Clopidogrel Loading Doses and Outcomes of Patients undergoing
Percutaneous Coronary Intervention for Acute Coronary
Syndromes

Current American College of Cardiology/American Heart Association guidelines for the treatment of unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) recommend initiation of clopidogrel treatment in patients for whom percutaneous coronary intervention (PCI) is planned and who are not at high risk for bleeding.^1,2 Although the guidelines indicate that a loading dose of 300 mg to 600 mg can be used when rapid onset-of-action is required, followed by a maintenance dose of 75 mg/day, the evidence supporting the efficacy of clopidogrel in preventing cardiovascular events in patients with acute coronary syndromes (ACS), including those undergoing PCI, is largely derived from clinical trials which have evaluated the standard loading dose of 300 mg followed by 75 mg/day.

Recent data suggest that the use of a 600 mg loading dose is associated with reduced resistance and increased responsiveness to clopidogrel, as well as a greater magnitude of platelet inhibition and faster onset-of-action when compared with a 300 mg loading dose in patients undergoing elective stenting.^3,4 In addition, two small randomized trials have suggested clinical benefits for the higher loading dose. The first, ARMYDA-2, demonstrated that a 600 mg loading dose of clopidogrel was associated with a significant reduction in periprocedural MI compared with 300 mg when given 4 to 8 hours prior to procedures in patients with stable angina or NSTEMI undergoing scheduled PCI.⁵ The second, by Cuisset et al, showed significant benefits with respect to platelet reactivity and the incidence of adverse cardiovascular events for a 600 mg vs. a 300 mg loading dose given 12 to 24 hours prior to stenting procedures in patients with NSTEMI.⁶

Additional studies, such as ISAR-CHOICE and ALBION,^7,8 have led to increased interest in the use of a 600 mg loading dose as well, although large, randomized, controlled trials comparing the 300 mg and 600 mg doses in ACS patients are lacking. A recent retrospective analysis found no incremental clinical benefit of a 600 mg versus a 300 mg loading dose in patients with stable angina undergoing PCI.⁹ To assess outcomes with high-dose versus standard-dose clopidogrel loading doses in ACS patients undergoing PCI in clinical practice, we performed a retrospective analysis of data from 2,484 patients in a United States national hospital database.

Methods

An in-patient database (Solucient ACTracker, Solucient Inc., Evanston, Illinois) in the United States was used for this retrospective study. The Solucient ACTracker is a de-identified database that provides comprehensive information on inpatient drug use, diagnoses, procedures, provider specialties and lab test results. One particularly valuable feature of this database is the availability of time information on select interventions such as drug administration, hospital admission andordering of lab tests, which allows researchers to examine the timeline of patient care in a hospital setting.

From the database, we identified a total of 2,484 patients who were admitted to an acute care hospital with a diagnosis of ACS (defined as unstable angina, NSTEMI or STEMI) between January 2003 and September 2004, who underwent PCI and received a periprocedural loading dose of clopidogrel during their index hospital stay (Table 1). A periprocedural loading dose of clopidogrel was defined as a dose given during the period from 10 hours before to 14 hours after initiation of PCI, as marked by the time of administration of anesthesia. Only 3.3% of the patients who received a periprocedural clopidogrel loading dose during this time period had received a dose of clopidogrel prior to the dosing time window. The loading dose was calculated as the sum of all clopidogrel doses received by a patient during this period, but excluded doses given after any cardiovascular event; such doses were excluded to prevent the inclusion of post-event supplemental doses. Patients receiving clopidogrel loading doses and undergoing PCI were included in the study and assessed for the endpoints of MI, stroke, repeat coronary revascularization and death in the hospital database. Rehospitalizations at the same institutions for up to 60 days following discharge were evaluated. No outpatient care information, including medication, was available. All-cause mortality, stroke and repeat revascularization data were identified by ICD-9 codes and discharge status information. Since ECG data were not part of the dataset, MI was identified by abnormal creatine kinase-MB (CK-MB; > 3 times the upper limit of normal) and/or troponin (> 1 time the upper limit of normal) peak value results after PCI.^1,2

For analysis of the effect of clopidogrel loading dose on outcomes, patients were categorized according to a loading dose of 300 mg (standarddose; n = 1,199; patients who received 300 mg total in the 24-hour PCI periprocedural window) or > 300 mg (high-dose; n = 1,285; patients who received doses in excess of 300 mg in the same time period). Rates of individual endpoints and the quadruple combined endpoint (death, MI, stroke or revascularization) were then compared. Bleeding events, as defined by all-cause in-patient bleeding/hemorrhage, were also evaluated.

Statistical analysis was performed using SAS version 9.1 (SAS Institute, Cary, North Carolina). Continuous variables were compared by t-test and categorical variables were compared by Fisher’s exact test. To compare event frequencies between patients of similar risk, patient risk level was estimated, and similar-risk patients were matched between the high and the standard loading dose group using the propensity score method.¹⁰ The propensity score method was estimated as a logistic regression with nonparsimonious specification that included a wide range of clinical factors captured through comorbidities and their interaction terms, admission type (urgent/emergency), as well as patient demographics and control for hospital characteristics. Patients of similar risk by the propensity score were matched between the high and standard loading dose groups, and were grouped into quintiles by predicted risk level. Event frequencies were compared for standard-dose and high-dose recipients within each propensity score quintile. For all statistical comparisons, p < 0.05 was considered to be significant.

Results

In this database, 1,199 patients received a clopidogrel loading dose = 300 mg, and 1,285 received a loading dose > 300 mg. For the > 300 mg dosing group, the mean dose was 458.63 mg (SD 127.53; range 375–1200; skewness 1.45; kurtosis 2.19).

Patient demographics and comorbidities are shown in Table 1. High-dose patients were more likely to be male and to have acute ischemic heart disease, and standard-dose patients were more likely to have cardiac dysrhythmias; there was also a difference favoring the high-dose group for lipidmetabolism disorders that approached significance (p = 0.078). Both groups were otherwise similar with respect to comorbidities. In general, the two dosing groups were well balanced with respect to hospital characteristics such as geographical distribution, hospital size and PCI volume (Table 2).

Table 3 details treatment patterns (interventions and medication use) for the two dosing groups during hospitalization. The percentage of patients admitted on an urgent or emergency basis was significantly higher for the high-dose group, as were the use of anticoagulants, aspirin and statins. Otherwise, the two groups were remarkably similar with respect to characteristics such as single-vessel involvement, thrombolytic use (indicative of STEMI), stent use and use of antiplatelet agents and glycoprotein IIb/IIIa inhibitors. We did not try to discern whether the significant differences in anticoagulant and aspirin use reflected proactive treatment of underlying conditions, or reactive treatment of emergent adverse events, as such an analysis was beyond the scope of this study.

Time distribution of clopidogrel loading relative to initiation of PCI is shown in Figure 1. These data show that 86.2% of patients received the first dose of clopidogrel by the time of PCI. Further analysis revealed that only 19.2% received the loading dose 6 hours or more prior to the procedure, as recommended by current guidelines,¹¹ 29.5 % received clopidogrel during the window from 8 to 4 hours prior to the procedure, 20.8% received clopidogrel at the time of PCI, and 13.8% received clopidogrel after PCI. These data are reflective of a “real-world” scenario, as many patients seen in clinical practice require urgent intervention and cannot wait 6 hours for initiation of PCI.

Risk for the combined endpoint (death, MI, stroke or revascularization) was significantly higher among patients receiving higher clopidogrel loading doses due to an increased rate of MI as identified from abnormal troponin and/or CKMB results after PCI (Table 4). There were no differences between the two groups with regard to stroke, revascularization or death. Bleeding events were infrequent in both dosing groups, and there were no statistically significant differences between the two groups (Table 4).

In order to mitigate the selection effect in these nonexperimental data, we employed a propensity scoring method with stratification. Utilizing the extensive information from the database, we estimated the clinical risk factors by conducting a logistic regression analysis with a nonparsimonious model that included patient demographics, clinical information (e.g., comorbidities, including cardiovascular diagnoses and interventions, withassociated interaction terms), as well as hospital-specific factors. The patients were stratified by propensity scores into equal-sized quintiles, such that patients with similar clinical risk from the two dosing groups were compared against each other (Table 5). The two dosing groups showed a similar patient distribution across the propensity score quintiles, suggesting similar risk distribution profiles between the two groups. The results across the propensity quintiles demonstrated a trend toward increased events with increased propensity score for the overall study population, as well as for the two dosing groups. Individual comparisons between the two groups by quintile showed significantly higher event rates for the high loading-dose group in the lowest quintile and in the third and fourth quintiles.

Discussion

This study was a retrospective analysis of the use of clopidogrel loading doses in patients with ACS undergoing PCI in acute care hospitals. As such, it included the full spectrum of patients with ACS in a usual care setting with no prespecified treatment protocol (thus, no interventions were prescheduled). The inclusion criteria stipulated that patients must have received a loading dose of clopidogrel between 10 hours before to 14 hours after PCI, and supplemental doses given after the patient experienced an event were not tabulated. Data were analyzed according to dosing groups: those who received 300 mg total in the 24-hour PCI periprocedural window, and those who received doses > 300 mg in the same time period.

The use of clopidogrel doses greater than the standard of 300 mg during the period from 10 hours before to 14 hours after PCI was not associated with a decreased risk in the combined endpoint of MI, stroke, revascularization or death for periods extending up to 60 days after treatment, primarily due to a higher incidence of MI (34.7% vs . 17.3%). Bleeding event rates did not differ between the two groups. When we matched and compared patients of similar risk using a propensity scoring analysis, we identified no evidence of benefit associated with the higher loading dose of clopidogrel.

A number of studies have evaluated clinical outcomes with a 600 mg clopidogrel loading dose in patients undergoing PCI,^5,6,12–14 but only two of these studies have compared the outcomes between the standard 300 mg loading dose with the higher dose.^5,6 Our finding that the use of a higher clopidogrel loading doses was not associated with improved outcomes in clinical practice appears to be at odds with the conclusions from smaller, randomized, comparative trials. ARMYDA-II,⁵ a randomized trial performed in two Italian centers, compared the effects of clopidogrel loading doses of 300 mg versus 600 mg given 4 to 8 hours prior to PCI in 255 patients with exertional angina or NSTEMI ACS. All patients continued treatment with clopidogrel 75 mg/day following PCI. Patients receiving the higher loading dose had a significant decrease in the 30-day rate of the composite endpoint of death, MI or revascularization (4% vs. 12%; p = 0.041) that was entirely due to a reduction in periprocedural MI. No differences in safety were observed between the high and standard loading doses.

Likewise, Cuisset et al showed significant benefits with respect to the incidence of cardiovascular events (acute/subacute stent thrombosis, recurrent ACS, stroke or death) for a 600 mg versus a 300 mg loading dose given 12 to 24 hours prior to stenting procedures in 292 patients with NSTEMI ACS.⁶ At the 1-month follow-up point in this randomized, single-center study, 18 cardiovascular events had occurred in the clopidogrel 300 mg group (12%), as compared with 7 in the 600 mg group (5%; p = 0.02). This difference remained significant even after adjustment for conventional cardiovascular risk factors (p = 0.035).

There are a number of potential explanations for the apparent disparity between findings from these smaller studies and those from the present analysis. First, it must be recognized that the results from ARMYDA-2 and Cuisset et al were generatedfrom randomized, controlled trials, as compared with the present study, which was derived from a retrospective database analysis. Second, clopidogrel loading doses were given as single doses within 4 to 8 hours prior to elective PCI in ARMYDA-2, and between 12 and 24 hours prior to PCI in Cuisset et al — in contrast with the actual dosing time period observed in the patient care setting in the present study.

Current ACC/AHA guidelines recommend that clopidogrel be administered at least 6 hours prior to PCI¹¹ (the CMS Hospital Quality Initiative, it should be noted, recommends that PCI be performed within 2 hours of hospital admission for patients with acute MI).¹⁵ In addition, a recent analysis of data from the CREDO trial to assess optimal timing for clopidogrel dosing¹⁶ found that differences in outcome between pretreatment with 300 mg clopidogrel and placebo did not reach significance unless administered 15 hours or more before PCI, with apparent optimal divergence of endpoint rates (death, MI or urgent target vessel revascularization) occurring at 24 hours pretreatment.

In our analysis, only 19.2% of cases were in compliance with the current ACC/AHA recommendation (i.e., clopidogrel administration ≥ 6 hours prior to PCI), a factor that could potentially account for the relatively high event rates in both dosing groups. Both the timing of clopidogrel dosing and the inclusion of a large proportion of nonelective procedures in our analysis were more reflective of actual clinical practice, where patients who require urgent interventions (52% of the patients in the present data) may not have the option to wait 6 hours prior to initiation of PCI. Furthermore, the present analysis included nearly 2,500 patients from 14 institutions, whereas the ARMYDA-2 trial enrolled only 255 patients at 2 centers, and Cuisset et al was a singlecenter study involving 292 patients.

Finally, there were significant differences in the composition of the patient populations for these studies. Most patients in ARMYDA-II had stable angina (typical effortangina plus positive stress test), while the minority had NSTEMI ACS. In contrast, all patients in Cuisset et al had NSTEMI ACS, and in the present retrospective analysis, the full spectrum of ACS (STEMI and NSTEMI) is represented. If an increased loading dose of clopidogrel were to provide incremental clinical benefit, one might expect this benefit to be more evident among patients with ACS who have a more thrombogenic milieu as compared with stable angina patients. In this regard, it is noteworthy that a retrospective single-institution study of 445 patients with stable angina demonstrated no benefit from a 600 mg versus a 300 mg loading dose of clopidogrel in preventing cardiac events, including MI, over 30 days.⁹

Studies of platelet function following the use of a standard 300 mg clopidogrel loading dose in patients undergoing PCI demonstrate wide interindividual variability in response, and a significant percentage of patients (~25%) exhibit relative resistance; in addition, variability in clopidogrel response may be related to interindividual pretreatment differences in platelet reactivity.^17-20 Comparative studies have shown that a 600 mg loading dose of clopidogrel is associated with more rapid and more potent inhibition of platelet activity and a reduced frequency of resistance in patients undergoing PCI compared with the standard 300 mg dose.^3,4 Although these data suggest a correlation between greater magnitude and consistency of platelet inhibition with a reduction in myocardial necrosis markers, the studies were not powered to evaluate clinical endpoints. Indeed, the investigators in these comparative studies concluded that observations regarding differences in platelet inhibition should be evaluated in largescale clinical trials.

Study Limitations

Several limitations of this study deserve mention. First, clinical follow up was limited to 60 days, and rehospitalization was only recorded if patients were readmitted to the index hospital. Patients admitted to a different hospital could not be tracked. Additionally, data on electrocardiographic or coronary angiographic findings were not available. Information on medication usage prior to hospitalization and after hospital discharge was also not available.

Second, although a large and geographically diverse study population was evaluated, neither treatment dose nor timing of dose administration (relative to the performance of PCI) was randomly allocated, but was observed in a retrospective cohort. We attempted to minimize any potential biases in patient selection through multivariate regression analysis and propensity scoring statistical methodology. However, to the extent that potential biases remain, the conclusions of this retrospective analysis cannot be considered definitive. The present study does, however, provide valuable insights into “real-world” practice and periprocedural (PCI) clinical outcomes stratified by dose of clopidogrel administered.

Conclusion

The use of clopidogrel loading doses higher than the standard 300 mg dose appears to be increasingly common in patients undergoing PCI in clinical practice, although this approach has not been supported by data from any large-scale comparative clinical trial(s). This retrospective analysis of almost 2,500 patients treated in acute care institutions indicated that loading doses of clopidogrel higher than 300 mg were not associated with additional clinical benefit in the routine care setting. Due to its retrospective nature, the present study lacked a controlled environment; in addition, using appropriate statistical methods may not have fully eliminated selection bias. Despite the limitations in the data, the present study demonstrates that there is no downside to the standard 300 mg loading dose of clopidogrel and no clear benefit of a > 300 mg loading dose of clopidogrel in the urgent setting. The higher dosing strategy needs to be evaluated in large-scale randomized trials involving patients with ACS who undergo PCI in order to ascertain the potential benefits and risks.

References

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