Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-ß peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSEs score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

OBJECTIVES: In this study, the authors sought to assess the relationship between AFF and outcomes, the treatment response to sacubitril/valsartan and first-detected AFF in patients with HFpEF enrolled in the PARAGON-HF trial. BACKGROUND: Atrial fibrillation and flutter (AFF) are common in heart failure with preserved ejection fraction (HFpEF) and increase the risk of adverse outcomes. METHODS: A total of 4,776 patients formed 3 groups: those with AFF according to electrocardiography (ECG) at enrollment (n = 1,552; 33%), those with history of AFF but without AFF on ECG at enrollment (n = 1,005; 21%), and those without history of AFF or AFF on ECG at enrollment (n = 2,219, 46%). We assessed outcomes, treatment response to sacubitril/valsartan in each group, and the risk associated with first-detected AFF in patients without any known AFF. The primary outcome was a composite of total heart failure hospitalizations and cardiovascular death. RESULTS: History of AFF and AFF at enrollment were associated with higher risk of the primary outcome (risk ratio [RR]: 1.36 [95% CI: 1.12-1.65] and RR: 1.31 [1.11-1.54], respectively), than no AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan. Post randomization AFF occurred in 12% of patients without previous AFF and was associated with 2.8-fold higher risk of the primary outcome, but it was not influenced by sacubitril/valsartan. CONCLUSIONS: History of AFF and AFF on ECG at enrollment were associated with a higher risk of the primary outcome. First-detected AFF was not influenced by sacubitril/valsartan, yet it was associated with increased risk of all subsequent outcomes and may represent a potential target for future HFpEF trials. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Influence of study discontinuation during the run-in period on the estimated efficacy of sacubitril/valsartan in the PARAGON-HF trial.

AIMS: The 4822 patients randomized in the PARAGON-HF trial were a subset of 5746 initially eligible patients who entered sequential run-in periods. We identified patient factors associated with study discontinuation during the run-in period and estimated the implications of these discontinuations for the overall study result. METHODS AND RESULTS: We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run-in period. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion. A total of 924 (16.1%) subjects failed to complete the run-in period. In multivariable models, non-completion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower haemoglobin, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, higher New York Heart Association functional class, prior heart failure (HF) hospitalization, and lack of prior use of renin-angiotensin system inhibitors or beta-blocker. In repeat analysis of the effect of randomized treatment in PARAGON-HF giving greater weight to participants resembling those who failed to complete the run-in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio 0.86; 95% confidence interval 0.74-1.00). CONCLUSION: Patients with more advanced HF were at higher risk for non-completion of the run-in period in PARAGON-HF. Re-analysis of study outcomes accounting for the effect of run-in non-completion did not alter the estimated treatment effects of sacubitril/valsartan vs. valsartan.

Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF.

BACKGROUND: Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone. OBJECTIVES: This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death). METHODS: N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint. RESULTS: At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates. CONCLUSIONS: Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Independent Prognostic Value of Serum Soluble ST2 Measurements in Patients With Heart Failure and a Reduced Ejection Fraction in the PARADIGM-HF Trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure).

BACKGROUND: Soluble ST2 (sST2) is associated with cardiac remodeling and fibrosis. In chronic heart failure, the predictive value of sST2 has not been evaluated in a model that includes both NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity cardiac troponin T), in a trial in which treatment had a major impact. Therefore, the effects of treatment on sST2 levels in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the relationships between sST2 and outcomes, and the prognostic utility of various sST2 partition values were examined. METHODS AND RESULTS: Baseline (n=2002), 1-month (n=1936), and 8-month postrandomization (n=1758) sST2 levels were compared between treatment groups (sacubitril/valsartan versus enalapril). Relationships between baseline sST2 and (1) heart failure hospitalization, (2) cardiovascular death, and (3) combined heart failure hospitalization and cardiovascular death were assessed using restricted cubic spline models. Adjusted Cox proportional hazards models were used to examine the impact of sST2 change from baseline to 1 month on the hazard of experiencing each outcome. Sacubitril/valsartan led to more reductions and fewer increases in sST2 levels versus enalapril. After adjusting for other predictors, including NT-proBNP and hs-TnT, baseline sST2 remained an independent predictor of outcomes. Associations between baseline sST2 and outcomes were linear. sST2 increases at 1 month were associated with worse subsequent outcomes and decreased with better outcomes (P=0.001, 0.012, and 0.009 for the 3 outcomes, respectively). CONCLUSIONS: Sacubitril/valsartan resulted in greater reductions and less increases in sST2 levels than enalapril. No specific threshold was associated with risk, as linear relationships between baseline sST2 and outcomes were observed. Changes in sST2 from baseline to 1 month were independently associated with the risk of outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01035255.

A comparative analysis of chiropractic and general practitioner patients in North America: findings from the joint Canada/United States Survey of Health, 2002-03.

BACKGROUND: Scientifically rigorous general population-based studies comparing chiropractic with primary-care medical patients within and between countries have not been published. The objective of this study is to compare care seekers of doctors of chiropractic (DCs) and general practitioners (GPs) in the United States and Canada on a comprehensive set of sociodemographic, quality of life, and health-related variables. METHODS: Data are from the Joint Canada/U.S. Survey of Health (JCUSH), 2002-03, a random sample of adults in Canada (N = 3505) and the U.S. (N = 5183). Respondents were categorized according to their pattern of health-care use in the past year. Distributions, percentages, and estimates (adjusted odds ratios) weighted to reflect the complex survey design were produced. RESULTS: Nearly 80% of respondents sought care from GPs; 12% sought DC care. Compared with GP only patients, DC patients in both countries tend to be under 65 and white, with arthritis and disabling back or neck pain. U.S. DC patients are more likely than GP only patients to be obese and to lack a regular doctor; Canadian DC patients are more likely than GP only patients to be college educated, to have higher incomes, and dissatisfied with MD care. Compared with seekers of both GP and DC care, DC only patients in both countries have fewer chronic conditions, take fewer drugs, and have no regular doctor. U.S. DC only patients are more likely than GP+DC patients to be uninsured and dissatisfied with health care; Canadian DC only patients are more likely than GP+DC patients to be under 45, male, less educated, smokers, and not obese, without disabling back or neck pain, on fewer drugs, and lacking a regular doctor. CONCLUSION: Chiropractic and GP patients are dissimilar in both Canada and the U.S., with key differences between countries and between DC patients who do and do not seek care from GPs. Such variation has broad and potentially far-reaching health policy and research implications.

The impact of psychosocial factors on neck pain and disability outcomes among primary care patients: results from the UCLA Neck Pain Study.

PURPOSE: The purpose of this study is to estimate the associations of psychosocial factors with pain and disability outcomes among neck-pain patients enrolled in a randomized clinical trial of chiropractic treatments. METHODS: Neck-pain patients were randomized to one of 8 modes of chiropractic treatment. Health status and psychosocial variables were measured at baseline. Changes in neck pain severity and disability from baseline to 6 months were the primary outcome variables. Multivariable regression models were used to estimate effects of psychosocial variables adjusted for potential confounders. RESULTS: Of 960 eligible patients, 336 were enrolled and 80% were followed up through 6 months. Coping strategies involving self-assurance resulted in better disability outcomes, whereas getting angry or frustrated resulted in worse pain and disability outcomes. Participants with high levels of social support from individuals were more likely to experience clinically meaningful reductions in pain and disability. No consistent relations of internal health locus of control, and physical and psychological job demands with improvements in pain and disability were detected. CONCLUSIONS: We found some evidence that certain coping strategies and types of social support are associated with pain and disability outcomes in this population of largely subacute and chronic neck-pain patients.

A randomized trial of chiropractic and medical care for patients with low back pain: eighteen-month follow-up outcomes from the UCLA low back pain study.

STUDY DESIGN: Randomized clinical trial. OBJECTIVES: To compare the long-term effectiveness of medical and chiropractic care for low back pain in managed care and to assess the effectiveness of physical therapy and modalities among patients receiving medical or chiropractic care. SUMMARY OF BACKGROUND DATA: Evidence comparing the long-term relative effectiveness of common treatment strategies offered to low back pain patients in managed care is lacking. METHODS: A total of 681 low back pain patients presenting to a managed-care facility were randomized to chiropractic with or without physical modalities, or medical care with or without physical therapy, and followed for 18 months. The primary outcome variables are low back pain intensity, disability, and complete remission. The secondary outcome is participants' perception of improvement in low back symptoms. RESULTS: Of the 681 patients, 610 (89.6%) were followed through 18 months. Among participants not assigned to receive physical therapy or modalities, the estimated improvements in pain and disability and 18-month risk of complete remission were a little greater in the chiropractic group than in the medical group (adjusted RR of remission = 1.29; 95% CI = 0.80-2.07). Among participants assigned to medical care, mean changes in pain and disability and risk of remission were larger in patients assigned to receive physical therapy (adjusted RR = 1.69; 95% CI = 1.08-2.66). Among those assigned to chiropractic care, however, assignment to methods was not associated with improvement or remission (adjusted RR = 0.98; 95% CI = 0.62-1.55). Compared with medical care only patients, chiropractic and physical therapy patients were much more likely to perceive improvement in their low back symptoms. However, less than 20% of all patients were pain-free at 18 months. CONCLUSIONS: Differences in outcomes between medical and chiropractic care without physical therapy or modalities are not clinically meaningful, although chiropractic may result in a greater likelihood of perceived improvement, perhaps reflecting satisfaction or lack of blinding. Physical therapy may be more effective than medical care alone for some patients, while physical modalities appear to have no benefit in chiropractic care.

Frequency and clinical predictors of adverse reactions to chiropractic care in the UCLA neck pain study.

STUDY DESIGN: Randomized clinical trial. OBJECTIVES: To document the types and frequencies of adverse reactions associated with the most common chiropractic treatments for neck pain, and to identify possible clinical predictors of adverse reactions to chiropractic treatment. SUMMARY OF BACKGROUND DATA: Chiropractic care is frequently sought by patients for relief from neck pain; however, adverse reactions related to its primary modes of treatment have not been well examined. METHODS: A total of 336 patients with neck pain presenting to 4 southern California health care clinics were randomized in a balanced 2 x 2 x 2 factorial design to manipulation with or without heat, and with or without electrical muscle stimulation (EMS); and mobilization with or without heat and with or without EMS. Discomfort or unpleasant reactions from chiropractic care were self-assessed at 2 weeks after the randomization/baseline visit. RESULTS: Of the 280 participants (83%) who responded, 85 (30.4%) had 212 adverse symptoms as a result of chiropractic care. Increased neck pain or stiffness was the most common symptom, reported by 25% of the participants. Less common were headache and radiating pain. Patients randomized to manipulation were more likely than those randomized to mobilization to have an adverse symptom occurring within 24 hours of treatment (adjusted odds ratio [OR] = 1.44, 95% confidence interval [CI] = 0.83, 2.49). Heat and EMS were only weakly associated with adverse symptoms (heat: OR = 0.94, 95% CI = 0.54, 1.62; EMS: OR = 1.09, 95% CI = 0.63, 1.89). Moderate-to-severe neck disability at baseline was strongly associated with adverse neurologic symptoms (OR = 5.70, 95% CI = 1.49, 21.80). CONCLUSIONS: Our results suggest that adverse reactions to chiropractic care for neck pain are common and that despite somewhat imprecise estimation, adverse reactions appear more likely to follow cervical spine manipulation than mobilization. Given the possible higher risk of adverse reactions and lack of demonstrated effectiveness of manipulation over mobilization, chiropractors should consider a conservative approach for applying manipulation to their patients, especially those with severe neck pain.

Adverse reactions to chiropractic treatment and their effects on satisfaction and clinical outcomes among patients enrolled in the UCLA Neck Pain Study.

BACKGROUND: Minor side effects associated with chiropractic are common. However, little is known about their predictors or the effects of reactions on satisfaction and clinical outcomes. OBJECTIVE: The objectives of this study are to compare the relative effects of cervical spine manipulation and mobilization on adverse reactions and to estimate the effects of adverse reactions on satisfaction and clinical outcomes among patients with neck pain. METHODS: Neck pain patients were randomized to receive cervical spine manipulation or mobilization. At 2 weeks, subjects were queried about possible treatment-related adverse reactions and followed for 6 months with assessments for pain and disability at 2, 6, 13, and 26 weeks. Numerical rating scales and the Neck Disability Index were used to measure pain and disability. Perceived improvement and satisfaction with care were assessed at 4 weeks. RESULTS: Of 960 eligible patients, 336 enrolled and 280 responded to the adverse event questionnaire. Thirty percent of respondents reported at least 1 adverse symptom, most commonly increased pain and headache. Patients randomized to manipulation were more likely than those randomized to mobilization to report an adverse reaction (adjusted odds ratio = 1.44, 95% confidence interval = 0.85, 2.43). Subjects reporting adverse reactions were less satisfied with care and less likely to have clinically meaningful improvements in pain and disability. CONCLUSIONS: Adverse reactions are more likely to be reported following cervical spine manipulation than mobilization. Chiropractors may reduce iatrogenesis and increase satisfaction and perhaps clinical outcomes by mobilizing rather than manipulating their neck pain patients.