Long-term effect of clopidogrel in patients with and without diabetes: A systematic review and meta-analysis of randomized controlled trials

Table 1 Definitions of the primary efficacy outcome in each of the included trials

Trial	Definition of primary efficacy outcome
CHANCE 2013	Stroke recurrence (ischemic or hemorrhagic).
CHARISM 2006	The composite of myocardial infarction, stroke, or death from cardiovascular causes.
CREDO 2002	The composite of death, myocardial infarction, and stroke.
CURE 2001	The composite of myocardial infarction, stroke, or death from cardiovascular causes.
POINT 2018	The composite of ischemic stroke, myocardial infarction, or death from ischemic vascular causes.
SPS3 2012	Stroke recurrence (ischemic or hemorrhagic).

Table 2 Characteristics of the excluded trials

Title	Reason for exclusion
A randomised, blinded, trial of clopidogrel vs aspirin in patients at risk of ischaemic events (CAPRIE)	Not clopidogrel + aspirin vs aspirin
Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation	Treatment duration < 3 mo; Not report subgroup results
Addition of clopidogrel to aspirin in 45852 patients with acute myocardial infarction: Randomised placebo-controlled trial	Treatment duration < 3 mo; Not report subgroup results
Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): Randomised, double-blind, placebo-controlled trial	Not clopidogrel + aspirin vs aspirin
Aspirin and extended-release dipyridamole vs clopidogrel for recurrent stroke	Not clopidogrel + aspirin vs aspirin
Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery	Treatment duration < 3 mo
Aspirin plus clopidogrel vs aspirin alone after coronary artery bypass grafting: The clopidogrel after surgery for coronary artery disease (CASCADE) Trial	Not report subgroup results
Clinical outcomes of patients with diabetic nephropathy randomized to clopidogrel plus aspirin vs aspirin alone	Duplicate trials
Clopidogrel with aspirin in acute minor stroke or transient ischemic attack (CHANCE) trial: One year outcomes	Duplicate trials
Dose comparisons of clopidogrel and aspirin in acute coronary syndromes	High dose vs low dose
Duration of Dual Antiplatelet Therapy after Implantation of Drug-Eluting Stents	Long-term vs short-term
Efficacy and safety outcomes of ticagrelor compared with clopidogrel in elderly Chinese patients with acute coronary syndrome	Not clopidogrel + aspirin vs aspirin
Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics	Treatment duration < 3 mo
Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study	Duplicate trials
Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): A randomised controlled pilot trial	Not report subgroup results
Prasugrel or double-dose clopidogrel to overcome clopidogrel low-response – The TAILOR randomized trial	Not clopidogrel + aspirin vs aspirin
Prasugrel vs clopidogrel for acute coronary syndromes without revascularization	Not clopidogrel + aspirin vs aspirin
Prasugrel vs clopidogrel in patients with acute coronary syndromes	Not clopidogrel + aspirin vs aspirin
PROCLAIM: Pilot study to examine the effects of clopidogrel on inflammatory markers in patients with metabolic syndrome receiving low-dose aspirin.	Treatment duration < 3 mo
Randomized clinical trial of the antiplatelet effects of aspirin-clopidogrel combination vs aspirin alone after lower limb angioplasty	Treatment duration < 3 mo
Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention	Not clopidogrel + aspirin vs aspirin
Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial	Not report subgroup results
Ticagrelor vs aspirin in acute stroke or transient ischemic attack	Not clopidogrel + aspirin vs aspirin
Ticagrelor vs clopidogrel in patients with acute coronary syndromes	Not clopidogrel + aspirin vs aspirin
Ticagrelor vs clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction	Not clopidogrel + aspirin vs aspirin
Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome	Not clopidogrel + aspirin vs aspirin
Twelve or 30 mo of dual antiplatelet therapy after drug-eluting stents	Long-term vs short-term
Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation	Not ACS or ischemic stroke patients

Table 3 Baseline characteristics of participants in the included trials

Trial	Country	Centers	Patients	Sample size	Male %	Mean age Y	Diabetes%	Treatment duration M	Lost to follow-up %	Blinding	ITT analysis
CHANCE 2013	China	114	Minor ischemic stroke or high-risk TIA	5170	66	63	21	3	0.7	Double-blind	Yes
CHARI-SM 2006	Worldwide	768	CVD or multiple risk factors	15603	70	64	42	28	0.5	Double-blind	Yes
CREDO 2002	United States and Canada	99	Those would undergo elective PCI	2116	71	62	26	12	1.1	Double-blind	Yes
CURE 2001	Worldwide	482	ACS without ST-segment elevation	12562	62	64	23	12	0.1	Double-blind	Yes
POINT 2018	Worldwide	269	Acute ischemic stroke or high-risk TIA	4881	55	65	27	3	4.1	Double-blind	Yes
SPS3 2012	Worldwide	82	Recent symptomatic lacunar infarcts	3020	63	63	36	41	2.0	Double-blind	Yes

ITT: Intention-to-treat; TIA: Transient ischemic attack; CVD: Cardiovascular disease; PCI: Percutaneous coronary intervention; ACS: Acute coronary syndromes.

Table 4 Antiplatelet treatments and the daily doses used in the included trials

Trial	Drug (daily doses, mg)
	Clopidogrel + Aspirin	Aspirin
CHANCE 2013	Clopidogrel (day 1: 300; day 2-90: 75) + Aspirin (day 1: 75-300; day 2-21: 75; day 22-90: placebo)	Aspirin (day 1: 75-300; day 2-90: 75)
CHARISM 2006	Clopidogrel (75) + Aspirin (75-162)	Aspirin (75-162)
CREDO 2002	Clopidogrel (day 1: 300; day 2 to 12 mo: 75) + Aspirin (day 1: 325; day 2 to 12 mo: 81-325)	Clopidogrel (day 2-28: 75) + Aspirin (day 1: 325; day 2 to 12 mo: 81-325)
CURE 2001	Clopidogrel (day 1: 300, and then 75) + Aspirin (75-325)	Aspirin (75-325)
POINT 2018	Clopidogrel (day 1: 600, and then 75) + Aspirin (50-325)	Aspirin (50-325)
SPS3 2012	Clopidogrel (75) + Aspirin (325)	Aspirin (325)