Better Clopidogrel Response Seen with Increased Smoking Levels

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Increased levels of smoking appear to translate to a better response to clopidogrel in diabetic patients on dual antiplatelet therapy after percutaneous coronary intervention (PCI), according to results of a pharmacodynamic study published in the March 2012 issue of JACC: Cardiovascular Interventions.

Cigarette smoking is a known inducer of the CYP1A2 enzyme, responsible for the initial step in the conversion of clopidogrel into its active metabolite, and previous studies have linked smoking with enhanced platelet inhibition.

Researchers led by Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine-Jacksonville (Jacksonville, FL), looked at cotinine levels in 134 type 2 diabetes patients who received PCI and were on dual antiplatelet therapy. Patients were stratified by smoking status (non, light, and heavy) and platelet function was assessed by multiple measures to assess the presence of a dose-response effect between smoking and clopidogrel.

Over a third of the patients (37%) were active smokers, with most falling in the nonsmoker category as stratified by cotinine levels:

• Nonsmoker: n = 85 (< 3 ng/mL of cotinine)
• Light smoker: n = 27 (3-199 ng/mL)
• Heavy smoker: n = 22 (≥ 200 ng/mL)

Dose-Response Curve Seen

Serum cotinine levels were inversely associated with levels of on-treatment platelet reactivity. Specifically, on light transmittance aggregometry (LTA), decreasing cotinine was associated with increasing maximal platelet aggregation (MPA) in response to both 5 µmol/L ADP and 20 µmol/L ADP (P < 0.001 for each trend). Likewise, late platelet aggregation (LPA) decreased with increasing cotinine levels on LTA 5 µmol/L and 20 µmol/L ADP (P < 0.001 for each trend).

Meanwhile, on the VerifyNow (Accumetrics, San Diego, CA) assay, P2Y12 reaction units (PRU) also decreased with increasing cotinine levels (P < 0.0001 for trend), while inhibition of platelet aggregation (IPA) increased with higher cotinine concentrations (P = 0.002 for trend). In addition, P2Y12 reactivity index (PRI) values on vasodilator-stimulated phosphoprotein assay decreased with increasing cotinine levels (P = 0.001 for trend).

The overall prevalence of high on-treatment platelet reactivity varied according to the definitions used for each measurement method:

• MPA: 69% (20 µmol/L ADP); 39% (5 µmol/L ADP)
• PRU: 48%
• IPA: 67%
• PRI: 73%

By all measures, increasing serum cotinine levels were associated with lower rates of high platelet reactivity (all P values for trend):

• MPA: P < 0.0001 (20 µmol/L ADP); P < 0.0001 (5 µmol/L ADP)
• PRU: P = 0.001
• IPA: P = 0.004
• PRI: P = 0.02

On multivariable analysis, light and heavy smokers were less likely to have high platelet reactivity compared with nonsmokers by most measures (table 1).

Table 1. Likelihood of High Platelet Reactivity by Smoking Status

“To the best of our knowledge, the present investigation is the first [pharmacodynamic] study to examine and demonstrate the presence of a dose-response effect of smoking on clopidogrel effects by using a more objective measure to quantify cigarette smoking as determined by assessing serum cotinine levels,” the authors observe.

They cite several factors that may contribute to the “smoker’s paradox,” including the fact that CYP1A2 activity is known to increase in proportion to the number of cigarettes smoked per day, “which may explain the dose-response effect observed in our study.” In addition, smokers have a higher platelet surface P2Y12 density, putting them at increased risk of recurrent ischemic events that can be suppressed to a greater extent by clopidogrel.

According to Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), the data fit with previous observations. “I think [the results are] probably true,” he told TCTMD in a telephone interview. “The nice thing was they measured cotinine levels and got a dose-response curve.”

Results Enhanced in Diabetics

He added that studying diabetics helped. “This looks pretty good because it’s in diabetics, who automatically have a little trouble responding to clopidogrel,” Dr. Bates said. “You take the guys that have the lowest response and that’s the easiest place to see something inducing a response. You may not have gotten as nice a result in nondiabetics.”

Dr. Bates noted that smoking is just one of many factors that influence clopidogrel response. “There’s a lot of drug interactions,” he said. “The trouble is you can have a number of different things that can impact the final result in a given patient—diabetes, calcium channel blockers, smoking, statins, obesity, renal insufficiency. It’s a balance of all these ups and downs.”

According to the authors, the findings may offer guidance for smokers with atherosclerosis who only require a single antiplatelet medication. “[I]t may be hypothesized that aspirin may offer less antithrombotic protection than clopidogrel does. . . . In fact, given the increased density of P2Y12 receptors among smokers, clopidogrel may be a more effective platelet inhibitor,” they point out.

Clopidogrel ‘Pharmacodynamically Inferior’ to Newer Drugs

But Dr. Bates was not convinced of this line of reasoning, calling it a good “academic” argument. “Right now, because of cost, people are going to get aspirin as the first drug unless they don’t tolerate it, and anyone with ACS or a stent is supposed to get both antiplatelet drugs anyway,” he said.

Dr. Bates pointed out, though, that the metabolic limitations of clopidogrel do not apply to newer antiplatelet drugs. “These data just point out the pharmacodynamic inferiority of clopidogrel vs. ticagrelor and prasugrel, but the clinical impact is not at all clear,” he said, adding that above all, the study should not be interpreted as supportive of smoking. “You don’t want to give people the argument that they should smoke to improve their clopidogrel response. They’re probably better off switching to prasugrel or ticagrelor.”

 

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Source:
Ueno M, Ferreiro JL, Desai B, et al. Cigarette smoking is associated with a dose-response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: Results of a pharmacodynamic study. J Am Coll Cardiol Intv. 2012;5:293-300.

 

 

Related Stories:

• Clopidogrel Response Affected by Smoking, Gender, and PPI Use
• Enhanced Benefit of Clopidogrel Seen in Moderate Smokers
• Smoking Enhances Platelet Inhibition by Clopidogrel

 

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