Statins Reduce Late Restenosis After SES Implantation

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Showing long-term antirestenotic properties, statins reduce late target lesion revascularization (TLR) in patients after sirolimus-eluting stent (SES) implantation, according to data from a large Japanese registry appearing online March 1, 2012, ahead of print in the American Journal of Cardiology. But the same results do not apply to bare-metal stents (BMS), pointing to different mechanisms of late restenosis with the 2 device types.

Researchers led by Yoshihisa Nakagawa, MD, of Tenri Hospital (Tenri, Japan), looked at 10,221 patients from the CREDO-Kyoto (Coronary Revascularization Demonstrating Outcome Study in Kyoto) PCI/CABG registry Cohort-2 who received either SES only (n = 5,029) or BMS only (n = 5,192) from 2005 through 2007. Within each arm, patients were then analyzed according to whether they received statins at discharge. Subjects were followed for 4 years to determine the effects on early and late restenosis.

Over the entire study period, TLR was lower in patients receiving SES vs. BMS (14.8% vs. 24.5%; P < 0.0001). While this also was true for early TLR (≤ 1 year; 7.8% vs. 22.2%; P < 0.0001), BMS proved superior for late TLR (> 1 year; 3.0% with BMS vs. 7.7% with SES; P < 0.0001).

After adjustment, SES were associated with both lower early TLR (HR 0.31; 95% CI 0.26-0.36; P < 0.0001) and higher late TLR (HR 1.63; 95% CI 1.15-2.31; P = 0.006).

Statin Benefits Felt in All Stenting Patients

Within the BMS arm, patients receiving statins (n = 2,576) had lower rates of all-cause death (8.1% vs. 12.6%; P < 0.0001), cardiovascular death (3.5% vs. 5.9%; P < 0.0001), and stroke (3.8% vs. 5.6%; P = 0.01) compared with patients not receiving statins (n = 2,616) out to 4 years, while rates of definite stent thrombosis (1.7% vs. 2.0%; P = 0.37), TLR (23.4% vs. 25.4%; P = 0.15), TVR (27.9% vs. 29.6%; P = 0.24), and other outcomes were equivalent.

Out to 4 years, patients receiving statins within the SES arm also had lower rates of all-cause death (7.9% vs. 13.1%; P < 0.0001) and cardiovascular death (3.7% vs. 7.3%; P < 0.0001) compared with SES patients not receiving statins. SES patients on statins also had lower rates of TLR, clinically driven TLR, and several other measures of revascularization, while the difference in definite stent thrombosis just missed statistical significance (table 1).

Table 1. Events at 4 Years in SES Patients According to Statin Use

When broken down into early and late TLR, statins made no difference in either stent type within 1 year. But between 1 and 4 years, SES patients receiving statins saw a decrease in TLR rates (table 2).

Table 2. Early and Late TLR According to Stent Type and Statin Status

After adjusting for confounders, statin use was associated with lower risk of late TLR in SES patients (adjusted HR 0.73; 95% CI 0.54-0.98; P = 0.04), while this was not the case in BMS patients (adjusted HR 0.74; 95% CI 0.46-1.20; P = 0.23).

The results, according to the authors, suggest that the underlying mechanisms of restenosis differ between BMS and SES. In particular, late restenosis with DES may derive from a number of factors including inflammation—thought to occur from polymer coatings—and long-term endothelial dysfunction via smooth muscle cell proliferation and delayed re-endothelialization. “Overall, DES-induced delayed healing could induce sustained inflammation and accelerated atherosclerosis, which might be a cause of late TLR,” they write.

As such, statins may decrease late TLR in DES patients through pleiotropic effects such as anti-inflammation, improved endothelial dysfunction, and antiatherosclerotic effects, which may even occur at non-stented sites, as evidenced by the lower rate of non-TLR in the SES arm. Because inflammation or endothelial dysfunction is thought to play a lesser role at BMS sites, statins may not be as effective in decreasing late TLR in such patients, the authors comment.

Statins Lauded But Underused

Overall, they stress that, “Statins should be administered in every patient undergoing PCI even if statin use was not associated with a decrease of late adverse events related to DES sites.” However, despite the acceptance of statins as important secondary preventive therapy, in the study, they were prescribed roughly 50% of the time at discharge.

In a telephone interview with TCTMD, Dennis T. Ko, MD, of the University of Toronto (Toronto, Canada), called that point “an important message,” though the extent of underuse might be particular to the Japanese population. “In North America, use of statins after angioplasty is probably higher. In Ontario, Canada, our numbers are 70 to 75 percent,” he said. “So statins are probably underutilized after angioplasty in Kyoto and probably to a smaller extent in North America, as well.”

Dr. Ko also agreed that it makes sense why statins would have a longer lasting impact on restenosis with DES, but not BMS. “BMS heal very quickly, so you don’t have a lot of inflammation after a very short period of time,” he said. “For DES, maybe the inflammatory process continues because it takes the artery a lot longer to heal, and the [statin] drug exerts some impact in the later term.”

Potency, Dosage Issues Raised

An important caveat, though, is that the study did not specify which statins were used. “The potency of statins vary significantly,” Dr. Ko pointed out. “That would make a difference. The statins they use in this study may be different than what we use in North America.”

If future research proves statins effective in lowering late events in DES patients, “administration of higher doses of statins would be a reasonable option in patients with high risk for late adverse events [after] DES implantation,” the authors observe.

Here, too, Dr. Ko was more cautious. “It’s difficult to know the dosing impact on TLR,” he said. “If you’re talking about dosing, people are really uncertain whether 10, 20, or 30 mg make a difference.”

In general, while Dr. Ko said he expects some clinicians to want more specific information regarding how statins affect late TLR, most will still advocate giving the drugs to all patients after PCI regardless. “For most cardiologists and patients, it’s accepted that statins are beneficial, and if only 50 percent of patients are getting them, that’s definitely too low,” he said.

Source:

Natsuaki M, Nakagawa Y, Morimoto T, et al. Impact of statin therapy on late target lesion revascularization after sirolimus-eluting stent implantation (from the CREDO-Kyoto Registry Cohort-2). Am J Cardiol. 2012;Epub ahead of print.

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