Pioglitazone Can Decrease Need for Revascularization in Diabetic Patients After BMS

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In combination with standard therapy, the thiazolidinedione drug pioglitazone appears to offer many benefits to patients implanted with bare-metal stents (BMS). Most notably, diabetic patients stand to obtain reductions in in-stent restenosis and short-term need for revascularization, researchers concluded in a meta-analysis published in the March 2011 issue of JACC: Cardiovascular Interventions.

For the meta-analysis, Dhavalkumar Patel, MD, MPH, of Washington Hospital Center (Washington, DC), and colleagues examined data from 6 studies involving 373 patients who underwent BMS implantation and were randomized to receive standard treatment with (n = 187) or without (n = 186) pioglitazone. The average dose of pioglitazone was 30 mg, and all but 1 study involved giving the drug after PCI.

There were no differences at baseline between the 2 groups in age, sex, body mass index, blood pressure, fasting blood sugar, HbA1c, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and smoking prevalence.

Better 6-Month Outcomes with Pioglitazone

Overall, the use of pioglitazone was associated with reduced late loss, larger minimum lumen diameter, and lower percent diameter stenosis (table 1).

Table 1. Six-Month Outcomes: Pioglitazone vs. Control

Compared with the control group, the pioglitazone group also had a significantly decreased rate of in-stent restenosis (18% vs. 40%; OR 0.26; 95% CI 0.12-0.56; P < 0.01). In addition, a comparison of revascularization rates for studies including only diabetic patients showed a markedly lower rate of revascularization with pioglitazone (11% vs. 41%; OR 0.19; 95% CI 0.07-0.48; P < 0.01). Although the same effect was not seen in studies involving nondiabetic patients who also received pioglitazone, the authors of the meta-analysis say this may simply be the result of small sample size.

Trials in which revascularization was performed solely on the basis of angiographic restenosis showed a similar benefit with pioglitazone in preventing revascularization (P = 0.003) as did trials in which revascularization was performed in the presence of ischemia (clinical symptom, positive stress test, and/or fractional flow reserve < 0.75; P = 0.004).

Intravascular ultrasound (IVUS) analysis also demonstrated decreased neointima formation in the pioglitazone group (mean difference 0.78 mm²; 95% CI 1.03-0.54; P < 0.01) as well as decreased neointimal index (mean difference 10.44%; 95% CI 13.87-7.02; P < 0.01).

Among the major clinical endpoints, there were fewer MIs within 6 months of PCI with pioglitazone, but the difference failed to reach statistical significance given the low number of events (P = 0.30). There was no difference in incidence of congestive heart failure or death.

Unknown Mechanism, But Promising Nonetheless

Although currently approved for diabetes, pioglitazone is of wider cardiovascular interest due to its anti-inflammatory and antiatherogenic properties. In the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial, pioglitazone therapy was associated with a significant decrease in all-cause mortality, MI, and stroke. Similarly, in the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) trial, there was a lower rate of atherosclerosis progression with pioglitazone than with glipizide at 18-month IVUS follow-up, suggesting pioglitazone may possess plaque-stabilizing properties in addition to its antiatherogenic effect.

According to Dr. Patel and colleagues, the ability of pioglitazone to suppress neointimal hyperplasia appears to be the result of direct antiproliferative and anti-inflammatory properties of the drug rather than a metabolic effect. At least 1 previous study has suggested that the antiproliferative actions of the thiazolidinedione class of drugs may be enhanced under high glucose conditions, leading Dr. Patel and colleagues to speculate that this may explain why the studies involving diabetic patients in their meta-analysis showed a greater benefit of pioglitazone therapy than those involving nondiabetics.

They also point out that in preclinical studies, pioglitazone demonstrated attenuated neointima formation by decreasing expression of inflammatory biomarkers, which may play a significant role in containing inflammation and neointimal hyperplasia after stent implantation. Pioglitazone also has been shown to enhance apoptosis, they add, which may result in regression of neointimal hyperplasia. It also decreases insulin sensitivity, thereby decreasing fasting insulin levels that promote neointimal proliferation after stenting.

Although the precise mechanism of pioglitazone in preventing neointima formation and in-stent restenosis remains unknown, Dr. Patel and colleagues conclude that the myriad positive effects suggest that “use of pioglitazone after BMS implantation might not only prevent [in-stent restenosis] but might also protect against future cardiovascular events.”

Patel D, Walitt B, Lindsay J, et al. Role of pioglitazone in the prevention of restenosis and need for revascularization after bare-metal stent implantation: A meta-analysis. J Am Coll Cardiol Intv. 2011;4:353-360.

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