Impact of a 600-mg Loading Dose of Clopidogrel on 30-Day Outcome in Unselected Patients Undergoing Percutaneous Coronary Intervention

doi:10.1016/j.amjcard.2008.07.007

The American Journal of Cardiology

Volume 102, Issue 10, 15 November 2008, Pages 1318-1322

https://doi.org/10.1016/j.amjcard.2008.07.007 Get rights and content

On the basis of biologic studies of platelet reactivity, the recent American College of Cardiology and American Heart Association guidelines recommend a 600-mg loading dose (LD) of clopidogrel in patients who undergo percutaneous coronary intervention (PCI). There is, however, a lack of studies addressing the clinical impact of such a clopidogrel LD. The aim of this study was to compare the clinical efficacy and safety of a 600-mg LD of clopidogrel with that of a 300-mg LD in an unselected cohort of patients who underwent PCI. A cohort of 4,105 unselected patients who underwent PCI were included in the study and divided according to the LD used: the high-LD group (600 mg) included 3,146 patients, and the low-LD group (300 mg) included 959. The primary end point was the rate of major adverse cardiovascular events (MACEs) at 1 month. Patients in the low-LD group more often had diabetes mellitus and histories of myocardial infarction (36.8% vs 31.9%, p = 0.01). Left ventricular ejection fractions were similar (0.49 ± 0.14 vs 0.48 ± 0.14, p = 0.25). Angiographic and procedural characteristics were identical between the 2 groups. Patients in the high-LD group had fewer MACEs after 1 month (2.9% vs 5.2%, p <0.001). In multivariate analysis, an LD of 600 mg was significantly associated with MACEs at 1-month follow-up, with an odds ratio of 0.62 (95% confidence interval 0.41 to 0.95, p = 0.03). In conclusion, a 600-mg LD was associated with a significant decrease in the rate of post-PCI MACEs at 1 month, without any in-hospital increase in bleeding complications. The results of this study therefore support the current guidelines of a 600-mg LD of clopidogrel in patients who undergo PCI.

Section snippets

Patient population

We retrospectively studied a cohort of 4,105 consecutive patients with coronary artery disease who were treated by PCI at our institution from April 2003 to December 2007. After approval from the institutional review board was obtained for a Health Insurance Portability and Accountability Act waiver, we extracted from the entire database all patients corresponding to the inclusion criteria and conducted a retrospective analysis of outcomes at 1-month follow-up. The patients were divided into 2

Results

Baseline characteristics are listed in Table 1. A higher percentage of patients with diabetes mellitus and histories of myocardial infarction was noted in the low-LD group (36.8% vs 31.9%, p = 0.01, and 38.3% vs 30.8%, p <0.0001, respectively). Heart failure symptoms and left ventricular ejection fractions were similar in the high- and low-LD groups (4.6% vs 5.6%, p = 0.2, and 0.49 ± 0.14 vs 0.48 ± 0.14, p = 0.3, respectively).

Angiographic and procedural characteristics are listed in Table 2,

Discussion

The results of the present study demonstrate that a 600-mg LD of clopidogrel in unselected patients who undergo PCI decreases the rate of postprocedural MACEs compared with a 300-mg LD. These results therefore support the current guidelines of a 600-mg LD of clopidogrel in patients who undergo PCI.¹⁴ Of importance we observed no difference in the rate of entry site or gastrointestinal bleeding between the 2 groups.

The 300-mg dose of clopidogrel derives from dose-finding data in healthy

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2012, International Journal of Cardiology
The convention of loading with clopidogrel 300 mg before coronary intervention may be due for change, but to what?
Newer antiplatelet agents may offer better outcomes, at some financial cost. Disappointingly for decision-making clinicians, head-to-head comparisons for the newer alternatives are not available. We systematically review and compare the three alternative strategies: clopidogrel 600 mg, prasugrel and ticagrelor. A total of 14 studies have compared these strategies with the long-standing convention of 300 mg.
Throughout this analysis, we consistently report incremental costs and consequences using clopidogrel 300 mg as the reference strategy. Risk ratios for major adverse cardiovascular events at 30 days were 0.74 (95% confidence interval 0.66–0.82, p = 0.002) for clopidogrel 600 mg, 0.78 (0.69–0.89; p < 0.001) for prasugrel and 0.88 (0.77–1.00; p = 0.045) for ticagrelor. All-cause mortality risk ratios were 0.87 (0.74–1.03) with clopidogrel 600 mg, 0.95 (0.78–1.16) with prasugrel and 0.78 (0.69–0.89) with ticagrelor. TIMI major bleeding has risk ratio 0.92 (0.74–1.16; p = 0.85) with clopidogrel 600 mg, 1.32 (1.03–1.16; p = 0.03) with prasugrel and 1.25 (1.03–1.53; p = 0.03) with ticagrelor. Incremental cost for the first year was £0.32 (US$0.50, €0.40) with clopidogrel 600 mg, £608 (US$977, €709) with prasugrel and £665 (US$1068, €775) with ticagrelor.
All three strategies have shown a similar reduction in MACE at 30 days by comparison to clopidogrel 300 mg. All three strategies offer progressive benefit, most marked with Ticagrelor. Whether this is worth both the risk of non-compliance with twice-a-day dosing in real-life patients lacking the same motivation as their trial-volunteer counterparts, and the 2000-fold difference in incremental cost, is the remaining matter for debate.
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We collected data from a period of peak use of drug-eluting stents, and in that sense this better reflects the vascular complications associated with their current use. A recent study suggests that even higher loading doses of antiplatelet medicines than used in this study, particularly when administered before percutaneous coronary intervention to improve stent patency, may lead to an increase in catheterization site complications.28 Further studies will be needed to evaluate this possibility.
Femoral artery complications after cardiac catheterization range from simple events to severe complications requiring invasive techniques or surgery with significant economic costs. This study evaluated early femoral arterial complications from percutaneous arterial access during diagnostic and interventional cardiac catheterizations in an era of widespread use of closure devices and intense anticoagulation.
Patients undergoing percutaneous cardiac catheterization via the femoral artery between August 2005 and December 2005 were identified using an ICD-9 patient database. Forty-six data points were extracted by retrospective chart review, including demographics, comorbidities, type of anticoagulation, procedural details, and postprocedural complications. Univariable analysis and binary logistic regression were used to determine factors associated with complications.
Eighty-two of 579 patients (14%) suffered complications. The most common complications were hematomas (51 patients, 10%) and active bleeding (14 patients, 2.4%). Closure devices were used in 470 patients. After multivariable correction, use of preprocedural (odds ratio [OR] = 5.65, 95% confidence interval [CI] 2.58-12.3, p < 0.001) and intraprocedural (OR = 4.88, 95% CI 1.95-12.3, p < 0.001) antithrombotic agents (antiplatelet and/or anticoagulants), intraprocedural clopidogrel (OR = 2.98, 95% CI 1.21-7.30, p = 0.017), and postprocedural heparin (OR = 29.4, 95% CI 3.56-250, p = 0.002) were associated with increased risk. Coronary artery disease was associated with increased risk (OR = 11.1, 95% CI 4.78-25.6, p < 0.001), while use of a closure device (OR = 0.263, 95% CI 0.125-0.553, p < 0.001), male gender (OR = 0.421, 95% CI 0.220-0.805, p = 0.009), and prior catheterization (OR = 0.033, 95% CI 0.012-0.095, p < 0.001) were protective.
With increasing numbers of complex coronary endovascular procedures and widespread use of high-dose multidrug antithrombotic therapy, femoral artery injuries will continue to be a significant risk for patients. Postprocedural monitoring with a high level of suspicion and use of vascular closure devices in high-risk patients may decrease the incidence of femoral artery complications. The use of vascular closure devices after low-risk procedures in male patients or those with previous ipsilateral catheterization might not be warranted but needs further study.
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A higher loading dose reduced the primary endpoint of death, MI, or TVR within 30 days (4% vs 12%, P = 0.041), driven primarily by a reduction in periprocedural MI.65 These findings have been replicated in a pure NSTE-ACS and an unselected population.54,66 No additional benefit was found from even higher loading doses (eg, 900 mg) among patients with ACS.67,68
The platelet plays an essential role in atherothrombosis. Clinically, platelet-rich thrombi underlie acute coronary syndromes (ACSs). Current therapies have improved outcomes, however, often at the expense of increased risk of bleeding. With the increase in our understanding of the underlying pathophysiology of ACSs, newer targets for antiplatelet therapies continue to emerge. Novel antiplatelet agents may provide even greater reductions in ischemic events with the potential for less bleeding. This article reviews the evidence for current antiplatelet agents in ACSs as well as for the newer agents in later phases of clinical testing.
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Coronary artery diseaseImpact of a 600-mg Loading Dose of Clopidogrel on 30-Day Outcome in Unselected Patients Undergoing Percutaneous Coronary Intervention

Section snippets

Patient population

Results

Discussion

J Thromb Haemost

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study

Lancet

Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation

Circulation

Identification of platelet ADP receptor targeted by antithrombotic drugs

Nature

Individual variations of platelet inhibition after loading doses of clopidogrel

J Intern Med

Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity

Circulation

Coronary artery disease
Impact of a 600-mg Loading Dose of Clopidogrel on 30-Day Outcome in Unselected Patients Undergoing Percutaneous Coronary Intervention