Efficacy and Safety of SID142 in Patients With Peripheral Arterial Disease: A Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel-Group, Phase III Clinical Trial.

PURPOSE: Renexin® is a combination pill of cilostazol and Ginkgo biloba leaf extract that is used for the improvement of ischemic symptoms associated with peripheral arterial disease (PAD). SID142 is a controlled-release tablet of cilostazol (200 mg) and G biloba leaf extract (160 mg) that was developed to address the limitation of BID administration with Renexin. This study aimed to verify that SID142 was not inferior to Renexin in the treatment of patients with PAD. METHODS: This was a multicenter, randomized, double-blind, active-controlled, parallel-group, Phase III clinical trial. Study subjects were randomized to receive SID142 once daily or Renexin twice a day for 12 weeks. The primary end point was a change in the patient assessment of lower leg pain intensity with the use of a visual analog scale (VAS) after 12 weeks of treatment. If the lower limit of the two-sided 95% CI was greater than -10, the study drug was declared noninferior to the reference drug. Secondary efficacy end points included cold sensation, ankle-brachial index, ankle systolic pressure, maximum walking distance, pain-free walking distance, and investigator's global assessment. Study group results were compared 4, 8, and 12 weeks after treatment. Adverse events were assessed as a safety end point. FINDINGS: In total, 344 subjects from 19 medical centers were screened, and a total of 170 subjects were randomly assigned to either the SID142 (n = 86) or the Renexin (n = 84) group. Analysis of the change in lower extremity pain at 12 weeks compared with baseline revealed that SID142 was not inferior to Renexin (21.44 [19.23] vs 22.30 [17.75]; 95% CI, -7.70 to 5.97; P = 0.5942). No significant differences were found between groups in any secondary efficacy end point. However, the incidence of adverse reactions was significantly lower in the SID142 group (22.35% vs 39.29%; P = 0.0171). IMPLICATIONS: SID142 once daily was not inferior to Renexin twice a day for efficacy in patients with PAD. SID142 had a favorable safety profile. CLINICALTRIALS: gov identifier: NCT03318276.

Effect of High-Dose Statin Therapy on Drug-Eluting Stent Strut Coverage.

OBJECTIVE: The influence of high-dose statin therapy on the serial stent healing process has not been fully investigated. Using optical coherence tomography, the effect of high-dose statin therapy on stent strut coverage was evaluated in drug-eluting stent-treated patients. APPROACH AND RESULTS: Sixty patients were randomly assigned to 2 groups according to the statin dose (atorvastatin 40 mg as high-dose statin therapy [n=29] versus pravastatin 20 mg as low-dose statin therapy [n=31]). Serial optical coherence tomographic evaluation post procedure and at the 3-month and 12-month follow-ups was performed in 50 patients with 54 stents (23 atorvastatin-treated patients versus 27 pravastatin-treated patients). The percentage of uncovered struts was defined as the ratio of uncovered struts/total struts. The primary end point was the percentage of uncovered struts at the 12-month follow-up. The secondary end point was the percentage of uncovered struts at the 3-month follow-up and the comparative percentage change (Δ) of uncovered struts at the 3- and 12-month follow-ups between the different dose statin therapies. The percentage of uncovered struts was 7.4% (range, 4.3%-10.4%) in atorvastatin-treated patients versus 10.6% (range, 5.7%-22.6%) in pravastatin-treated patients at the 3-month follow-up (P=0.13) and 1.3% (0.3%-3.8%) versus 2.5% (0.9%-9.7%), respectively, at the 12-month follow-up (P=0.01). The percentage Δ of uncovered struts from 3 to 12 months of follow-up was -7.9±8.5% in atorvastatin-treated patients versus -9.3±12.5% in pravastatin-treated patients (P=0.67). CONCLUSIONS: This study suggested that high-dose statin therapy might provide a beneficial effect for the vascular healing process after drug-eluting stent implantation.

Effect of high-dose statin loading on biomarkers related to inflammation and renal injury in patients hospitalized with acute heart failure. Randomized, controlled, open-label, prospective pilot study.

BACKGROUND: High-dose statin loading is known to reduce periprocedural myocardial infarction and contrast-induced acute kidney injury in patients undergoing percutaneous coronary intervention. However, the clinical role of high-dose statin loading in patients with acute heart failure (AHF) remains unknown. METHODS AND RESULTS: In a prospective, single-center, randomized, controlled, open-label pilot study, patients hospitalized with AHF were randomly assigned to receive oral high-dose atorvastatin loading (80 mg for 3 days, followed by 10 mg/day until discharge) or no statin therapy, on top of optimal HF treatment. The primary outcome measures were changes to the level of biomarkers related to inflammation and renal injury from admission to hospital day 4. No significant changes in the levels of NT-proBNP (-2,627±4,956 vs. -2,981±6,951 pg/ml, P=0.845), hsCRP (-6.1±16.4 vs. -2.1±16.2 mg/L, P=0.105), cystatin C (0.002±0.185 vs. 0.009±0.216 mg/L, P=0.904), ACR (-886.3±1,984.9 vs. -165.6±825.2 mg/day, P=0.124) were observed in either group. In-hospital mortality (4.3% vs. 3.8%, P>0.999) and all-cause mortality at 90 days (4.3% vs. 3.8%, P>0.999) were not significantly different between groups. CONCLUSIONS: This pilot study showed that oral high-dose atorvastatin loading may be used safely in patients with AHF, but is not effective in reducing the levels of circulating biomarkers related to inflammation and renal injury during hospitalization.

Efficacy of early intensive rosuvastatin therapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (ROSEMARY Study).

The purpose of the study was to investigate whether early high-dose potent statin therapy in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention can reduce infarct size compared with conventional low-dose statin therapy. In a randomized placebo-controlled multicenter trial, 185 patients were assigned either to an early high-dose rosuvastatin group (n = 92, rosuvastatin 40 mg before treatment plus maintenance for 7 days) or to a conventional low-dose rosuvastatin group (n = 93, placebo before treatment plus rosuvastatin 10-mg maintenance for 7 days). Serial cardiac magnetic resonance imaging (MRI) was performed during the acute (3 to 7 days) and chronic (3 months) phases. The primary end point was relative infarct volume assessed by MRI at 3 months. Baseline characteristics were similar between the 2 groups, except hypertension, which was more prevalent in the high-dose group. Serial MRI data were available for 121 patients (high-dose group n = 54 and low-dose group n = 67). The relative infarct volumes in the acute (23.0 ± 9.5% vs 20.5 ± 11.7%, p = 0.208) and chronic (15.9 ± 8.3% vs 15.8 ± 9.7%, p = 0.943) phases were not different between the groups. No differences between groups were observed for periprocedural microvascular circulation evaluated by Thrombolysis In Myocardial Infarction flow grade, myocardial blush grade, ST-segment resolution, microvascular obstruction on cardiac MRI, or clinical outcomes. In conclusion, early high-dose rosuvastatin therapy in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention did not improve periprocedural myocardial perfusion or reduce infarct volume measured by MRI compared with the conventional low-dose rosuvastatin regimen.

Efficacy of high-dose atorvastatin loading before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: the STATIN STEMI trial.

OBJECTIVES: This study sought to determine the efficacy of high-dose atorvastatin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND: Previous randomized trials have demonstrated that statin pre-treatment reduced major adverse cardiac events (MACEs) in patients with stable angina pectoris and acute coronary syndrome. However, no randomized studies have been carried out with STEMI patients in a primary PCI setting. METHODS: A total 171 patients with STEMI were randomized to 80-mg atorvastatin (n = 86) or 10-mg atorvastatin (n = 85) arms for pre-treatment before PCI. All patients were prescribed clopidogrel (600 mg) before PCI. After PCI, both groups were treated with atorvastatin (10 mg). The primary end point was 30-day incidence of MACE including death, nonfatal MI, and target vessel revascularization. Secondary end points included corrected thrombolysis in myocardial infarction frame count, myocardial blush grade, and ST-segment resolution at 90 min after PCI. RESULTS: MACE occurred in 5 (5.8%) and 9 (10.6%) patients in the 80-mg and 10-mg atorvastatin pre-treatment arms, respectively (p = 0.26). Corrected thrombolysis in myocardial infarction frame count was lower in the 80-mg atorvastatin arm (26.9 +/- 12.3 vs. 34.1 +/- 19.0, p = 0.01). Myocardial blush grade and ST-segment resolution were also higher in the 80-mg atorvastatin arm (2.2 +/- 0.8 vs. 1.9 +/- 0.8, p = 0.02 and 61.8 +/- 26.2 vs. 50.6 +/- 25.8%, p = 0.01). CONCLUSIONS: High-dose atorvastatin pre-treatment before PCI did not show a significant reduction of MACEs compared with low-dose atorvastatin but did show improved immediate coronary flow after primary PCI. High-dose atorvastatin may produce an optimal result for STEMI patients undergoing PCI by improving microvascular myocardial perfusion. (Efficacy of High-Dose AtorvaSTATIN Loading Before Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction [STATIN STEMI]; NCT00808717).