 2014 who were diagnosed with acute ST-segment elevation myocardial infarction

1 Diagnosis of acute ST-segment elevation myocardial infarction was based on the criteria of the European Society of Clinical Oncology (ESC 2012), American College of Cardiology (ACC 2013)

2 Patients were indicated with first phase percutaenous coronary intervention as recommended by the Vietnam National Heart Association [8]

3 Patients agreed to participate in the study

2.1.2 Exclusion criteria

Previously administrated with thrombolytic agents, anticoagulants, platelet aggregation inhibitors, anti-inflammatory agents; taking oral anticoagulants for 10 days; contraindications to use of anti- platelet aggregation agents

2.2 RESEARCH METHODOLOGY

2.2.1 Research design

Prospective study, vertically follow-up, with comparisons

2.2.2 Sample size and sampling method

2.2.3 Research facilities

2.2.3.1 Blood test

Biochemical tests of blood parameters, general analysis of peripheral blood cells, measurement of platelet aggregation, basic coagulation were carried out according to standards of departments

in Bach Mai Hospital

2.2.3.4 Coronary capture and intervention

Cardiovascular intervention unit, Vietnam National Heart Institute, Bach Mai Hospital

2.2.4 Research steps

 Thorough clinical examination according to symptoms

 Full range of routine laboratory tests: ECG, cardiac Doppler ultrasonography, biochemical tests of blood, general analysis of peripheral blood cells, primary blood clotting, platelet aggregation measurements (platelet aggregation and peripheral blood cells were carried out twice: upon admission without clopidogrel dose and 4 hours after clopidogrel administration) Patients were given anticoagulants and anti-platelet aggregation agents when they were diagnosed with acute ST-segment elevation myocardial infarction Medications include anticoagulants, oral aspirin 300mg and oral clopidogrel 300mg or 600mg before the intervention Conservative treatment was combined according to standards in both groups, such

as beta blockers, angiotensin converting enzyme inhibitors, statins, proton pump inhibitors, etc Capture and intervention of coronary at the Cardiovascular Intervention Unit, Vietnam National Heart Institute, Bach Mai Hospital

 After the intervention, the same medications were applied to both groups until the end of the study

 Major clinical events during hospitalization and during

follow-up period were monitored

2.3 DATA PROCESSING

Data were processed according to medical statistical method

2.4 RESEARCH DESIGN

96 patients diagnosed ST segment elevation myocardial

infarction patients with percutaneous coronary intervention

Clinical examination, sub clinical tests and conservative treatment under regimen

Group 1: 46 patients using 600mg loading

dose of clopidogrel before coronary

- Comparing efficacy of 600mg loading dose of clopidogrel and 300mg loading dose of clopidogrel on platelet aggregation

- Evaluating efficacy of coronary intervention between two groups of using 600mg loading dose of clopidogrel and 300mg loading dose of clopidogrel

Conclusion:

- Objective 1

- Objective 2

Radom distribution

CHAPTER 3

RESEARCH FINDINGS

In the period from December 2011 to January 2014, a study on

96 patients with acute ST-segment elevation myocardial infarction treated at the Vietnam National Heart Institute, Bach Mai Hospital was conducted Patients were divided into two groups: Group I: 600mg loading dose of clopidogrel Group II: 300mg loading dose of clopidogrel

3.1 GENERAL CHARACTERISTICS OF STUDY GROUPS

The majority of patients in both groups were aged 50 and older, 90/96 patients, accounting for 93.7% The average age of patients was 64.8 ± 10.5 Age distribution between the two groups was not statistically significant with p> 0.05 Male patients were more than female patients, 70/96 patients, accounting for 72.9% There was no gender difference between the two groups with p> 0.05

3.2 COMPARING EFFICACY OF 600MG LOADING DOSE

OF CLOPIDOGREL AND 300MG LOADING DOSE OF CLOPIDOGREL ON PLATELET AGGREGATION OF WITH ACUTE ST SEGMENT ELEVATION MYOCARDIAL INFARCTION TREATED BY PERCUTANEOUS CORONARY INTERVENTION

3.2.1 Platelet aggregation before and after clopidogrel loading dose between two groups

Diagram 3.2 Platelet aggregation before and after clopidogrel

loading dose between two groups.

Comment: Platelet aggregation level before clopidogrel loading

dose between the two groups is not statistically significant with p> 0.05 Platelet aggregation level after clopidogrel loading dose between the two groups was statistically significant with p <0.05

3.2.2 Response level of two groups

Table 3.15 Response level of two groups

Group

Response level

600mg 300mg Patients % Patients %

Non- response ( A <10%) 2 4.3 2 4.0 Average response ( A: 10% -

p < 0,05

Figure 3.3 Response level of two groups

Comments: The proportion of patients with good response to 600mg

loading dose of clopidogrel group was significantly higher than that

of the 300mg loading dose of clopidogrel group with p <0.05

3.3 EVALUATING EFFICACY OF PERCUTANEOUS CORONARY INTERVENTION WHEN USING 600MG LOADING DOSE OF CLOPIDOGREL CLINICALLY, SUB CLINICALLY AND FOLLOW-UP

3.3.1 Results of coronary intervention between the two groups

3.3.1.1 Electrocardiography fluctuations after coronary

intervention between the two groups

Table 3.19 Electrocardiographic fluctuations after coronary

intervention between the two groups

Time of doing

ECG Group

Before intervention

After intervention p

before and after

Comments: Electrocardiographic fluctuations after coronary

intervention in 600mg loading dose of clopidogrel group compared

to 300mg loading dose of clopidogrel was statistically significant with p <0.05

3.3.1.2 Changes in coronary artery flow (TIMI) after coronary intervention between the two groups

Table 3.20 Changes in coronary artery flow (TIMI) after coronary

intervention between the two groups

Time of TIMI

Group

Before intervention

After intervention p

before and after

Comment: After the intervention, in the group of 600mg loading

dose of clopidogrel, 44 patients achieved TIMI 3 (95.7%) and 2 patients reached TIMI 2 (4.3%), in the group of 300mg loading dose

of clopidogrel, 39 patients reached TIMI 3 (78.0%) and 11 patients

reached TIMI 2 (22.0%), the difference was statistically significant between the two groups with p <0.05

3.3.1.3 Changes in myocardial perfusion level (TMP) after coronary intervention between the two groups

Table 3.21 Changes in myocardial perfusion level (TMP) after

coronary intervention between the two groups

Comments: The number of patients with TMP 3 perfusion was

higher in the 600mg loading dose of clopidogrel group than those in the 300mg loading dose of clopidogrel group, which was statistically significant with p <0.05

3.3.2 Results in early clinical treatment and follow-up

3.3.2.1 Comparing chest pain symptoms in both groups before and after coronary intervention

Table 3.24 Compare chest pain symptoms in both groups before and

after coronary intervention

Group Chest

pain

Before intervention

After intervention p before

Comment: Greatly reduced chest pain symptoms in the 600mg

loading dose of clopidogrel group was more significantly significant than those in the 300mg loading dose of clopidogrel group with p

Comment: The difference in NYHA between the two groups after

the intervention was statistically significant with p <0.05

3.3.2.3 Comparing Killip between the two groups after coronary intervention

Table 3.26 Compare Killip between the two groups after coronary

intervention

Group

Killip

Group of 600mg Group of 300mg Patients % Patients %

Comment: The difference in Killip between the two groups after the

intervention was statistically significant with p <0.05

3.3.2.4 Survival rate from vertical follow-up between the two 600

mg and 300 mg loading doses of clopidogrel

Figure 3.11 Survival rate from vertical follow-up between the two

groups

Comments: Survival rate from vertical follow-up between the two

600 mg and 300 mg loading doses of clopidogrel was not statistically significant with p> 0.05

3.3.2.5 Cardiovascular events during follow-up between the two groups

Table 3.29 Cardiovascular events during follow-up between the two

Comments: The group of 600mg loading dose of clopidogrel

reported 1 case of fatality, the group of 300mg loading dose of clopidogrel reported 2 cases of fatality during follow-up, this difference was not statistically significant with p> 0,05 There were

no cases of cerebrovascular accident, recurrent MI, recurrent occluded stent during follow-up in both groups

3.3.3 Complications and undesired effects

There were no cases of complications from intervention between the two groups Both groups in our study did not report any adverse effects after the use of 300mg loading dose of clopidogrel and 600 mg loading dose of clopidogrel

CHAPTER 4 DISCUSSIONS 4.1 GENERAL CHARACTERISTICS OF RESEARCH GROUPS

Of 96 patients in the study, the group of 600mg loading dose

of clopidogrel showed an average age of 62.7 ± 9.8 (42-79), the group of 300mg loading dose of clopidogrel was 66.8 ± 10, 8 (39 - 89), this difference was not statistically significant with p> 0.05 Those results are similar to many published studies at home and abroad The mean age in the study is 64.8 ± 10.5 years The majority

of patients in the study were aged 50 or older (90/96 patients accounting for 93.7%)

The percentage of males suffering from MI was higher than that of females in both groups (70 male patients, accounting for 72.9% and 26 female patients, accounting for 27.1%) The difference

of sex ratio between the two groups was not statistically significant with p> 0.05

4.2 EFFICACY OF 600MG AND 300MG LOADING DOSES

OF CLOPIDOGREL ON PLATELET AGGREGATION OF ACUTE ST SEGMENT ELEVATION MYOCARDIAL INFARCTION TREATED BY PERCUTANEOUS CORONARY INTERVENTION

4.2.1 Discussing platelet counts, platelet aggregation prior to and after treatment of each group and between the two groups

Diagram 3.2 reveals that after using 600mg loading dose of clopidogrel, platelet aggregation of patients were decreased significantly compared to those of 300mg loading dose of clopidogrel This difference was statistically significant with p <0.05