‘Smoker’s Paradox’ Eliminated With Double Dose of Clopidogrel: GRAVITAS Analysis

Individuals who smoke and are treated with clopidogrel have significantly lower rates of persistent platelet reactivity when compared to those who do not smoke, according to an analysis of the GRAVITAS trial.

Next Step: ‘Smoker’s Paradox’ Eliminated With Double Dose of Clopidogrel: GRAVITAS Analysis

In addition to confirming the so-called smoker’s paradox—whereby smokers derive greater pharmacodynamic benefit from clopidogrel than their nonsmoking counterparts—investigators report that the difference in platelet reactivity essentially disappears when smokers and nonsmokers are treated with a double-dose of clopidogrel.

Lead investigator Grant Reed, MD, of the Cleveland Clinic in Ohio, said the results lend support to individualizing antiplatelet therapy, given that not everybody responds in the same manner to clopidogrel. “In clinical practice, and the way most interventionalists are practicing now, it’s not a strategy of tailored antiplatelet therapy but [one of] just putting on everybody on clopidogrel or one of the new P2Y12-inhibiting agents such as prasugrel or ticagrelor,” he told TCTMD. “It's perhaps something that needs to be readjusted.”

The study was published online February 23, 2016, ahead of print in Catheterization and Cardiovascular Interventions.

Known Phenomenon

The smoker’s paradox with clopidogrel has been documented in several studies, with numerous reports showing that while smoking has substantial negative effects on cardiovascular health, smokers have greater platelet inhibition and lower rates of high on-treatment reactivity than nonsmokers. Clopidogrel, a prodrug, is converted to its active metabolite via cytochrome CYP1A2, an isoenzyme responsible for the first of 2 oxidative steps, and cigarette smoking is a known inducer of CYP1A2.

Several clinical trials have hinted that the better inhibition of platelets with clopidogrel among smokers might translate into clinical benefit.

“There has been some controversy about what exactly the smoker's paradox means,” said Reed. “What has been shown in substudies of certain clinical trials, including CLARITY-TIMI 28, CHARISMA, CURRENT-OASIS 7, smokers seemed to be the patients who had the biggest clinical benefit from clopidogrel. This isn’t to say that everybody should start smoking, but perhaps there might be an avenue for tailoring antiplatelet therapies for patients. It might be the nonsmoking group that might need more aggressive antiplatelet therapy.” 

The researchers studied the influence of smoking on the antiplatelet effect of clopidogrel in a post hoc analysis of GRAVITAS. Briefly, the study included 5,429 patients who underwent platelet function tests with the VerifyNow assay (then Accumetrics; now Accriva Diagnostics) after PCI. In the trial, investigators identified 2,214 patients with high residual platelet reactivity—defined as platelet reactivity units (PRU) ≥ 230—and randomized them to the standard dose of clopidogrel (75 mg per day with no additional loading dose) or double-dose clopidogrel (additional 600 mg loading dose followed by 150 mg daily). The results, published in 2011, showed the double dose failed to reduce the risk of cardiovascular death, MI, or stent thrombosis compared with the standard dose.

In the latest analysis, which stratified all patients by smoking status, Reed and colleagues found that smokers had lower platelet reactivity on clopidogrel than nonsmokers (median 183 PRU for smokers vs 211 PRU for nonsmokers; P < .001). 

Next they focused on the 2,214 individuals with high-residual platelet reactivity. Among those randomized to standard-dose clopidogrel, smokers had significantly lower on-treatment platelet reactivity than their nonsmoking counterparts at 30 days and 6 months. In contrast, when they analyzed on-treatment platelet reactivity between smokers and nonsmokers in the double-dose clopidogrel arm of GRAVITAS, there was no observed difference in response to treatment.

For Reed, the findings suggest that doubling the dose of clopidogrel in nonsmokers equalizes the treatment effect to what is seen in smokers.  

“All patients had high on-treatment platelet reactivity at baseline as per the design of the study, but smokers tended to have a lower PRU,” said Reed. “Over time, they tended to respond better to the standard-dose clopidogrel. . . . When given the double-dose of clopidogrel, however, this difference in PRU went away. This is to say that the double-dose of clopidogrel was sufficient to allow the nonsmokers to catch up the smoking group.”

Reed said that while their results suggest the “one-size approach” to antiplatelet therapy might not be best approach, the analysis only looks at the pharmacologic/pharmacodynamic response to clopidogrel and not clinical outcomes. GRAVITAS was underpowered, he pointed out, with event rates approximately half of what trial investigators anticipated. “The question is, should we be targeting nonsmokers with the higher dose of clopidogrel, or with prasugrel or ticagrelor,” said Reed. “Does it improve their outcomes? It’s a question we raise, but unfortunately we’re not able to answer it.”

Totality of Evidence Not Disputable 

Paul Gurbel, MD, of the Inova Heart and Vascular Institute (Baltimore, MD), said the results from the GRAVITAS analysis highlighting a better response to clopidogrel in smokers are consistent with those of other published studies, stating that the “totality of the evidence that smoking enhances the antiplatelet effect of clopidogrel is not disputable, at least not at the 75-mg dose.”

In a viewpoint published in 2012 in the Journal of the American Medical Association, Gurbel and colleagues analyzed data from several clinical trials, among them CURE, CAPRIE, and CREDO, and showed that the benefit of clopidogrel plus aspirin over aspirin monotherapy was solely derived from the effect in smokers.

“In nonsmokers, there was no treatment effect,” Gurbel commented to TCTMD. For example, in CAPRIE, a study testing clopidogrel against aspirin in patients at risk of ischemic events, there was a significant interaction based on smoking status. The treatment effect of clopidogrel in CAPRIE was driven largely by patients who smoked, such as those with peripheral artery disease, he noted.

He also pointed to his own data from the PARADOX study, published in 2013, which showed the active metabolite of clopidogrel was greater in smokers. The researchers suspect the increase in the active metabolite was related to increases in CYP1A2 activity, he said. Gurbel also suggested the biology of the thrombus may differ between smokers and nonsmokers, with the thrombus in smokers more responsive to P2Y12 blockade.

As for the “catch-up” observed by Reed and colleagues, the finding was “interesting,” said Gurbel, who hypothesized the double dose might lead to increases in the active metabolite of clopidogrel for nonsmokers. As for prescribing nonsmokers a double dose of clopidogrel at present, or even prescribing a more potent alternative, such as prasugrel or ticagrelor, Gurbel said this needs further prospective study.

Reed GW, Cannon CP, Waalen J, et al. Influence of smoking on the antiplatelet effect of clopidogrel differs according to clopidogrel dose: insights from the GRAVITAS trial. Catheter Cardiovasc Intv. 2016;Epub ahead of print.

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  • Reed reports no conflicts of interest.
  • GRAVITAS was funded by Accumetrics.

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