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Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis From the FOURIER Randomized Clinical Trial.
Deedwania, P, Murphy, SA, Scheen, A, Badariene, J, Pineda, AL, Honarpour, N, Keech, AC, Sever, PS, Pedersen, TR, Sabatine, MS, et al
JAMA cardiology. 2021;(2):139-147
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Abstract
IMPORTANCE The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk. OBJECTIVE To investigate outcomes with evolocumab in patients with and without MetS. DESIGN, SETTING, AND PARTICIPANTS The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020. INTERVENTIONS Patients were randomized to evolocumab or placebo. MAIN OUTCOMES AND MEASURES The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke. RESULTS Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P < .001 for the primary and 1.38 [1.20-1.57]; P < .001 for the key secondary end point). Evolocumab reduced low-density lipoprotein cholesterol similarly in patients with MetS (median [interquartile range], 92 [79-109] mg/dL vs 30 [19-48] mg/dL; P < .001) and without MetS (median [interquartile range], 92 [81-108] mg/dL vs 29 [18-44] mg/dl; P < .001). For the primary end point, the hazard ratios (95% CI) with evolocumab vs placebo were 0.83 (0.76-0.91) and 0.89 (0.79-1.01) in patients with and without MetS (P for interaction = .39). For the key secondary end point, the corresponding hazard ratios (95% CIs) were 0.76 (0.68-0.86) and 0.86 (0.74-1.01) (P for interaction = .23), respectively. Evolocumab did not increase the risk of new-onset diabetes or other major safety outcomes including worsening glycemic control, compared with placebo in patients with MetS. CONCLUSIONS AND RELEVANCE Patients with atherosclerotic cardiovascular disease and MetS have substantial residual risk of cardiovascular events despite statin therapy. Evolocumab significantly reduced low-density lipoprotein cholesterol and cardiovascular risk in patients with MetS without increasing new-onset diabetes, worsening glycemic control, or other major safety events. These data suggest the addition of evolocumab to statin therapy in patients with atherosclerotic cardiovascular disease and MetS is safe and efficacious to reduce residual cardiovascular risk. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01764633.
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N-acetylcysteine administration prevents nonthyroidal illness syndrome in patients with acute myocardial infarction: a randomized clinical trial.
Vidart, J, Wajner, SM, Leite, RS, Manica, A, Schaan, BD, Larsen, PR, Maia, AL
The Journal of clinical endocrinology and metabolism. 2014;(12):4537-45
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Abstract
CONTEXT The acute phase of the nonthyroidal illness syndrome (NTIS) is characterized by low T3 and high rT3 levels, affecting up to 75% of critically ill patients. Oxidative stress has been implicated as a causative factor of the disturbed peripheral thyroid hormone metabolism. OBJECTIVE The objective of the study was to investigate whether N-acetylcysteine (NAC), a potent intracellular antioxidant, can prevent NTIS in patients with acute myocardial infarction. DESIGN This was a randomized, multicenter clinical trial. SETTINGS Consecutive patients admitted to the emergency and intensive care units of two tertiary hospitals in southern Brazil were recruited. Patients and intervention included 67 patients were randomized to receive NAC or placebo during 48 hours. Baseline characteristics and blood samples for thyroid hormones and oxidative parameters were collected. MAIN OUTCOME Variation of serum T3 and rT3 levels was measured. RESULTS Baseline characteristics were similar between groups (all P > .05). T3 levels decreased in the placebo group at 12 hours of follow-up (P = .002) but not in NAC-treated patients (P = .10). Baseline rT3 levels were elevated in both groups and decreased over the initial 48 hours in the NAC-treated patients (P = .003) but not in the control group (P = .75). The free T4 and TSH levels were virtually identical between the groups throughout the study period (P > .05). Measurement of total antioxidant status and total carbonyl content demonstrated that oxidative balance was deranged in acute myocardial infarction patients, whereas NAC corrected these alterations (P < .001). CONCLUSIONS NAC administration prevents the derangement in thyroid hormone concentrations commonly occurring in the acute phase of acute myocardial infarction, indicating that oxidative stress is involved in the NTIS pathophysiology.
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ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses.
Wright, JT, Probstfield, JL, Cushman, WC, Pressel, SL, Cutler, JA, Davis, BR, Einhorn, PT, Rahman, M, Whelton, PK, Ford, CE, et al
Archives of internal medicine. 2009;(9):832-42
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Abstract
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is reevaluated considering information from new clinical trials, meta-analyses, and recent subgroup and explanatory analyses from ALLHAT, especially those regarding heart failure (HF) and the association of drug treatment with new-onset diabetes mellitus (DM) and its cardiovascular disease (CVD) consequences. Chlorthalidone was superior to (1) doxazosin mesylate in preventing combined CVD (CCVD) (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.13-1.27), especially HF (RR, 1.80; 95% CI, 1.40-2.22) and stroke (RR, 1.26; 95% CI, 1.10-1.46); (2) lisinopril in preventing CCVD (RR, 1.10; 95% CI, 1.05-1.16), including stroke (in black persons only) and HF (RR, 1.20; 95% CI, 1.09-1.34); and (3) amlodipine besylate in preventing HF, overall (by 28%) and in hospitalized or fatal cases (by 26%). Central independent blinded reassessment of HF hospitalizations confirmed each comparison. Results were consistent by age, sex, race (except for stroke and CCVD), DM status, metabolic syndrome status, and renal function level. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing end-stage renal disease overall, by DM status, or by renal function level. In the chlorthalidone arm, new-onset DM was not significantly associated with CCVD (RR, 0.96; 95% CI, 0.88-2.42). Evidence from subsequent analyses of ALLHAT and other clinical outcome trials confirm that neither alpha-blockers, angiotensin-converting enzyme inhibitors, nor calcium channel blockers surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing HF, and new-onset DM associated with thiazides does not increase CVD outcomes.