Increasing Cardiac Rehabilitation Participation Through a "Nearer to Home" Patient Referral Program.

PURPOSE: Time to travel to cardiac rehabilitation (CR) centers is a barrier to participation, and tertiary referral centers often care for patients living at a substantial distance. We sought to determine the impact of referring eligible patients to CR centers closer to home or workplace on overall participation rate. METHODS: An observational review was conducted in patients from a large cardiovascular program who were referred to CR (January 1, 2015, through December 31, 2016). Those declining participation due to distance from their home were identified and provided coordinated referral to a CR program they chose near their home or workplace. RESULTS: Of the 2912 patients referred to CR, 673 (23%) participated and 1900 declined due to distance. Contact was made in 2017 with 1237 of the 1900 of whom 1083 recalled a discussion of distance referral and completed the phone survey. Participants mean age was 64 yr, predominantly White (88%), male (65%), married (66%), and 70% had ≥ comorbidity. Out of the 1083 referred to a local CR program, 78% reported attending. Of those who attended CR, 55% (469/849) would not have attended had they not been referred to a program closer to their home or workplace. Overall participation increased from 23% to >50% of those referred from our institution. CONCLUSIONS: Coordinating CR referrals from the discharging facility to facilities closer to home or workplace is an effective means for increasing participation. The very low-cost effort has the potential to have a very meaningful impact on the long-term outcome of cardiovascular patients.

Mechanisms of in vivo release of triamcinolone acetonide from PLGA microspheres.

Little is known about the underlying effects controlling in vitro-in vivo correlations (IVIVCs) for biodegradable controlled release microspheres. Most reports of IVIVCs that exist are empirical in nature, typically based on a mathematical relationship between in vitro and in vivo drug release, with the latter often estimated by deconvolution of pharmacokinetic data. In order to improve the ability of in vitro release tests to predict microsphere behavior in vivo and develop more meaningful IVIVCs, the in vivo release mechanisms need to be characterized. Here, two poly(lactic-co-glycolic acid) (PLGA) microsphere formulations encapsulating the model steroid triamcinolone acetonide (Tr-A) were implanted subcutaneously in rats by using a validated cage model, allowing for free fluid and cellular exchange and microsphere retrieval during release. Release kinetics, as well as mechanistic indicators of release such as hydrolysis and mass loss, was measured by direct analysis of the recovered microspheres. Release of Tr-A from both formulations was greatly accelerated in vivo compared to in vitro using agitated phosphate buffered saline +0.02% Tween 80 pH7.4, including rate of PLGA hydrolysis, mass loss and water uptake. Both microsphere formulations exhibited erosion-controlled release in vitro, indicated by similar polymer mass loss kinetics, but only one of the formulations (low molecular weight, free acid terminated) exhibited the same mechanism in vivo. The in vivo release of Tr-A from microspheres made of a higher molecular weight, ester end-capped PLGA displayed an osmotically induced/pore diffusion mechanism based on confocal micrographs of percolating pores in the polymer, not previously observed in vitro. This research indicates the need to fully understand the in vivo environment and how it causes drug release from biodegradable microspheres. This understanding can then be applied to develop in vitro release tests which better mimic this environment and cause drug release by the relevant mechanistic processes, ultimately leading to the development of mechanism based IVIVCs.

Mechanistic analysis of triamcinolone acetonide release from PLGA microspheres as a function of varying in vitro release conditions.

In vitro tests for controlled release PLGA microspheres in their current state often do not accurately predict in vivo performance of these products during formulation development. Here, we introduce a new mechanistic and multi-phase approach to more clearly understand in vitro-in vivo relationships, and describe the first "in vitro phase" with the model drug, triamcinolone acetonide (Tr-A). Two microsphere formulations encapsulating Tr-A were prepared from PLGAs of different molecular weights and end-capping (18kDa acid-capped and 54kDa ester-capped). In vitro release kinetics and the evidence for controlling mechanisms (i.e., erosion, diffusion, and water-mediated processes) were studied in four release media: PBST pH 7.4 (standard condition), PBST pH 6.5, PBS+1.0% triethyl citrate (TC), and HBST pH 7.4. The release mechanism in PBST was primarily polymer erosion-controlled as indicated by the similarity of release and mass loss kinetics. Release from the low MW PLGA was accelerated at low pH due to increased rate of hydrolysis and in the presence of the plasticizer TC due to slightly increased hydrolysis and much higher diffusion in the polymer matrix. TC also increased release from the high MW PLGA due to increased hydrolysis, erosion, and diffusion. This work demonstrates how in vitro conditions can be manipulated to change not only rates of drug release from PLGA microspheres but also the mechanism(s) by which release occurs. Follow-on studies in the next phases of this approach will utilize these results to compare the mechanistic data of the Tr-A/PLGA microsphere formulations developed here after recovery of microspheres in vivo. This new approach based on measuring mechanistic indicators of release in vitro and in vivo has the potential to design better, more predictive in vitro release tests for these formulations and potentially lead to mechanism-based in vitro-in vivo correlations.