ABSTRACT
OBJECTIVE: Treatment of peripheral artery disease (PAD), Fontaine Stage IIb with vasoactive substances is of limited efficacy and does not last beyond the active treatment. Glyceryl trinitrate (GTN) is a vasodilating agent that relaxes vascular smooth muscle cells. The aim was to prove the concept that GTN sublingual powder has sustained clinical efficacy and adequate safety in these patients. METHODS: This was a multicentre, randomised, double blind, placebo controlled, forced titration, proof of concept study (phase IIa). Patients had a treadmill test at baseline, after 12 weeks of GTN/placebo administration, and at 19 and 26 weeks (without treatment). Primary objectives were an increase in initial claudication distance (ICD) and absolute claudication distance (ACD) at 12 weeks. RESULTS: Ninety-five patients were screened and 73 randomised, of which 53 patients completed the 12 week treatment phase (GTN 26, placebo 27). At a baseline ICD of 59.2 ± 32.8 m (GTN) and 57.5 ± 39.7 m (placebo), GTN led to a placebo corrected ICD increase of 23.2% vs. baseline (p = .35). Baseline ACD was 105.3 ± 52.9 m (GTN) and 106.1 ± 95.0 m (placebo), and GTN led to a placebo corrected increase of 3.6% (p = .44), with substantial interindividual variation. The change in claudication distance was greater in patients with an ICD of ≥50 m at baseline (ΔICD 29.3%; p = .19), and an ACD ≥ 100 m (ΔACD 8.5%; p = .40). The effect lasted beyond the active treatment period as shown by a 49.3% increase in ICD (p = .31) and a 20.6% increase in ACD (p = .21) by week 26. GTN sublingual powder was well tolerated. CONCLUSION: Intermittent treatment with nitroglycerin sublingual powder may represent a potential treatment option for patients with PAD stage Fontaine IIb, with an immediate and a sustained effect. The observed increases in ACD and ICD were however not statistically significant in this phase IIa proof of concept study. Further studies are required.
Subject(s)
Ambulatory Care , Exercise Tolerance/drug effects , Intermittent Claudication/drug therapy , Nitroglycerin/administration & dosage , Peripheral Arterial Disease/drug therapy , Vasodilator Agents/administration & dosage , Administration, Sublingual , Adult , Aged , Aged, 80 and over , Double-Blind Method , Drug Administration Schedule , Female , Germany , Humans , Intermittent Claudication/diagnosis , Intermittent Claudication/physiopathology , Male , Middle Aged , Nitroglycerin/adverse effects , Outpatients , Peripheral Arterial Disease/diagnosis , Peripheral Arterial Disease/physiopathology , Powders , Proof of Concept Study , Recovery of Function , Time Factors , Treatment Outcome , Vasodilator Agents/adverse effectsABSTRACT
BACKGROUND: In the presence of a coronary occlusion, pre-existing small collateral vessels (arterioles) develop into much larger arteries (biological bypasses) that have the potential to allow a certain level of perfusion distal to the blockage. Termed arteriogenesis, this phenomenon proceeds via a complex combination of events, with nitric oxide (NO) playing an essential role. The aim of this study was to investigate the effects of supplemental administration of NO donors, i.e., short-acting nitroglycerin (NTG) or slow-release pelleted isosorbide dinitrate (ISDN), on collateral development in a repetitive coronary artery occlusion model in rats. METHODS: Coronary collateral growth was induced via a repetitive occlusion protocol (ROP) of the left anterior descending coronary artery (LAD) in rats. The primary endpoints were the histological evaluation of rat heart infarct size and ST-segment elevation (ECG-analysis) upon final permanent occlusion of the LAD (experimentally induced myocardial infarction). The effects of NTG or ISDN were also evaluated by administration during 5 days of ROP. We additionally investigated whether concomitant application of NTG can compensate for the anti-arteriogenic effect of acetylsalicylic acid (ASA). RESULTS: After 5 days of ROP, the mean infarct size and degree of ST-elevation were only slightly lower than those of the SHAM group; however, after 10 days of the protocol, the ROP group displayed significantly less severe infarct damage, indicating enhanced arteriogenesis. Intermittent NTG application greatly decreased the ST-elevation and infarct size. The ISDN also had a positive effect on arteriogenesis, but not to the same extent as the NTG. Administration of ASA increased the infarct severity; however, concomitant dosing with NTG somewhat attenuated this effect. CONCLUSION: Intermittent treatment with the short-acting NTG decreased the size of an experimentally induced myocardial infarct by promoting coronary collateral development. These new insights are of great relevance for future clinical strategies for the treatment of occlusive vascular diseases.
