No Clinical Interaction Between Calcium Channel Blockers, Clopidogrel
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Despite platelet function studies showing that calcium channel blockers (CCBs) may lessen the effectiveness of clopidogrel, a retrospective analysis shows no clinical interaction between the 2 agents. The study was published online February 7, 2012, ahead of print in Circulation: Cardiovascular Interventions.
CCBs are metabolized by the same CYP3A4 enzymes as clopidogrel, leading to the theory that the antihypertensive agents can interfere with the conversion of clopidogrel to its active form, thereby reducing the drug’s clinical efficacy.
In the new study, Christopher W. Good, DO, of the Geisinger Clinic (Danville, PA), and colleagues analyzed results of the CREDO (Clopidogrel for the Reduction of Events During Observation) trial. CREDO was a placebo-controlled trial of 2,116 patients undergoing PCI who were randomized to 2 different clopidogrel regimens (300-mg loading dose pre-procedure plus 75 mg daily for 1 year or no loading dose and the same daily dose for 28 days). For the current analysis, endpoints and risk reductions with clopidogrel were reexamined according to whether patients were also on CCBs.
One-year Outcome Unaffected by CCB Status
Of the entire cohort, 27% (580) were also on CCBs, compared with 73% (1,536) who were not. Patients on CCBs tended to be older, more commonly female, and have higher BMIs and more comorbidities. Among patients on CCBs at enrollment, at 28 days, the combined endpoint of death, MI, and stroke was reached in 6% of patients on clopidogrel vs. 9% of those on placebo (HR 0.71; 95% CI 0.39-1.29). The results were similar in patients not on CCBs (HR 0.87; 95% CI 0.57-1.33), showing no treatment effect.
At 1 year, the combined endpoint was still similar in CCB-treated patients between those on clopidogrel and those on placebo (10% vs. 15%; HR 0.68; 95% CI 0.42-1.09). This included a decrease in MI in patients receiving clopidogrel (P = 0.024). The treatment effect of clopidogrel for the 1-year combined endpoint was again similar in patients not on CCBs (8% vs. 10%; HR 0.78; 95% CI 0.56-1.09). Further analysis found no interaction between clopidogrel treatment effect and CCBs (P = 0.64). After adjustment for differences between patients who were on or off CCBs, there remained no interaction between the two treatments (P = 0.58; HR for patients not on CCBs 0.87; 95% CI 0.62-1.23; HR for patients on CCBs 0.74; 95% CI 0.45-1.21).
“In this post hoc analysis of the CREDO trial, we found no evidence that patients on CCBs derive less benefit from clopidogrel,” Dr. Good and colleagues conclude. “In fact, the relative risk reduction associated with pretreatment with a loading dose and long-term clopidogrel was numerically greater among those patients on a CCB than among those who were not on a CCB.”
CCB Data Similar to Atorvastatin? PPIs?
In a telephone interview with TCTMD, Dr. Good noted that the study evokes a broader issue for cardiologists. “There’ve been many people who have been making decisions based on ex vivo platelet studies and we don’t have the information to know if there’s really a clinical interaction between multiple classes of medication and clopidogrel,” he said. In particular, platelet function studies have indicated a lack of efficacy when clopidogrel was combined with atorvastatin or proton-pump inhibitors (PPIs). In both cases, “it was after they had clinical trial information that this was shown not to be the case,” Dr. Good added.
His study serves a similar purpose. “As a cardiologist treating a patient, this is not a clinically relevant interaction, and I would still treat patients that I’m going to be putting on Plavix with both atorvastatin and a CCB,” Dr. Good said. “We would actually be doing patients with coronary disease who are going to be on Plavix a disservice not to be treating them with statins and CCBs for their risk factors.”
Bernd Jilma, MD, of the Medical University of Vienna (Vienna, Austria), coauthored one of the platelet function studies linking CCBs with poor clopidogrel response. The study, published in JACC (Siller-Matula JM, et al. 2008;52:1557-1563), showed that in a cohort of 200 patients, concurrent use of CCBs and clopidogrel decreases platelet inhibition and increases the risk of adverse clinical outcomes.
Role of Platelet Function Testing Debated
In an e-mail communication with TCTMD, Dr. Jilma indicated that he remains unconvinced by the current results, pointing out that “we lack information on the type of CCB used. In addition, the HR indicates that in this study, clopidogrel was not superior to placebo; thus it follows that the trial was not powered for a CCB subgroup analysis.”
Regardless, “there is good evidence that amlodipine intake is associated with poor pharmacodynamics response, and that CCB intake irrespective of clopidogrel use is associated with an increased risk, potentially as a consequence of underlying disease,” Dr. Jilma said.
Therefore, “such patients could be preferentially tested for non-responsiveness,” he added. “If [CCBs] are necessary, I would test individual patients both before and after the start of CCB use, and be cautious in those whose CCB intake deteriorated the clopidogrel response.”
But such precautions are simply unnecessary, Dr. Good maintained. “With CCBs, with our data and other recent data, this is pretty reassuring clinical information that we can use calcium-channel blockers and clopidogrel together,” he said. “Speaking as a clinician, I don’t think anybody avoids atorvastatin in patients they’re going to put on clopidogrel, and there’s a similar feeling about CCBs at this point.”
Source:
Good CW, Steinhubl SR, Brennan DM, et al. Is there a clinically significant interaction between calcium channel antagonists and clopidogrel? Results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Circ Cardiovasc Interv. 2012;5:77-81.
Disclosures:
- Drs. Good and Jilma report no relevant conflicts of interest.
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Jason R. Kahn, the former News Editor of TCTMD, worked at CRF for 11 years until his death in 2014…
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