Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

Improving awareness of the HCR-20 and risk assessment process.

BACKGROUND: In 2011 Mrs A assaulted two people, one who died. In the hours prior to the attack she made multiple attempts to gain help including attending accident and emergency, contact with an inpatient service and the police. Subsequent investigation highlighted that her risk was not well documented or understood. OBJECTIVE: This quality improvement project aimed to improve knowledge and awareness of HCR-20 risk assessments amongst mental health professionals. METHOD: The Quality Improvement approach was taken and various initiatives were introduced to improve knowledge of the location and purpose of the HCR-20 and to ensure that these risk assessments were regularly updated. RESULTS: The results indicated that knowledge relating to the HCR-20 significantly improved amongst staff and breaches of deadlines for updating these risk assessments dramatically declined after the induction of the interventions. CONCLUSION: Including the 'risk formulation' and 'scenarios' from the HCR-20 in clients' crisis plans, introducing training relating to the HCR-20, and including discussions relating to the HCR-20 at the beginning of CPA meetings resulted in improved MDT awareness and knowledge of the HCR-20. A broader understanding and awareness of risk factors enabled the service to move towards a culture of risk being everyone's business.

Aortic Stiffness, Pulse Pressure, and Cerebral Pulsatility Progress Despite Best Medical Management: The OXVASC Cohort.

BACKGROUND: Increased cerebral arterial pulsatility is associated with cerebral small vessel disease, recurrent stroke, and dementia despite the best medical treatment. However, no study has identified the rates and determinants of progression of arterial stiffness and pulsatility. METHODS: In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), arterial stiffness (pulse wave velocity [PWV]) and aortic systolic, aortic diastolic, and aortic pulse pressures (aoPP) were measured by applanation tonometry (Sphygmocor), while middle cerebral artery (MCA) peak (MCA-PSV) and trough (MCA-EDV) flow velocity and Gosling pulsatility index (PI; MCA-PI) were measured by transcranial ultrasound (transcranial Doppler, DWL Doppler Box). Repeat assessments were performed at the 5-year follow-up visit after intensive medical treatment and agreement determined by intraclass correlation coefficients. Rates of progression and their determinants, stratified by age and sex, were determined by mixed-effects linear models, adjusted for age, sex, and cardiovascular risk factors. RESULTS: In 188 surviving, eligible patients with repeat assessments after a median of 5.8 years. PWV, aoPP, and MCA-PI were highly reproducible (intraclass correlation coefficients, 0.71, 0.59, and 0.65, respectively), with progression of PWV (2.4%; P<0.0001) and aoPP (3.5%; P<0.0001) but not significantly for MCA-PI overall (0.93; P=0.22). However, PWV increased at a faster rate with increasing age (0.009 m/s per y/y; P<0.0001), while aoPP and MCA-PI increased significantly above the age of 55 years (aoPP, P<0.0001; MCA-PI, P=0.009). Higher aortic systolic blood pressure and diastolic blood pressure predicted a greater rate of progression of PWV and aoPP, but not MCA-PI, although current MCA-PI was particularly strongly associated with concurrent aoPP (P<0.001). CONCLUSIONS: Arterial pulsatility and aortic stiffness progressed significantly after 55 years of age despite the best medical treatment. Progression of stiffness and aoPP was determined by high blood pressure, but MCA-PI predominantly reflected current aoPP. Treatments targetting cerebral pulsatility may need to principally target aortic stiffness and pulse pressure to have the potential to prevent cerebral small vessel disease.

Design of a randomised, double-blind, crossover, placebo-controlled trial of effects of sildenafil on cerebrovascular function in small vessel disease: Oxford haemodynamic adaptation to reduce pulsatility trial (OxHARP).

BACKGROUND: Cerebral small vessel disease (SVD) is associated with increased cerebrovascular pulsatility, endothelial dysfunction, and impaired vascular reactivity. Vasodilating phosphodiesterase inhibitors may improve cardiovascular pulsatility and reactivity, and potentially reduce progression of SVD.Hypothesis: Sildenafil, a PDE5 inhibitor, will reduce cerebrovascular pulsatility and increase cerebrovascular reactivity compared to placebo, and is non-inferior to cilostazol, a PDE3 inhibitor. METHODS: OxHARP is a randomised, double-blind, crossover trial of sildenafil 50 mg thrice daily, cilostazol 100 mg twice daily and placebo in 75 patients with mild to moderate small vessel disease and a previous lacunar or cryptogenic stroke or TIA. Participants undergo a physiological assessment at baseline and on each treatment, including transcranial Doppler ultrasound (TCD, DWL DopplerBox) to assess cerebrovascular pulsatility and reactivity to 4-6% carbon dioxide. In up to 60 patients, cerebrovascular pulsatility, perfusion and reactivity will also be assessed by MRI. OUTCOME MEASURES: The primary outcome is difference in middle cerebral artery pulsatility (Gosling's Pulsatility Index, PI) after 3 weeks of sildenafil versus placebo. Secondary outcomes including non-inferiority of sildenafil vs cilostazol in effects on PI, percentage increase in MCA blood flow velocity and BOLD-fMRI response during inhalation of 4-6% carbon dioxide. DISCUSSION: Reduction in cerebral pulsatility and increased cerebrovascular reactivity during treatment with sildenafil would indicate potential benefit to prevent progression of SVD, suggesting a need for trials with clinical outcomes.Trial Registration OxHARP is registered with ClinicalTrials.org, NCT03855332.

Body Mass Index and Arterial Stiffness Are Associated With Greater Beat-to-Beat Blood Pressure Variability After Transient Ischemic Attack or Minor Stroke.

[Figure: see text].

Progression of Beat-to-Beat Blood Pressure Variability Despite Best Medical Management.

Beat-to-beat variability in blood pressure (BP) is associated with recurrent stroke despite good control of hypertension. However, no study has identified rates of progression of beat-to-beat BP variability (BPV), its determinants, or which patient groups are particularly affected, limiting understanding of its potential as a treatment target. In consecutive patients one month after a transient ischaemic attack or nondisabling stroke (Oxford Vascular Study), continuous noninvasive BP was measured beat-to-beat over 5 minutes (Finometer). Arterial stiffness was measured by carotid-femoral pulse wave velocity (Sphygmocor). Repeat assessments were performed at the 5-year follow-up visit and agreement determined by intraclass correlation coefficient. Rates of progression of systolic BPV (SBPV) and diastolic BPV (DBPV) and their determinants were estimated by mixed-effect linear models, adjusted for age, sex, and cardiovascular risk factors. One hundred eighty-eight of 310 surviving, eligible patients had repeat assessments after a median of 5.8 years. Pulse wave velocity was highly reproducible but SBPV and DBPV were not (intraclass correlation coefficient: 0.71, 0.10, and 0.16, respectively), however, all 3 progressed significantly (pulse wave velocity, 2.39%, P<0.0001; SBPV, 8.36%, P<0.0001; DBPV, 9.7, P<0.0001). Rate of progression of pulse wave velocity, SBPV, and DBPV all increased significantly with age (P<0.0001), with an increasingly positive skew and were particularly associated with female sex (pulse wave velocity P=0.00035; SBPV P<0.0001; DBPV P<0.0001) and aortic mean SBP (SBPV P=0.037, DBPV P<0.0001). Beat-to-beat BP variability progresses significantly in high-risk patients, particularly in older individuals with elevated aortic systolic pressure. Beat-to-beat BPV and its progression represent potential new therapeutic targets to reduce cardiovascular risk.

Age and sex distribution of beat-to-beat blood pressure variability after transient ischemic attack and minor stroke: A population-based study.

BACKGROUND: Beat-to-beat blood pressure variability is associated with increased stroke risk but its importance at different ages is unclear. AIMS: To determine the age-sex distribution of blood pressure variability in patients with transient ischemic stroke or minor stroke. METHODS: In consecutive patients within six weeks of transient ischemic stroke or non-disabling stroke (Oxford Vascular Study), non-invasive blood pressure was measured beat-to-beat over five minutes (Finometer). The age-sex distribution of blood pressure variability (residual coefficient of variation) was determined for systolic blood pressure and diastolic blood pressure. The risk of top-decile blood pressure variability was estimated (logistic regression), unadjusted, and adjusted for age, sex, and cardiovascular risk factors. RESULTS: In 908 of 1013 patients, excluding 54 in atrial fibrillation and 51 with low quality recordings, residual coefficient of variation was positively skewed with a median systolic residual coefficient of variation of 4.2% (IQR 3.2-5.5) and diastolic residual coefficient of variation of 3.9% (3.0-5.5), with 90th centile thresholds of 7.2 and 7.3%. Median systolic residual coefficient of variation was higher in patients under 50 years (4.5 and 3.0-5.3) compared to 60-70 years (4.1 and 3.2-5.2), but rose to 4.5% (3.5-6.9) above 80 years, with an increasingly positive skew. The proportion of patients with markedly elevated blood pressure variability in the top-decile increased significantly per decade (OR 1.72, p < 0.001), after adjustment for sex and risk factors. CONCLUSIONS: Median beat-to-beat blood pressure variability fell in midlife, reflecting loss of physiological, organized blood pressure variability. However, rates of markedly elevated blood pressure variability significantly increased with greater age, suggesting that blood pressure variability may be particularly important in older patients.

Physiological determinants of residual cerebral arterial pulsatility on best medical treatment after TIA or minor stroke.

Cerebral arterial pulsatility is strongly associated with cerebral small vessel disease and lacunar stroke yet its dependence on central versus local haemodynamic processes is unclear. In a population-based study of patients on best medical managment, 4-6 weeks after a TIA or non-disabling stroke, arterial stiffness and aortic systolic, diastolic and pulse pressures were measured (Sphygmocor). Middle cerebral artery peak and trough flow velocities and Gosling's pulsatility index were measured by transcranial ultrasound. In 981 participants, aortic and cerebral pulsatility rose strongly with age in both sexes, but aortic diastolic pressure fell more with age in men whilst cerebral trough velocity fell more in women. There was no significant association between aortic systolic or diastolic blood pressure with cerebral peak or trough flow velocity but aortic pulse pressure explained 37% of the variance in cerebral arterial pulsatility, before adjustment, whilst 49% of the variance was explained by aortic pulse pressure, arterial stiffness, age, gender and cardiovascular risk factors. Furthermore, arterial stiffness partially mediated the relationship between aortic and cerebral pulsatility. Overall, absolute aortic pressures and cerebral blood flow velocity were poorly correlated but aortic and cerebral pulsatility were strongly related, suggesting a key role for transmission of aortic pulsatility to the brain.

The importance of seeing the patient: test-enhanced learning with standardized patients and written tests improves clinical application of knowledge.

Previous research has shown that repeated retrieval with written tests produces superior long-term retention compared to repeated study. However, the degree to which this increased retention transfers to clinical application has not been investigated. In addition, increased retention obtained through written testing has not been compared to other forms of testing, such as simulation testing with a standardized patient (SP). In our study, 41 medical students learned three clinical topics through three different learning activities: testing with SPs, testing using written tests, and studying a review sheet. Students were randomized in a counter-balanced fashion to engage in one learning activity per topic. They participated in four weekly testing/studying sessions to learn the material, engaging in the same activity for a given topic in each session. Six months after initial learning, they returned to take an SP test on each topic, followed by a written test on each topic 1 week later. On both forms of final testing, we found that learning through SP testing and written testing generally produced superior long-term retention compared to studying a review sheet. SP testing led to significantly better performance on the final SP test relative to written testing, but there was no significant difference between the two testing conditions on the final written test. Overall, our study shows that repeated retrieval practice with both SPs and written testing enhances long-term retention and transfer of knowledge to a simulated clinical application.