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The addition of high-dose atorvastatin to double-dose clopidogrel increases platelet inhibition in patients undergoing elective percutaneous coronary intervention (PCI) who show high on-treatment platelet reactivity, according to a study in the February 2013 issue of JACC: Cardiovascular Interventions.

For the ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity) study, investigators led by Mario Leoncini, MD, of Misericordia e Dolce Hospital (Prato, Italy), randomized 76 stable CAD patients with high pre-stenting platelet reactivity to double-dose (150 mg) clopidogrel with (n = 38) or without (n = 38) high-dose (80 mg) atorvastatin daily for 30 days.

Platelet Function Measured

Platelet reactivity was measured with the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). 

At 10 days, P2Y12 reaction units (PRU) had declined from baseline in both arms. At 30 days, however, the atorvastatin group experienced a greater relative reduction in PRU, the primary endpoint (35 ± 16% vs. 23 ± 16%; P < 0.001), and percent platelet inhibition (IPA; 37 ± 14% vs. 28 ±15%; P < 0.01) than the control group. Iso-TRAP reaction units (BASE), meanwhile, were similar at 30 days (table 1).

Table 1. Platelet Function Parameters at 30 Days

At 10 days, the proportion of patients who had become optimal responders trended higher in the atorvastatin group compared with controls (74% vs. 63%; P = 0.1) and by 30 days the difference had become significant (84% vs. 58%; P = 0.02).

Factors associated with 30-day optimal response were:

• Age (OR 0.94; P = 0.032)
• Noncarrier status of the CYP2C19*2 loss-of-function allele (OR 2.9; P = 0.043)
• Baseline higher PRU (OR 0.98; P = 0.005)
• Use of atorvastatin (OR 3.8; P = 0.011)

A PRU value of less than 298 was identified as the best cut-off for predicting optimal response at 30 days (OR 10.7; 95% CI 3.3-34.8; P = 0.0001).

At 30 days, LDL cholesterol levels had declined from baseline in patients receiving atorvastatin (81 ±17 mg/dL vs. 117± 34 mg/dL; P < 0.01) and were markedly lower than in control patients (105 ± 37 mg/dL; P < 0.01). However, no correlations were found between various lipid fractions and PRU or BASE values.

At 30-day follow-up, rates of periprocedural MI were similar in the atorvastatin and control groups (16% and 21%, respectively; P = 0.7); no other ischemic events, major bleeding, or transfusions were reported. Two patients, both in the atorvastatin arm, experienced transaminase increases greater than twice the upper limit of normal.

Beyond Lipid-Lowering

“Statins are known to have multiple nonlipid-lowering (‘pleiotropic’) effects,” the authors write. In addition to being vasoprotective and anti-inflammatory, they “reduce platelet aggregation, dense granule release, and platelet-mediated thrombus formation, all rapidly and in a dose-dependent manner. Moreover, the combination of standard-dose clopidogrel with atorvastatin leads to further reductions in ADP- and TRAP-induced platelet activation.”

In an accompanying editorial, Laurent Bonello, MD, PhD, and colleagues, of Université Aix-Marseille (Marseille, France), observe that although the study carries few clinical implications, “it is important in validating a potential mechanism of action of statins and further acknowledges their pleiotropic effects. In addition, it underlines the complex interplay taking place in atherothrombosis and, most importantly, the interactions between commonly used drugs.”

In a telephone interview with TCTMD, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), echoed the latter point. “Mechanistic studies like this are really worthwhile because we don’t often study drug interactions,” he said. “We do trials of drug A vs. drug B or placebo, but rarely of drug A plus drug B. So we don’t really know in real life how these drugs interact.”

Ironically, he pointed out, several years ago attention was focused on a possible adverse interaction between atorvastatin and clopidogrel, and “now the pendulum has swung completely the other way.”

In fact, signals from 2 earlier trials appear to support the idea of a potentiation of clopidogrel by statins, Dr. Bhatt noted. Post hoc analyses from the CAPRI and CHARISMA trials, which compared clopidogrel with aspirin, found the greatest benefit in patients receiving both clopidogrel and statins, he reported. Moreover, other data show that if cholesterol is lowered in hypercholesterolemic patients, their platelets respond better to aspirin.

Dr. Bhatt said he is somewhat skeptical of the pleiotropic effects of statins, noting that the more ‘on-target’ effect of the drug class in decreasing cholesterol should not be discounted. “There are good reasons to think that antiplatelet therapy and statin therapy are additive in their benefits and potentially synergistic,” he commented. “But even if we’re wrong about that, it doesn’t really matter because guidelines say that patients who are on antiplatelet therapy, at least for secondary prevention, almost always need to be on a statin.”

Mechanism May Make a Difference

According to Andrew L. Frelinger III, PhD, of Harvard Medical School (Boston, MA), there may be a clinical advantage to adding an agent such as atorvastatin that brings multiple mechanisms to bear on the overall antithrombotic mission rather than putting all therapeutic eggs in the 1 basket of P2Y12 receptor inhibition. The jury is still out on that question, he said, but a possible interpretation of the failure of clopidogrel dose-adjustment trials such as GRAVITAS is that specific mechanisms of platelet inhibition—beyond simple P2Y12 receptor blockage—may be more important clinically than reduced PRU values per se.

Dr. Frelinger added that lipid lowering has many facets, some of which are directly related to platelet reactivity. “I would want to look at possible changes in the lipid composition of platelet membranes,” he said, noting that “those would affect multiple [types of] platelet receptors.”

Acknowledging that statins are already a staple of CAD treatment, Dr. Frelinger said mechanistic studies remain valuable because “until we understand the mechanisms involved, we don’t know if we have reached the maximal benefit that can be derived from them.”

Study Details

All patients were statin naïve and prior to PCI received 100 mg of aspirin daily and a 600-mg loading dose of clopidogrel followed by a 75-mg maintenance dose for at least 7 days.

Baseline characteristics were balanced between the study groups. The mean age was 67 years, about one-third had diabetes, and 42% had poor renal function.

Sources:

1. Leoncini M, Toso A, Maioli M, et al. High-dose atorvastatin on the pharmacodynamic effects of double-dose clopidogrel in patients undergoing percutaneous coronary interventions: The ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity) study. J Am Coll Cardiol Intv. 2013;6:169-179.
2. Bonello L, Paganelli F, Laine M. Pharmacological interactions: The next frontier? J Am Coll Cardiol Intv. 2013:6:180-181.

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