Statistical considerations for cardiovascular clinical trials straddling the continuum of pandemic phases.

In 2020, the NIH and FDA issued guidance documents that laid the foundation for human subject research during an unprecedented pandemic. To bridge these general considerations to actual applications in cardiovascular interventional device trials, the PAndemic Impact on INTErventional device ReSearch (PAIINTERS) Working Group was formed in early 2021 under the Predictable And Sustainable Implementation Of National CardioVascular Registries (PASSION CV Registries). The PAIINTER's Part I report, published by Rymer et al. [5], provided a comprehensive overview of the operational impact on interventional studies during the first year of the Pandemic. PAIINTERS Part II focused on potential statistical issues related to bias, variability, missing data, and study power when interventional studies may start and end in different pandemic phases. Importantly, the paper also offers practical mitigation strategies to adjust or minimize the impact for both SATs and RCTs, providing a valuable resource for researchers and professionals involved in cardiovascular clinical trials.

One-Year Follow-Up of Vascular Intervention Trials Disrupted by the COVID-19 Pandemic: A Use-Case landscape.

INTRODUCTION: The COVID-19 pandemic had an unprecedented impact on cardiovascular clinical research. The decision-making and state of study operations in cardiovascular trials 1-year after interruption has not been previously described. METHODS: In the spring of 2020, we created a pandemic impact task force to develop a landscape of use case scenarios from 17 device trials of peripheral artery disease (PAD) and coronary artery disease (CAD) interventions. In conjunction with publicly available (clinictrials.gov) study inclusion criteria, primary endpoints and study design, information was shared for this use-case landscape by trial leadership and data owners. RESULTS: A total of 17 actively enrolling trials (9 CAD and 8 PAD) volunteered to populate the use case landscape. All 17 were multicenter studies (12 in North America and 5 international). Fifteen studies were industry-sponsored, of which 13 were FDA approved IDEs, one was PCORI-sponsored and two were sponsored by the NIH. Enrollment targets ranged from 150 to 9000 pts. At the time of interruption, 5 trials were <20 % enrolled, 9 trials were 50-80 % enrolled and 3 trials were >80 % enrolled. At 1 year, the majority of studies were continuing to enroll in the context of more sporadic but ongoing pandemic activity. CONCLUSIONS: At 1 year from the first surge interruptions, most trials had resumed enrollment. Trials most heavily interrupted were trials early in enrollment and those trials not able to pivot to virtual patient and site visits. Further work is needed to determine the overall impact on vascular intervention trials disrupted during the COVID-19 pandemic.

Peer providers and linkage with buprenorphine care after hospitalization: A retrospective cohort study.

Background: People with opioid use disorder (OUD) are increasingly started on buprenorphine in the hospital, yet many patients do not attend outpatient buprenorphine care after discharge. Peer providers, people in recovery themselves, are a growing part of addiction care. We examine whether patients who received a low-intensity, peer-delivered intervention during hospitalization had a greater rate of linking with outpatient buprenorphine care relative to those not seen by a peer. Methods: This was a retrospective cohort study of adults with OUD who were started on buprenorphine during hospitalization. The primary outcome was receipt of a buprenorphine prescription within 30 days of discharge. Secondary outcomes included attendance at a follow-up visit with a buprenorphine provider within 30 days and hospital readmission within 90 days. Modified Poisson regression analyses tested for differences in the rate ratios (RR) of each binary outcome for patients who were versus were not seen by a peer provider. Peer notes in the electronic health record were reviewed to characterize peer activities. Results: 111 patients met the study inclusion criteria, 31.5% of whom saw a peer provider. 55.0% received a buprenorphine prescription within 30 days of hospital discharge. Patients with versus without peer provider encounters did not significantly differ in the rates of receiving a buprenorphine prescription (RR = 1.06, 95% CI: 0.74-1.51), hospital readmission (RR = 1.45, 95% CI: 0.80-2.64), or attendance at a buprenorphine follow-up visit (RR = 1.03, 95% CI: 0.68-1.57). Peers most often listened to or shared experiences with patients (68.6% of encounters) and helped facilitate medical care (60.0% of encounters). Conclusions: There were no differences in multiple measures of buprenorphine follow-up between patients who received this low-intensity peer intervention and those who did not. There is need to investigate what elements of peer provider programs contribute to patient outcomes and what outcomes should be assessed when evaluating peer programs.

Modification of cutaneous vasodilator response to heat stress by daytime exogenous melatonin administration.

In humans, the nocturnal fall in internal temperature is associated with increased endogenous melatonin and with a shift in the thermoregulatory control of skin blood flow (SkBF), suggesting a role for melatonin in the control of SkBF. The purpose of this study was to test whether daytime exogenous melatonin would shift control of SkBF to lower internal temperatures during heat stress, as is seen at night. Healthy male subjects (n = 8) underwent body heating with melatonin administration (Mel) or without (control), in random order at least 1 wk apart. SkBF was monitored at sites pretreated with bretylium to block vasoconstrictor nerve function and at untreated sites. Cutaneous vascular conductance, calculated from SkBF and arterial pressure, sweating rate (SR), and heart rate (HR) were monitored. Skin temperature was elevated to 38 degrees C for 35-50 min. Baseline esophageal temperature (Tes) was lower in Mel than in control (P < 0.01). The Tes threshold for cutaneous vasodilation and the slope of cutaneous vascular conductance with respect to Tes were also lower in Mel at both untreated and bretylium-treated sites (P < 0.05). The Tes threshold for the onset of sweating and the Tes for a standard HR were reduced in Mel. The slope of the relationship of HR, but not SR, to Tes was lower in Mel (P < 0.05). These findings suggest that melatonin affects the thermoregulatory control of SkBF during hyperthermia via the cutaneous active vasodilator system. Because control of SR and HR are also modified, a central action of melatonin is suggested.

Neuropeptide Y antagonism reduces reflex cutaneous vasoconstriction in humans.

Previous studies have provided evidence of a non-noradrenergic contributor to reflex cutaneous vasoconstriction in humans but did not identify the transmitter responsible. To test whether neuropeptide Y (NPY) has a role, in two series of experiments we slowly reduced whole body skin temperature (TSK) from 34.5 to 31.7 degrees C. In protocol 1, Ringer solution and the NPY receptor antagonist BIBP-3226 alone were delivered intradermally via microdialysis. In protocol 2, yohimbine plus propranolol (Yoh + Pro), Yoh + Pro in combination with BIBP-3226, and Ringer solution were delivered to antagonize locally the vasomotor effects of NPY and norepinephrine. Blood flow was measured by laser Doppler flowmetry (LDF). Mean arterial blood pressure (MAP) was monitored at the finger (Finapres). In protocol 1, cutaneous vascular conductance (CVC) fell by 45%, to 55.1 +/- 5.6% of baseline at control sites (P < 0.05). At BIBP-3226-treated sites, CVC fell by 34.1% to 65.9 +/- 5.0% (P < 0.05; P < 0.05 between sites). In protocol 2, during body cooling, CVC at control sites fell by 32.6%, to 67.4 +/- 4.3% of baseline; at sites treated with Yoh + Pro, CVC fell by 18.7%, to 81.3 +/- 4.4% of baseline (P < 0.05 vs. baseline; P < 0.05 vs. control) and did not fall significantly at sites treated with BIBP-3226 + Yoh + Pro (P > 0.05; P < 0.05 vs. other sites). After cooling, exogenous norepinephrine induced vasoconstriction at control sites (P < 0.05) but not at sites treated with Yoh + Pro + BIBP-3226 (P > 0.05). These results indicate that NPY participates in sympathetically mediated cutaneous vasoconstriction in humans during whole body cooling.

Evidence for a role for vasoactive intestinal peptide in active vasodilatation in the cutaneous vasculature of humans.

Active vasodilatation (AVD) in human, non-glabrous skin depends on functional cholinergic fibres but not on acetylcholine (ACh). We tested whether AVD is a redundant system in which ACh and vasoactive intestinal polypeptide (VIP) are co-released from cholinergic nerves. (1) We administered VIP by intradermal microdialysis to four discrete areas of skin in the presence of different levels of the VIP receptor antagonist, VIP(10-28), also delivered by microdialysis. Skin blood flow (SkBF) was continuously monitored by laser Doppler flowmetry (LDF). Mean arterial pressure (MAP) was measured non-invasively and cutaneous vascular conductance (CVC) calculated as LDF/MAP. Subjects were supine and wore water-perfused suits to control whole-body skin temperature (Tsk) at 34 degrees C. Concentrations of 54 microM, 107 microM, or 214 microM VIP(10-28) were perfused via intradermal microdialysis at 2 microl min-1 for approximately 1 h. Then 7.5 microM VIP was added to the perfusate containing VIP(10-28) at the three concentrations or Ringer solution and perfusion was continued for 45-60 min. At the control site, this level of VIP caused approximately the vasodilatation typical of heat stress. All VIP(10-28)-treated sites displayed an attenuated dilatation in response to the VIP. The greatest attenuation was observed at the site that received 214 microM VIP(10-28) (P < 0.01). (2) We used 214 microM VIP(10-28) alone and with the iontophoretically administered muscarinic receptor antagonist atropine (400 microA cm-2, 45 s, 10 mM) in heated subjects to test the roles of VIP and ACh in AVD. Ringer solution and 214 microM VIP(10-28) were each perfused at two sites, one of which in each case was pretreated with atropine. After 1 h of VIP(10-28) treatment, individuals underwent 45-60 min of whole-body heating (Tsk to 38.5 degrees C). VIP(10-28), alone or in combination with atropine, attenuated the increase in CVC during heat stress, suggesting an important role for VIP in AVD.

Cutaneous vasoconstrictor response to whole body skin cooling is altered by time of day.

To test for a diurnal difference in the vasoconstrictor control of the cutaneous circulation, we performed whole body skin cooling (water-perfused suits) at 0600 (AM) and 1600 (PM). After whole body skin temperature (T(sk)) was controlled at 35 degrees C for 10 min, it was progressively lowered to 32 degrees C over 18-20 min. Skin blood flow (SkBF) was monitored by laser-Doppler flowmetry at three control sites and at a site that had been pretreated with bretylium by iontophoresis to block noradrenergic vasoconstriction. After whole body skin cooling, maximal cutaneous vascular conductance (CVC) was measured by locally warming the sites of SkBF measurement to 42 degrees C for 30 min. Before whole body skin cooling, sublingual temperature (T(or)) in the PM was significantly higher than that in the AM (P < 0.05), but CVC, expressed as a percentage of maximal CVC (%CVC(max)), was not statistically different between AM and PM. During whole body skin cooling, %CVC(max) levels at bretylium-treated sites in AM or PM were not significantly reduced from baseline. In the PM, %CVC(max) at control sites fell significantly at T(sk) of 34.3 +/- 0.01 degrees C and lower (P < 0.05). In contrast, in the AM %CVC(max) at control sites was not significantly reduced from baseline until T(sk) reached 32.3 +/- 0.01 degrees C and lower (P < 0.05). Furthermore, the decrease in %CVC(max) in the PM was significantly greater than that in AM at T(sk) of 33.3 +/- 0.01 degrees C and lower (P < 0.05). Integrative analysis of the CVC response with respect to both T(or) and T(sk) showed that the cutaneous vasoconstrictor response was shifted to higher internal temperatures in the PM. These findings suggest that during whole body skin cooling the reflex control of the cutaneous vasoconstrictor system is shifted to a higher internal temperature in the PM. Furthermore, the slope of the relationship between CVC and T(sk) is steeper in the PM compared with that in the AM.

Sympathetic nonnoradrenergic cutaneous vasoconstriction in women is associated with reproductive hormone status.

We tested whether a nonnoradrenergic component of reflex vasoconstriction of skin blood flow (SkBF) is sensitive to female reproductive hormones. Six women taking oral contraceptives underwent whole-body cooling during high-hormone (HH) and low-hormone (LH) phases of oral contraceptive use. SkBF was monitored by laser Doppler flowmetry (LDF) at sites treated by intradermal injection of yohimbine-propranolol (5 mM and 1 mM; YOPR) to block the effects of norepinephrine (NE) or at saline (Sal) control sites. Mean arterial pressure (MAP) was measured with the use of the Penaz method. Cutaneous vascular conductance (CVC = LDF/mean arterial pressure) was expressed as a percentage of baseline. Whole body skin temperature was decreased from 34 to 31 degrees C in HH and LH. In both HH and LH, CVC at Sal-treated sites was reduced during cooling (CVC = 53.1 +/- 8.6% and 54.4 +/- 4.2%, both P < 0.05). In HH, CVC at YOPR sites was reduced during cooling (78.8 +/- 3.6%, P < 0.05). In contrast, CVC at YOPR sites was not reduced significantly during cooling in LH (CVC = 95.9 +/- 2.8%, P > 0.05). Across phases, CVC at YOPR sites during cooling was significantly different (P < 0.05). After cooling, the effects of NE at YOPR sites were completely blocked. These data indicate that a nonnoradrenergic mechanism of reflex cutaneous vasoconstriction is present in women and is associated with reproductive hormone status.