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Of Swiss Alchemists and Road Hazards
“Alle Ding’ sind Gift und nichts ohn’ Gift; allein die Dosis macht, dass ein Ding kein Gift ist”
[ All things are poison and nothing is without poison; only the dose permits something not to be poison ] – Paracelsus
Although he was born Phillip von Hohenheim, he later changed his name to Philippus Theophrastus Aureolus Bombasticus von Hohenheim, and called himself Paracelsus (literally: equal to or greater than Celsus — a Roman encyclopedist known for medical writings). No, he was not a 15th century version of the artist-formerly-known-as-Prince (glyph), but he is sometimes referred to as “the father of toxicology”, in addition to his other scientific pursuits in medicine, alchemy, astrology and occultism. He covered a lot of ground. But he was absolutely right in observing that pushing the dose of an otherwise therapeutic substance can have adverse consequences.
Looking at the current study by Wang et al,1 one could go in one of two directions. First, you can beat your chest and invoke the “see-I-told-you-so-more-is-not-always-better” mantra, and point to the bad ol’ days of the oral glycoprotein IIb/IIIa antagonists (when more-was-clearly-worse) and the down-side of higher-dose aspirin therapy. Or…you can dismiss these findings as hopelessly confounded and methodologically flawed, bombastically proclaiming that there is nothing of substance here.
Our view (no real surprise here) is somewhere in between. There is both baby and bathwater, and the trick is to figure out which is which, with only a brief (and incomplete) glimpse at the tub.
Wang et al present a retrospective review of a multiinstitutional database (Solucient ACTracker). They identified 2,484 patients admitted with a diagnosis of ACS between January 2003 and September 2004, who underwent PCI on that hospitalization. The patients were divided into two groups — those who received a standard-dose 300 mg clopidogrel load (n = 1,199), and those who received a highdose (> 300 mg) clopidogrel load (n = 1,285). For the purposes of this study, “load” was defined as the total dose of clopidogrel in the 24-hour periprocedural period (we will come back to that later). The primary endpoint (a composite of death, myocardial infarction, stroke and coronary revascularization) was significantly higher in the high-dose clopidogrel load group (37.1% versus 20.5%; p < 0.001) — largely driven by differences in myocardial infarction (34.7% versus 17.3%; p < 0.0001) — with no difference in bleeding rates (scale not identified). Recognizing that there were baseline differences between the groups, the authors assigned propensity scores to each patient to compare groups of similar clinical risk; with this more sophisticated analysis, there was no clinical benefit associated with higher clopidogrel loading doses, and generally higher event rates across the propensity score strata in the higher-dose group.
In recent years, two clopidogrel-related issues have provided interventional cardiologists with a LOT of substrate for discussion: the optimal dose of clopidogrel and the optimal timing of clopidogrel administration. The two are in fact related, because while most of us would agree that having therapeutic levels of clopidogrel (whatever that is) on board prior to a higher-risk interventional procedure is vastly preferable (and recommended in the current Guidelines2), the harsh realities of the clinical world do intrude from time to time. Patients may present atypically. They may come forward either very rapidly, or very slowly to the catheterization laboratory. Bypass surgery may be necessary. The reality is that there are many reasons why the timing of clopidogrel loading is not always optimal. Consequently, we have tried to modify the dose, thinking that if we give more, it may be possible to achieve steady-state (and presumably therapeutic) levels more rapidly — the reason we give a loading dose in the first place. We have also learned that with higher loading doses comes a greater degree of early peak platelet inhibition,3 even on a background of chronic clopidogrel therapy,4 and perhaps fewer clinical events in smaller randomized studies,5,6 although moving to 900 mg in ISAR-CHOICE7 seemed to provide no incremental benefit in the degree of platelet inhibition, perhaps related to limits on how much clopidogrel you can absorb at one time. Newer, faster-acting, more potent thienopyridines are looming on the horizon,8 as are rapidly-reversible, faster-onset P2Y12 inhibitors.9
What does the current study add to our knowledge? It suggests that higher loading doses of clopidogrel may provide no real benefit, but this message has to be interpreted very cautiously. Their definition of a “loading” dose is a little odd, since it may also include oral doses from the day before (although that seemed rare in this study) or the day after (not really described in the paper). The fact that the mean dose in the higher-dose group was 459 ± 128 mg strongly suggests that the latter may have occurred not infrequently — this was not a clean comparison of a 300 mg load versus a 600 mg load.
Another problem has to do with the definition of myocardial infarction (CK-MB > 3 times the upper limit of normal [ULN] and/or troponin > 1 times the ULN). Given the clinical imbalances that existed between the standard- and highdose groups (the high-dose group was older, had more men, more urgent admissions and more adjunctive anticoagulants), it is not inconceivable that there were also imbalances in the “baseline” cardiac enzymes (and baseline degree of platelet activation) between the groups.
There are other logistical concerns. If problems developed, wouldn’t patients be more likely to get additional doses, or a higher postprocedure load (if one was used)? Put another way, are the adverse events chickens, or eggs? Propensity analysis is helpful in accounting for some of the imbalances, but is unlikely to account for all of them.
However, there is a valid point raised by the authors — beautiful theory aside — this is the real world … this is how these drugs and these loading doses are actually being used in modernday practice. Yes, we know in our heart-of-hearts that preloading is better, but we manage to meet the 6-hour Guideline recommendation in < 20% of our patients. Further complicating this, as we saw in the recently-presented PRAGUE 8 data at the ESC Meeting in Vienna,10 is the fact that pretreatment > 6 hours before PCI (at least with 600 mg of clopidogrel) does not appear to be superior to just giving 600 mg at the end of the procedure in elective interventions in stable patients.
The results of the present study are reminiscent of the words of Steven Wright: “I couldn’t fix your brakes, so I made your horn louder”. Getting enough thienopyridine on board soon enough prior to PCI is the “brakes”. Tweaking the dose of clopidogrel because we can’t seem to impact on the logistics of getting it in sooner is “making the horn louder”. However, tweaking the dose does not necessarily address the underlying problem. And, as Wang et al have suggested, the horn may not actually be any louder, at least in some patients. No, they have not definitively proved that higher loading doses of clopidogrel are worse — there are simply too many potential confounders. But what they have shown very nicely is that the intricate interplay of clopidogrel dose and timing needs to be carefully considered if we are going to get out patients back on the road … to recovery.References
1. Wang C, Kereiakes DJ, Bae J, et al. Clopidogrel loading doses and outcomes of patients undergoing percutaneous coronary intervention for acute coronary syndromes. J Invasive Cardiol 2007;19:431–436.
2. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention-Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006;47:216–235.
3. Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006;48:931–938.
4. Kastrati A, von Beckerath N, Joost A, et al. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation 2004;110:1916–1919.
5. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005; 111: 2099–2106.
6. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48:1339–1345.
7. von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-,600-,and 900-mg loading doses of clopidogrel: Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005;112:2946–2950.
8. Wiviott SD, Antman EM, Gibson CM, et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: Design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON- TIMI 38). Am Heart J 2006;152:627– 635.
9. Greenbaum AB, Grines CL, Bittl JA, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: Results from a 2-part, phase II, multicenter, randomized, placeboand active-controlled trial. Am Heart J 2006;151:689, e681–689, e610.
10. Widimsky P. Optimal pre-PCI clopidogrel loading: 600mg before every coronary angiography vs. 600 mg in cath-lab only for PCI patients. A randomized multicenter trial: PRAGUE-8. Presented at ESC Vienna; 2007.
