Effect of lipid-lowering therapy on carotid plaque burden in older adults.

BACKGROUND: Little is known about the benefits of lipid-lowering medications in those age ≥ 75 years. We assessed the effect of lipid-lowering medications on progression to severe atherosclerosis in patients age > 75. METHODS: Data was retrospectively obtained from the Stroke Prevention & Atherosclerosis Research Centre, Canada. Atherosclerosis burden was measured as carotid total plaque area (TPA), a powerful predictor of cardiovascular risk. Survival time free of severe atherosclerosis (SFSA) was defined as the period when TPA remained <1.19 cm2. Kaplan-Meier, multiple Cox proportional hazard and hierarchical mixed-effect models were used to determine the effects of lipid-lowering medications on progression to severe atherosclerosis. RESULTS: In total 1404 cases (mean age 81 ± 4 years; women 52%) were included. Those taking lipid-lowering medications were more likely to have a history of diabetes and a higher burden of atherosclerosis at baseline. In Kaplan-Meier analysis, the SFSA was significantly longer in those receiving lipid-lowering therapy. In multivariable-adjusted analyses, those not receiving lipid lowering therapy (irrespective of their vascular disease at baseline) were more likely to have TPA > 1.19 cm2 (hazard ratio (HR) = 1.37, 95% confidence interval (CI): 1.09,0.71). Similar findings were observed in mixed effects models when plaque progression was defined as any change >0.05 cm2 per year (odds ratio (OR):2.17, 95% CI:1.38,3.57). CONCLUSION: Lipid-lowering therapy is effective in controlling the burden of atherosclerosis among older adults with and without vascular disease. The measurement of plaque burden can guide selection and follow-up of those who may benefit from treatment.

The impact of socioeconomic status on the burden of atherosclerosis, and the effect of intensive preventive therapy on its progression: A retrospective cohort study.

BACKGROUND AND AIMS: Socioeconomic status (SES) is associated with cardiovascular disease. However, the relationship between SES and atherosclerosis is not well documented. This study aims to explore this relationship. METHODS: This is a retrospective cohort study in London, Ontario Canada. It includes 6,907 subjects from a vascular prevention centre at baseline, with long term follow up from 1989 to 2021 (total ultrasound examinations 27,103). Using carotid ultrasound, the burden of atherosclerosis was measured as total plaque area (TPA). The Ontario Marginalization Index (OMI) was used to identify SES of participants' neighborhoods. We used a Bayesian hierarchical regression and mixed effects model to identify associations between SES, baseline TPA and plaque progression. In 2003, we implemented more intensive therapy of vascular risk factors after 2003 (called "Treating arteries instead of risk treating factors"); therefore, we compared our findings before and after 2003. RESULTS: SES was found to have a significant association with TPA, with lower SES associated with higher TPA (adjusted odds ratio [OR] = 2.22, 95% Credible interval [CrI]: 1.37, 3.66). While we observed a higher rate of plaque progression with lower SES in those treated before 2003 (OR = 1.46, 95% CrI:1.04, 2.06), there was no significant association between plaque progression and SES after implementation more intensive therapy (OR = 0.99, 95% CrI: 0.78, 1.27). CONCLUSIONS: SES has a strong association with atherosclerosis and should be considered an important risk factor in clinical practice and vascular disease research. Intensive preventive therapy can prevent plaque progression irrespective of baseline SES.

Lipid-Modifying Therapies and Stroke Prevention.

PURPOSE OF REVIEW: We reviewed lipid-modifying therapies and the risk of stroke and other cerebrovascular outcomes, with a focus on newer therapies. RECENT FINDINGS: Statins and ezetimibe reduce ischemic stroke risk without increasing hemorrhagic stroke risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors similarly reduce ischemic stroke risk in statin-treated patients with atherosclerosis without increasing hemorrhagic stroke, even with very low achieved low-density lipoprotein cholesterol levels. Icosapent ethyl reduces the risk of total and first ischemic stroke in patients with established cardiovascular disease or diabetes mellitus. Clinical outcome trials are underway for newer lipid-modifying agents, including inclisiran, bempedoic acid, and pemafibrate. New biologic agents including evinacumab, pelacarsen, olpasiran, and SLN360 are also discussed. In addition to statins and ezetimibe, PCSK9 inhibitors and icosapent ethyl reduce the risk of ischemic stroke without increasing the risk of hemorrhagic stroke. These therapies dramatically expand options for reducing stroke in high-risk settings.

Optimal Medical Management of Asymptomatic Carotid Stenosis.

Asymptomatic carotid stenosis (ACS) due to atherosclerosis is a risk factor for ipsilateral ischemic cerebrovascular events and cognitive impairment. The prognosis of ACS has improved over the past 4 decades due largely to improvements in medical management. Most patients with ACS can be managed without revascularization, but some patients with vulnerable plaque should be considered for revascularization. Regardless of the decision to refer for revascularization, all patients with ACS should receive intensive medical management. This includes lifestyle modification (Mediterranean diet, exercise, and smoking cessation) and pharmacological therapy (antiplatelets, lipid-lowering agents, blood pressure reduction, and glycemic control). Patients with ACS often have atherosclerosis in other critical locations, and thus optimal medical therapy is likely to reduce events outside the carotid arteries. The nature of optimal medical therapy is described.

Association Between Stroke and Subsequent Risk of Suicide: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Poor mental health and depression are well-recognized sequelae of stroke; however, the association between stroke and subsequent risk of suicide is unknown. METHODS: We systematically searched MEDLINE, Embase, PsycINFO, and Google Scholar from their inception to September 15, 2020, using keywords and database-specific subjects. We independently adjudicated and selected observational studies that reported suicide attempts or death by suicide in stroke survivors and a comparison group, consisting either of people without a history of stroke or the general population. We evaluated study quality using the Newcastle Ottawa scale. Using random-effects meta-analysis, we calculated the pooled adjusted risk ratio (RR) of suicide in stroke survivors and separately calculated the pooled adjusted RR of suicide attempt and death by suicide. Using prespecified analyses, we explored study-level factors to explain heterogeneity. RESULTS: We screened 4093 articles and included 23 studies of fair quality, totaling over 2 million stroke survivors, of whom 5563 attempted suicide or died by suicide. Compared to the nonstroke group, the pooled adjusted RR of suicide in stroke survivors was 1.73 (95% CI, 1.53-1.96, I2=93%), with a significantly (P=0.03) higher adjusted risk of suicide attempt (RR, 2.11 [1.73-2.56]) than of death by suicide (RR, 1.61 [1.41-1.84]). A longer follow-up time in cohort studies was associated with a lower risk of suicide (RR, 0.97 [0.95-0.99] for every 1-year increase). CONCLUSIONS: Stroke should be considered as a risk factor for suicide. Comprehensive strategies to screen and treat depression and suicidal ideation in stroke survivors should be developed to reduce the burden of suicide in stroke survivors.

Interaction of smoking, hyperhomocysteinemia, and metabolic syndrome with carotid atherosclerosis: A cross-sectional study in 972 non-diabetic patients.

OBJECTIVES: Little is known about the interactions between hyperhomocysteinemia and metabolic syndrome (MetS) in individuals at risk for atherosclerosis. The aim of this study was to assess the burden of atherosclerosis in patients with MetS and hyperhomocysteinemia. METHODS: We assessed the interaction of MetS with other risk factors including hyperhomocysteinemia in 972 patients with a history of stroke, transient ischemic attack, or carotid stenosis. MetS was defined as by the International Diabetes Federation as body mass index ≥30 kg/m² and two or more of the following: hypertension, high triacylglycerides, and low high-density lipoprotein. We defined hyperhomocysteinemia as plasma total homocysteine ≥14 µmol/L. Patients with diabetes were excluded. Carotid total plaque area (TPA), a strong predictor of cardiovascular risk, was measured by carotid ultrasound. The association of TPA with MetS, and interaction with related risk factors, was assessed by multiple linear regression. RESULTS: Complete data were available on 972 non-diabetic patients. Of these, 179 (18.4%) had MetS. Patients with MetS and hyperhomocysteinemia (P < 0.001) or smoking (P = 0.02) had a higher TPA compared with those with MetS and normal plasma total homocysteine levels. In linear regression, there was a significant association of MetS (P = 0.004), hyperhomocysteinemia (P = 0.01), and smoking (P = 0.004) with increased TPA. CONCLUSIONS: Patients with MetS and smoking or hyperhomocysteinemia are at particularly high cardiovascular risk. Targeted atherosclerosis prevention should include identification and treatment of MetS, smoking, and hyperhomocysteinemia (including that due to unrecognized metabolic vitamin B12 deficiency).

Vitamin B 12 deficiency and hyperhomocysteinaemia in outpatients with stroke or transient ischaemic attack: a cohort study at an academic medical centre.

OBJECTIVE: We sought to assess the current magnitude of the opportunity for secondary stroke prevention with B vitamins. DESIGN: A cohort study. SETTING: The Urgent TIA (Transient Ischaemic Attack) Clinic at an academic medical centre. MAIN OUTCOME MEASURES: We assessed the prevalence of biochemical vitamin B12 deficiency (B12Def, serum B12 <156 pmol/L), hyperhomocysteinaemia (HHcy; plasma total homocysteine [tHcy] >14 µmol/L) and metabolic B12 deficiency (MetB12Def, serum B12 <258 pmol/L and HHcy) between 2002 and 2017, by age group and by stroke subtype. RESULTS: Data were available in 4055 patients. B12Def was present in 8.2% of patients overall; it declined from 10.9% of patients referred before 2009 to 5.4% thereafter (p=0.0001). MetB12Def was present in 10.6% of patients, and HHcy was present in 19.1% of patients. Among the patients aged ≥80 years, MetB12Def was present in 18.1% and HHcy in 35%. Among the 3410 patients whose stroke subtype was determined, HHcy was present in 18.4% of patients: 23.3% of large artery atherosclerosis, 18.1% of cardioembolic, 16.3% of small vessel disease, 10.8% of other unusual aetiologies and 13.6% of undetermined subtypes (p=0.0001). CONCLUSIONS: Despite a decline in our referral area since 2009, B12Def, MetB12Def and HHcy remain common in patients with stroke/TIA. Because these conditions are easily treated and have serious consequences, all patients with stroke/TIA should have their serum B12 and tHcy measured.

Decline in the Severity of Carotid Atherosclerosis and Associated Risk Factors From 2002 to 2014.

Background and Purpose- Several recent studies suggest declining rates of carotid revascularization for patients with carotid stenosis. We investigated whether carotid atherosclerosis severity has declined in recent years. Methods- We used carotid ultrasound to evaluate stenosis and plaque area in 6039 patients presenting to vascular medicine clinics in 3 eras: 2002 to 2005, 2006 to 2009, and 2010 to 2014. Results- The total plaque area at the time of referral to the clinics declined by 24% between 2002 and 2014; the percentage of patients presenting with carotid stenosis >60% declined by 29.9%, and the number presenting with >80% stenosis declined by 36.4%. There were significant reductions in plasma lipids and blood pressure during the same interval. Conclusions- Atherosclerosis severity seems to be declining over time. Better treatment of risk factors in the community may be responsible.

Utilization of Vasculoprotective Therapy for Peripheral Artery Disease: A Systematic Review and Meta-analysis.

INTRODUCTION: Practice guidelines recommend that patients with peripheral artery disease receive antiplatelets, statins, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). We sought to quantify the rates of prescribing these therapies in patients with peripheral artery disease in the literature. METHODS: We performed a systematic review and meta-analysis of treatment prescribing rates in observational studies containing peripheral artery disease patients published on or after the year 2000. We also assessed whether prescribing rates are increasing over time. RESULTS: A total of 86 studies were available for analysis. The aggregate sample size across all studies was 332,555. The pooled estimates for utilization of antiplatelets, statins, and ACE inhibitors or ARBs were 75% (95% confidence interval [CI], 71%-79%), 56% (95% CI, 52%-60%), and 53% (95% CI, 49%-58%), respectively. Statin use was directly related to publication year (+2.0% per year, P < .001), but this was not the case for antiplatelets (P = .68) or ACE inhibitors or ARBs (P = .066). CONCLUSIONS: Although some improvement in statin prescribing has occurred in recent years, major practice gaps exist in the treatment of peripheral artery disease. Effective measures to close these gaps should be implemented.

Effects of Eplerenone on Resistance to Antihypertensive Medication in Patients with Primary or Secondary Hyperaldosteronism.

BACKGROUND AND OBJECTIVES: Resistant hypertension is an important problem; nearly half of diagnosed hypertensives are not controlled to target blood pressure levels, and approximately 90% of strokes occur among patients with resistant hypertension. Primary aldosteronism accounts for approximately 20% of resistant hypertension, but the role of secondary hyperaldosteronism in resistant hypertension is seldom considered. We assessed the effects of eplerenone in patients with hypertension and either primary or secondary hyperaldosteronism. METHODS: Patients with a history of resistant hypertension and a supine plasma aldosterone level ≥ 360 pmol/L were randomized to eplerenone versus placebo in a fully blinded study for one year. A medication intensity score was developed to assess the resistance of hypertension to medication (blood pressure × medication intensity). We assessed the effects of eplerenone on blood pressure and on resistance to concomitant medication. RESULTS: Final results were available in 37 patients (19 on eplerenone and 18 on placebo). Resistance to medication, as assessed by the intensity of concomitant medication required to maintain blood pressure control, was markedly reduced by eplerenone: medication intensity scores declined by -0.50 ± 1.04 (SD) on placebo versus -2.11 ± 1.45 with eplerenone (P = 0.0001), the Systolic Resistance Score declined by -80.00 ± 122.93 on placebo versus -334.05 ± 21.73 on eplerenone (P = 0.0001), and the Diastolic Resistance Score increased by 1.28 ± 31.65 on placebo and declined by -40.74 ± 57.08 on eplerenone (P = 0.009). CONCLUSIONS: Eplerenone significantly reduced resistance to concomitant antihypertensive medication in both primary and secondary hyperaldosteronism.

Physiological Phenotyping for Personalized Therapy of Uncontrolled Hypertension in Africa.

OBJECTIVES: African and African American hypertensives tend to retain salt and water, with lower levels of plasma renin and more resistant hypertension. We tested the hypothesis that physiological phenotyping with plasma renin and aldosterone would improve blood pressure control in uncontrolled hypertensives in Africa. METHODS: Patients at hypertension clinics in Nigeria, Kenya, and South Africa with a systolic blood pressure >140 mm Hg or diastolic pressure > 90 mm Hg despite treatment were allocated to usual care (UC) vs. physiologically individualized care (PhysRx). Plasma renin activity and aldosterone were measured using ELISA kits. Patients were followed for 1 year; the primary outcome was the percentage of patients achieving blood pressure <140 mm Hg and diastolic <90 mm Hg. RESULTS: Results are presented for the 94/105 participants who completed the study (42 UC, 52 PhysRx). Control of both systolic and diastolic pressures was obtained in 11.1% of UC vs. 50.0% of PhysRx (P = 0.0001). Systolic control was achieved in 13.9% of UC vs. 60.3% of PhysRx (P = 0.0001); diastolic control in 36.1% of UC vs. 67.2% of PhysRx, vs. (P = 0.003). Number of visits and total number of medications were not significantly different between treatment groups, but there were differences across the sites. There were important differences in prescription of amiloride as specified in the PhysRx algorithm. CONCLUSIONS: Physiologically individualized therapy based on renin/aldosterone phenotyping significantly improved blood pressure control in a sample of African patients with uncontrolled hypertension. This approach should be tested in African American and other patients with resistant hypertension. Registered as ISRCTN69440037.

Population-based stroke and dementia incidence trends: Age and sex variations.

INTRODUCTION: We discovered a concomitant decline in stroke and dementia incidence rates at a whole population level in Ontario, Canada. This study explores these trends within demographic subgroups. METHODS: We analyzed administrative data sources using validated algorithms to calculate stroke and dementia incidence rates from 2002 to 2013. RESULTS: For more than 12 years, stroke incidence remained unchanged among those aged 20 to 49 years and decreased for those aged 50 to 64, 65 to 79, and 80+ years by 22.7%, 36.9%, and 37.9%, respectively. Dementia incidence increased by 17.3% and 23.5% in those aged 20 to 49 and 50 to 64 years, respectively, remained unchanged in those aged 65 to 79 years, and decreased by 15.4% in those aged 80+ years. DISCUSSION: The concomitant decline in stroke and dementia incidence rates may depict how successful stroke prevention has targeted shared risk factors of both conditions, especially at advanced ages where such risk factors are highly prevalent. We lend support for the development of an integrated system of stroke and dementia prevention.

High Frequency of Variants of Candidate Genes in Black Africans with Low Renin-Resistant Hypertension.

OBJECTIVES: Black subjects tend to retain salt and water, be more sensitive to aldosterone, and have suppression of plasma renin activity. Variants of the renal sodium channel (ENaC, SCNN1B) account for approximately 6% of resistant hypertension (RHT) in Blacks; other candidate genes may be important. METHODS: Six candidate genes associated with low renin-resistant hypertension were sequenced in Black Africans from clinics in Kenya and South Africa. CYP11B2 was sequenced if the aldosterone level was high (primary aldosteronism phenotype); SCNN1B, NEDD4L, GRK4, UMOD, and NPPA genes were sequenced if the aldosterone level was low (Liddle phenotype). RESULTS: There were 14 nonsynonymous variants (NSVs) of CYP11B2: 3 previously described and associated with alterations in aldosterone synthase production (R87G, V386A, and G435S). Out of 14, 9 variants were found in all 9 patients sequenced. There were 4 NSV of GRK4 (R65L, A116T, A142V, V486A): at least one was found in all 9 patients; 3 were previously described and associated with hypertension. There were 3 NSV of SCNN1B (R206Q, G442V, and R563Q); 2 previously described and 1 associated with hypertension. NPPA was found to have 1 NSV (V32M), not previously described and NEDD4L did not have any variants. UMOD had 3 NSV: D25G, L180V, and T585I. CONCLUSIONS: A phenotypic approach to investigating the genetic architecture of RHT uncovered a surprisingly high yield of variants in candidate genes. These preliminary findings suggest that this novel approach may assist in understanding the genetic architecture of RHT in Blacks and explain their two fold risk of stroke.

Second-Generation Antidepressants and Hyponatremia Risk: A Population-Based Cohort Study of Older Adults.

BACKGROUND: Hyponatremia may occur after initiation of a second-generation antidepressant drug. However, the magnitude of this risk among older adults in routine care is not well characterized. STUDY DESIGN: Retrospective, population-based, matched-cohort study. SETTING & PARTICIPANTS: In Ontario, Canada, 2003 to 2012, we compared older adults with a mood or anxiety disorder who were dispensed 1 of 9 second-generation antidepressant drugs with matched adults with comparable indicators of baseline health who were not dispensed an antidepressant drug (n=138,246 per group). A similar comparison was made in a subpopulation with available laboratory data (n=4,186 per group). PREDICTOR: Second-generation antidepressant prescription versus no antidepressant prescription. OUTCOMES: The primary outcome was hospitalization with hyponatremia. A secondary outcome was hospitalization with both hyponatremia and delirium. MEASUREMENTS: We assessed hospitalization with hyponatremia using a diagnosis code and, in the subpopulation, serum sodium values. We assessed hospitalization with hyponatremia and delirium using a combination of diagnosis codes. RESULTS: Second-generation antidepressant use versus nonuse was associated with higher 30-day risk for hospitalization with hyponatremia (450/138,246 [0.33%] vs 84/138,246 [0.06%]; relative risk [RR], 5.46 [95% CI, 4.32-6.91]). This association was consistent in the subpopulation with serum sodium values (73/4,186 [1.74%] vs 18/4,186 [0.43%]; RR, 4.23 [95% CI, 2.50-7.19]; absolute risk increase, 1.31% [95% CI, 0.87%-1.75%]). Second-generation antidepressant use versus nonuse was also associated with higher 30-day risk for hospitalization with both hyponatremia and delirium (28/138,246 [0.02%] vs 7/138,246 [0.005%]; RR, 4.00 [95% CI, 1.75-9.16]). LIMITATIONS: Measures of serum sodium could be ascertained in only a subpopulation. CONCLUSIONS: Use of a second-generation antidepressant in routine care by older adults is associated with an approximate 5-fold increase in 30-day risk for hospitalization with hyponatremia compared to nonuse. However, the absolute increase in 30-day incidence is low.