Platelet Function in Patients with Diabetes Mellitus: From a Theoretical to a Practical Perspective
Table 1
A summary of key antiplatelet drug clinical trials in patients with diabetes mellitus.
Study
(DM/total)
Setting
Groups
Endpoint. Follow-up period
Pertinent findings
Clopidogrel
CURE Clopidogrel in unstable Angina to prevent recurrent events
2,838/12,562
UA, NSTEMI
Clopidogrel (300 mg LD, 75 mg MD) versus placebo in addition to standard aspirin therapy. RCT
Composite cardiovascular death, MI, or stroke. Mean followup 9 months
Higher absolute risk reduction of primary outcome (16.7% to 14.2%) in DM than non-DM patients (9.9% to 7.9%), but a clopidogrel benefit of borderline statistical significance with lower relative risk reduction compared to the overall cohort (15% versus 20% resp.)
OPTIMUS Optimizing antiplatelet therapy in Diabetes Mellitus
40/40
DM patients on DAT with HTPR
Clopidogrel 75 mg MD versus Clopidogrel 150 mg MD. RCT
Platelet function testing at 60 days
Two thirds (40/64) of screened DM patients had “suboptimal response to clopidogrel” 75 mg (HTPR). Platelet aggregation in response to ADP was significantly reduced in DM patients receiving clopidogrel 150 mg compared with the 75 mg group ()
OASIS-7 (CURRENT) Clopidogrel and Aspirin optimal dose usage to reduce recurrent events—seventh organization to assess strategies in ischemic syndromes
5,880/25,087
ACS patients planned for invasive strategy
Clopidogrel (600 mg LD, 150 mg MD for 6 days, then 75 mg MD) versus Clopidogrel (300 mg LD, 75 mg MD). Aspirin (300–325 mg MD) versus aspirin (75–100 mg MD). 2 × 2 factorial design
Composite cardiovascular death, MI, or stroke. 30 days
No overall statistical significance between the two clopidogrel regimes on primary endpoint. No significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome. Reduced secondary outcome of stent thrombosis with high-dose Clopidogrel in subset of patients undergoing PCI
GRAVITAS Gauging responsiveness with a verifynow assay—impact on Thrombosis and safety
1,004/2,214
Patients post PCI with HTPR on DAT by verifynow assay
41% of screened patients (2214 of 5429) had HTPR on Clopidogrel 75 mg. Lower P2Y12 platelet reactivity with higher-dose Clopidogrel but no difference in the primary composite endpoint at 6 months
CHARISMA Clopidogrel for High Atherothrombotic risk and ischemic stabilization, management, and avoidance
6,556/15,603
Patients with stable cardiovascular disease or multiple risk factors
Clopidogrel 75 mg versus placebo in addition to aspirin 75–162 mg daily
Composite cardiovascular death, MI, stroke. Median 28 months follow-up
No difference in primary endpoint between aspirin and DAT. Increased hemorrhagic events with DAT. Increased mortality in patients with DM nephropathy treated with DAT
Cilostazol
ACCEL/RESISTANCE Adjunctive Cilostazol versus high maintenance dose Clopidogrel in patients with Clopidogrel resistance
14/60
Patients with HTPR after clopidogrel 300 mg loading
Clopidogrel 75 mg + cilostazol 100 mg bd versus Clopidogrel 150 mg. All patients on aspirin 200 mg/day. RCT
Platelet function testing at 30 days
Adjunctive cilostazol reduced the rate of HTPR and intensified platelet inhibition as compared with high-maintenance dose clopidogrel 150 mg/day
OPTIMUS-2 Optimizing antiplatelet therapy in diabetes mellitus 2
20/20
DM patients on DAT (aspirin 81 mg, clopidogrel 75 mg daily)
Enhanced P2Y12 platelet receptor signaling inhibition with cilostazol in adjunct to standard DAT. Significant side effects with cilostazol with high rate of drug withdrawal
DECREASE Registry drug-eluting stenting followed by Cilostazol treatment reduces adverse serious cardiac events
867/3,099
Patients after DES implantation
DAT (aspirin,and clopidogrel) versus TAT (aspirin, clopidogrel and cilostazol). Registry
Death, MI and stent thrombosis. 12 months
Cilostazol significantly reduced the 12-month risk of stent thrombosis and MI after DES implantation when added to DAT. No increase in major or minor bleeding complications
CILON-T Influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stent implantation
307/960
Patients after DES implantation
DAT (aspirin and clopidogrel) versus TAT (aspirin, clopidogrel and cilostazol). Open-label, blind evaluation
Cardiac death, MI, ischemic stroke, and TLR at 6 months
Enhanced platelet inhibition with TAT but no difference in composite adverse events at 6 months (entire cohort or DM patients). Higher adverse events with TAT versus DAT in females and elderly patients
Prasugrel
TRITON-TIMI 38 Trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition With Prasugrel-Thrombolysis in Myocardial infarction 38
3,146/3,608
Patients with moderate-to-high-risk UA/NSTEMI, STEMI for PCI
Clopidogrel (300 mg LD and 75 mg MD) versus Prasugrel (60 mg LD and 10 mg MD)
CV death, MI and stroke. Bleeding safety endpoint
DM patients on prasugrel had higher reduction in endpoint compared to clopidogrel than non-DM patients (HR 0.72 versus 0.86, ). Benefit of prasugrel was greater amongst DM patients on insulin (HR, 0.63; ). Patients without DM had significantly increased risk of TIMI major hemorrhage on prasugrel versus clopidogrel (1.6% versus 2.4%; ) but DM patients had similar bleeding rates on the two drugs (). Greater net treatment benefit with prasugrel versus clopidogrel in DM patients
Ticagrelor
PLATO platelet inhibition and patient outcomes
4,662/18,624
Patients with moderate-to-high-risk UA/NSTEMI, STEMI for PCI
Clopidogrel (300 mg LD and 75 mg MD) versus Ticagrelor (180 mg LD and 90 mg bd MD)
CV death, MI and stroke. Bleeding safety endpoint. 6–12months
Ticagrelor was associated with a lower composite endpoint with no increase in bleeding in the entire cohort as well as DM patients. Effects were irrespective of DM status, insulin treatment, and glycemic control
