Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Rosuvastatin in patients with arterial hypertension and dyslipidemia: effects on microcirculation and pulse wave parameters

Aim. To investigate the parameters of pulse wave contour analysis (PWCA) and microcirculation (MC) in patients with arterial hypertension (AH), dyslipidemia (DLP), and high cardiovascular risk levels (SCORE >5%); to compare the dynamics of these parameters during the treatment with rosuvastatin or atorvastatin. Material and methods. The study included 82 patients (mean age 53±10 years) with the high-risk AH (SCORE levels >5%), DLP, and no strict contraindications to statins. All patients were randomised into two comparable groups: Group I (n=40; mean age 51±10 years), receiving atorvastatin and standard AH treatment; and Group II (n=42; mean age 52±10 years), receiving rosuvastatin and standard AH treatment. At baseline and after 5 weeks, all patients underwent the MC assessment (conjunctival biomicroscopy) and PWCA (AngioScan-01). The following parameters were assessed: stiffness index (SI), reflection index (RI), augmentation index (AIx), and increased pulse wave amplitude (PWA). Results. In the atorvastatin group, mean SI values were 5,87±2,05 m/s, RI values 35,64±19,98%, mean AIx values for heart rate of 75 beats per minute (AIx75) 41,21±14,56%, and mean central blood pressure (BP, Spa) levels 144,35±22,31 mm Hg. In the rosuvastatin group, the respective values were 5,01±2,56 m/s (SI), 37,01±14,56% (RI), 41,23±14,35% (AIx75), and 148,98±7,89 mm Hg (BP, Spa). All participants demonstrated PW Types A and B, as a marker of increased arterial stiffness, and positive AIx and AIx75 values. The treatment with atorvastatin and rosuvastatin was associated with a significant reduction in ∆SI (-0,87 and -0,89 m/s, respectively). Both groups demonstrated a non-significant reduction in ∆RI (-7,89 and -7,21%, respectively) and ∆AIx (-1,88 and -1,92%, respectively). PWA increased by 1,82±0,62 times in the atorvastatin group and by 1,95±0,81 times in the rosuvastatin group. At baseline, both groups demonstrated disturbed conjunctival MC (arterio-venular coefficient 1:3, stasis, and Stage III erythrocyte aggregation). Atorvastatin and rosuvastatin treatment was linked to a regression in the last two parameters, which could be explained by the improved vascular wall elasticity. Conclusion. In high-risk patients with AH, the PWCA data suggested an increase in arterial stiffness, which was combined with conjunctival MC disturbances. Statin therapy improved not only blood lipid levels, but also MC, vascular stiffness, and endothelial function parameters, which was more pronounced in the rosuvastatin group

Antiinflammatory therapy with canakinumab for atherosclerotic disease

BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. Copyright © 2017 Massachusetts Medical Society