Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Influence of surface and structural properties on the initial release of risperidone from polymeric drug carriers

In this work, implantable drug formulation with risperidone on the basis of poly(L-lactide-co-glycolide) (L-PLGA) and poly(D,L-lactide-co-glycolide) (D,L-PLGA) as drug carries was developed. The influence of surface and structural properties on the initial release of risperidone during the first twenty four hours was determined. In this aim, high-performance liquid chromatography, nuclear magnetic resonance spectroscopy, scanning electron microscope and atomic force microscope were used. Significant differences between L-PLGA and D,L-PLGA matrices in all analyzed data were noted. The burst effect was not revealed for any of the studied polymers, however the released drug was almost five times larger for D,L-PLGA matrices. The L-PLGA copolymer revealed a significantly longer average length of the lactidyl and glycolidyl blocks than D,L-PLGA. Moreover, various characters of surface for analyzed matrices were shown, i.e. in case of L-PLGA the surface was porous and in case of D,L-PLGA it was nonporous. Undoubtedly, there were dependences between risperidone's initial release and the topography and the structure of polymeric matrices. We suppose that the larger drug release for L-PLGA was more associated with surface properties and thus structure of matrices. The obtained results showed the great potential of both polymers and possibility to choose the optimal polymer

Role of surface and structure in the initial release of risperidone from L-PLGA and D,L-PLGA matrices

W niniejszej pracy była opracowywana implantacyjna postać leku zawierająca rysperydon wytworzona z poli(L-laktydo-ko-glikolidu) (L-PLGA) oraz poli(D,L- laktydo-ko-glikolidu) (D,L-PLGA) zastosowanych jako nośniki leku. Ustalano wpływ właściwości powierzchniowych i strukturalnych na początkowe uwalnianie rysperydonu podczas pierwszych 24 godzin inkubacji. W tym celu zastosowano wysokosprawną chromatografię cieczową, spektroskopię magnetycznego rezonansu jądrowego, skaningową kalorymetrię różnicową, skaningowy mikroskop elektronowy oraz mikroskop sił atomowych. We wszystkich analizowanych danych zaobserwowano różnice pomiędzy matrycami wykonanymi z L-PLGA, a matrycami sporządzonymi z D,L-PLGA. Nie wykazano efektu wyrzutu dla żadnego z badanych polimerów, jakkolwiek ilość uwolnionego leku w przypadku matryc D,L-PLGA była prawie pięciokrotnie wyższa. Kopolimer L-PLGA charakteryzował się znacząco większą średnią długością blokówlaktydylowych iglikolidylowych niż D,L-PLGA. Co więcej, zaobserwowano inny charakter powierzchni analizowanych matryc, to znaczy w przypadku L-PLGA powierzchnia była porowata, podczas gdy w przypadku D,L-laktydu nie obserwowano perforacji. Niewątpliwie istnieje zależność między początkowym uwalnianiem rysperydonu, a topografią i strukturą matryc polimerowych. Przypuszcza się, że większe uwalnianie leku z L-PLGA było bardziej związane z właściwościami powierzchniowymi niż ze strukturą matryc. Otrzymane wyniki wskazują na ogromny potencjał obu tych polimerów i możliwość wybrania optymalnego materiału.In this work, implantable drug formulation with risperidone on the basis of poly(L-lactide-co-glyco- lide) (L-PLGA) and poly(D,L-lactide-co-glycolide) (D,L-PLGA) as drug carries has been developed. The influence of surface and structural properties on the initial release of risperidone during the first 24 hours has been determined. In this aim, high-performance liquid chromatography, nuclear magnetic resonance spectroscopy, differential scanning calorimetry, scanning electron microscope and atomic force mic¬roscope were used. The differences between L-PLGA and D,L-PLGA matrices in all analyzed data were noted. The burst effect was not revealed for any of the studied polymers, however the released drug was almost five times larger for D,L-PLGA matrices. The L-PLGA copolymer revealed a significantly longer average length of the lactidyl and glycolidyl blocks than D,L-PLGA. Moreover, various characters of surface for analyzed matrices were shown, i.e. in the case of L-PLGA the surface was porous and in the case of D,L-PLGA it was nonporous. Undoubtedly, there were dependences between risperidone's initial release and the topography and the structure of polymeric matrices. We suppose that the larger drug release for L-PLGA was more associated with surface properties than with structure of matrices. The obtained results show the great potential of both polymers and possibility to choose the optimal material

Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol

Background: Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives: In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods: ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions: In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402