Understanding the CDL requirements for getting a CDL (commercial driver's license) is essential if you want to become a truck driver. These also apply to the CLP or commercial learner's permit, which you'll have to get in order to train and before you get a CDL. The Federal CDL requirements (see below) apply to all U.S. states. Then, check out the CDL requirements in your state. Each state has its own minimum standards for the licensing of commercial drivers, and they differ from state to state.
Have a valid regular (non-commercial) driver's license and be at least 18 years old (in most states).
To drive a commercial motor vehicle across state lines (interstate).
To drive a commercial motor vehicle that contains hazardous materials.
An applicant "must provide to the State proof of citizenship or lawful permanent residency" per 49 CFR 383.71.
Social security card, or proof of the number.
Another document such as a birth certificate or green card.
Pass all applicable background screens.
The applicant "must provide the names of all States where the applicant has been licensed to drive any type of motor vehicle during the previous 10 years" – FMCSA.
Must surrender your regular state driver license once you earn a CDL.
Must certify that he/she is not "subject to any disqualification under FMCSA 383.51 (complete list of disqualifications), or any license disqualification under State law, and that he/she does not have a driver's license from more than one state or jurisdiction".
Be able to speak and read English to drive a CMV in the United States. In addition, the state written exams will only be given in English. The FMCSA has more about this here.
There have been several changes over the years in the "compliance requirements" area by the FMCSA (Federal Motor Carrier Safety Administration). Like their name implies, the FMCSA exists to keep U.S. roads safer, mainly by preventing commercial truck related accidents.
Since the Commercial Motor Vehicle Safety Act of 1986, drivers cannot hold a CDL in more than one state. This ended the practice of drivers getting multiple driver's licenses and hiding bad records they may have had in a different state.
New Hazardous Materials Endorsement Requirements. Check out our step-by-step guide on How to Get Your Hazmat Endorsement.
In late 2013, states had to start enforcing the texting prohibition rule.
Then, starting in 2014, commercial drivers had to ""self-certify" medical information and were only allowed to use "authorized" medical examiners who are on the National Medical Registry.
More information about these changes can be found from the FMCSA.
The physical demands of the trucker's job depends on which type of driving he's doing. But no matter which type, a driver must be physically physically capable of operating a commercial motor vehicle and to perform the varied types of non-driving trucking duties. This includes handling long periods of driving, irregular sleep schedules, potential family and/or social challenges, and job related stress. In addition, some jobs require heavy lifting in the loading/unloading process, twisting and bending, getting in and out of the truck many times a day, occasional (depending where you work) installing of tire chains, and many other possible physical activities.
You must have a valid Medical Examiner's Certificate (DOT card), or a photographic copy of your valid Certificate, to receive a CDL or CLP. This is a federally mandated (U.S. Department of Transportation) document that certifies you meet all physical and medical standards for operating a commercial motor vehicle and the original or photographic copy must be in your possession whenever you are driving.
Starting in 2014, commercial drivers have to "self-certify" medical information and are only allowed to use "authorized" medical examiners who are on the National Medical Registry. To find a medical examiner who is certified by the FMCSA to perform DOT physical exams click here.
Non-Excepted Interstate: This just means that you must meet the Federal DOT medical card requirements and operate across state lines.
Excepted Interstate: You do NOT have to meet the Federal DOT medical card requirements and operate across state lines.
Non-Excepted Intrastate: You must meet the Federal DOT medical card requirements and operate only in your home state.
Excepted Intrastate: You do NOT have to meet the Federal DOT medical card requirements and operate only in your home state.
The Medical Examination Report For Commercial Driver Fitness Determination is a FMCSA form used by medical examiners. This form will give you a good idea of the medical qualifications for drivers, as will the complete list (from FMCSA 391.41) further down on that page.
Standard: At least 20/40 acuity (Snellen) in each eye with or without correction. At least 70 degrees peripheral in horizontal meridian measured in each eye. Eye glasses or contact lenses are acceptable, but the use of corrective lenses should be noted on the Medical Examiner's Certificate.
You cannot be a diabetic who requires insulin via needle injection. However, note that certain drivers may be exempt.
Elevated Blood Sugar levels: 200 or above is considered "dangerous". However, there appears to be no evidence to support that 200 or more (blood sugar level) is a disqualification, despite this being reported by many other websites. For a discussion of this apparent inaccuracy, see here.
Other conditions like sleep apnoea may also be a disqualification.
To get a CDL, you must pass knowledge and skills tests. The CDL manual will help you pass the state exams. This manual is not a substitute for a truck driver training class or program. Formal training is the most reliable way to learn the many special skills required for safely driving a large commercial vehicle and becoming a professional driver in the trucking industry.
The person must have taken and passed a general knowledge test – get some more info on which tests to take here or just go to the CDL Practice Test Center and take some tests.
For the road and skills test you must use the same class of commercial vehicle you need to get licensed for.
Pre-Trip Vehicle Inspection – You need to know your vehicle is safe to drive. Sections 11, 12, and 13 of the CDL Manual covers how you need to explain what you are inspecting and for what reason.
Basic Vehicle Control – You will be tested on your control of your vehicle. This includes moving vehicle forward, backward, and within a defined area.
Did you recently drive a CMV (or the military equivalent of commercial motor vehicle) in the military? You may be able to waive the skills test portion of the commercial driver license skills test. Military drivers must apply within one year of separation from active duty.
The Commercial Driver License (CDL) skills test waiver form may be used by service members who are currently licensed and who are or were employed within the last 90 days in a military position requiring the operation of a military motor vehicle equivalent to a Commercial Motor Vehicle (CMV). This waiver allows a qualified service member to apply for a CDL without skills testing. CDL knowledge (written) test(s) cannot be waived. The transfer of School Bus(S) and/or Passenger (P) endorsements under this Waiver Program are prohibited.
Check out the article "Troops to Trucks program helps military drivers transition into civilian world" for more information.
Here's an Application for the Military Skills Test Waiver.
More information about the Military Waiver can be found from the FMCSA.


text:
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redpajama_set_name: RedPajamaCommonCrawl


Liberna is a conflation of Liber (book) and Bernard – was housed in the library of his private home in Hilversum.
is housed in a large study room – the Liberna Studienraum – together with the reference library. This room also serves as an exhibition space for objects from the collection. A new series of catalogues has been launched ("The Liberna at the Draiflessen Collection"). The first exhibition in the study room, Marken und Monogramme, dealt with printers' marks and artists' monograms of the late fifteenth and early sixteenth century (see exh. cat. Mettingen 2013 in the list of catalogues at the end of this article). The current exhibition on Saint Anne, Die Heilige Anna – Bildform und Verehrung, showing medieval manuscripts, woodcuts and engravings, runs until 15 March 2015.
Albrecht Dürer and Rembrandt van Rijn. Dürer was also represented by first editions of his art-theoretical works and by many of his illustrations to other books. The prints offer a good opportunity to study his graphic art in depth.
Rembrandt made very few book illustrations. One of these, an etching titled The Ship of Fortune, served as an illustration to Elias Herckmans's Der Zee-vaert Lof (1634). A copy of this book is in the collection. Bernard Brenninkmeijer also succeeded in acquiring an early drawing by Rembrandt (see Mettingen 2012, no. 104). Another drawing – assigned in Werner Sumowski's Drawings of the Rembrandt School, vol. VI, no. 1528, to Salomon Koninck – has recently been attributed to Rembrandt by Bernhard Schnackenburg (see exh. cat. Mettingen 2012, no. 105).
art historian Edmund Schilling (1888–1974), was engaged as an adviser. Schilling, a drawings specialist, had been curator of prints and drawings at the Städelsches Kunstinstitut in Frankfurt am Main, and had advised collectors, dealers and museum staff about their purchases. Schilling's role is not very well documented, because he did not conduct any purchases himself, but we may assume that he acted as an adviser to Eisemann on this score. The main acquisitions for the Liberna Collection were Dutch and German Old Master drawings, but occasionally there were also successful bids on "foreign" masterpieces, such as a landscape drawing by Fra Bartolommeo from an album with drawings by this master, sold at Christie's, London, on 20 November 1957.
In the war years, purchases were confined to the London art market, particularly the auction houses of Christie's and Sotheby's and the art dealer Colnaghi. The first acquisitions, in 1941, offer a varied picture: in addition to printed books and graphic works by Dürer and Rembrandt, sixteen drawings by Dutch and Flemish artists from a dismantled scrapbook were acquired, including five sketches by Jan van Goyen, a design for a title page by Hendrik Hondius, a watercolor of a house front by Isaac van Ostade and a self-portrait drawn on vellum by Cornelis Visscher. The works acquired in the war years include a design by Crispijn de Passe the Elder for one of the prints in the series Speculum Passionis Christi and a watercolor by Jacob Jordaens, probably a tapestry design. Both drawings relate to books in the library.
The De Passe drawing may be compared with the books published and illustrated by this master, while the subject of the Jordaens drawing, Amor docet Musicam, fits in perfectly with the contemporary emblem books and songbooks in the collection.
In 1950 the Liberna Collection moved from London to Hilversum. Bernard Brenninkmeijer continued collecting, not only on the London art market but also in Amsterdam, New York, Zürich and other places. The library was significantly enriched by the acquisition of a hand-colored copy of the twelve-volume Blaeu Atlas (1667) and major purchases from renowned book collectors, such as C.W. Dyson Perrins, Sir Thomas Barlow, Paul May and the Dukes of Arenberg.
By the early 1970s the collection of drawings numbered almost two hundred sheets (including ca. 165 works by Dutch and Flemish masters) and the time had come to document Mr. Brenninkmeijer's holdings. The collection required permanent supervision, and the need was felt for a collection catalogue. In April 1975 I was appointed curator of the Liberna Collection, a post which I held until my retirement in 2013.
Although the library was the most important part of the collection (it was considered one of the finest private collections of early printed books in the Netherlands), as an art historian I was extremely interested in the prints and drawings. Many of the drawings were unpublished. Fortunately I was able to build up a discreet network of curators from Dutch and foreign print rooms. Thanks to these contacts the collection was studied by various specialists, who came to Hilversum to share their knowledge with us. As a result, quite a few of our drawings have appeared in various publications, though without mention of their provenance. Two drawings by Allaert van Everdingen, for example, are included in Alison Davies's 2007 monograph on the artist (cat. nos. 96 and 230), and three red-chalk drawings by Moses ter Borch appear in Alison McNeill-Kettering's book on the Ter Borch Studio Estate, published in 1988 (vol. II App. 1, cat. nos. 63, 64, 65). In the journal Delineavit et Sculpsit, I discussed individual drawings: Van Goyen, in no. 5, May 1991; Pieter Jansz, in no. 7, June 1992; Leendert Overbeek, in no. 19, November 1998).
A chimney-piece design by Jacob de Wit is the subject of my contribution to Kunst op papier in de achttiende eeuw: Liber Amicorum Charles Dumas (October 2014).
the outstanding sketch by Anthony van Dyck for the San Rosaria altarpiece in Palermo, which Christopher Brown has called "undoubtedly the most important surviving drawing from Van Dyck's Italian years" (exh. cat. New York/Fort Worth 1991, p. 167). Right now two tapestry designs by Pieter Coecke van Aelst, both from a series of the Life of Paul, are on loan to the Coecke exhibition at the Metropolitan Museum in New York (exh. cat. nos. 26 and 41). Needless to say, it is an honor for the Liberna Collection to contribute to important exhibitions and to be included in scholarly catalogues.
counterpart of a Van Huijsum drawing in the Hermitage – with the same dimensions and provenance – is still in existence (see exh. cat. Mettingen 2012, no. 120).
As stated earlier, the significance of the Liberna Collection lies not only in the individual quality of the works of art, but also in the integration of the different parts – the illustrated books and manuscripts together with the prints and drawings – which allows one to study the objects in a wider context. An album of ten designs by Adriaen van de Venne for illustrations to several books by Jacob Cats is the perfect exhibition partner of the many Cats editions in the collection. Another Dutch poet whose works are present in the collection, the more serious Joost van den Vondel, is portrayed in a delicate chalk portrait by Jan Lievens.
The integration of the various fields is apparent from the subject of the first major exhibition of the Liberna Collection at Draiflessen, organized on the occasion of its transferal to Mettingen in 2012. The exhibition, titled Von der Schönheit der Präzision. Faszination Buchkunst und Grafik mit der Liberna Collection, contained nearly eighty highlights, including illuminated manuscripts, printed books, and prints and drawings (see below), as well as some loans from other museums.
Thera Folmer-von Oven has been an associate member of CODART since 2004. From 1975 to 2013 she was the curator of the Liberna Collection in Hilversum. She has been a member of the editorial board of Delineavit et Sculpsit. Journal for Dutch and Flemish Prints and Drawings since its foundation in 1989.
The books were published in the seven-volume Catalogue of Books of the Liberna Foundation (arranged by subject), between 1977 and 1984. A separate catalogue of the manuscripts and miniatures appeared in 1982. The drawings were published in J. Bolten and A.T. Folmer-von Oven, Liberna Foundation Catalogue of Drawings, Hilversum 1989. All catalogues are privately published and not for sale.
Von der Schönheit der Präzision / On the Beauty of Precision / Over de schoonheid van precisie. Mettingen (Draiflessen Collection) 2012. With an introduction on the history of the Liberna Collection and an essay on the drawings by Thera Folmer-von Oven.
Marken und Monogramme / Merken en Monogrammen / Marks and Monograms, Die Liberna in der Draiflessen Collection 1/2013. Edited by Dagmar Täube, with contributions by Iris Mentrup and Thera Folmer-von Oven, Mettingen 2013.
Die Heilige Anna – Bildform und Verehrung / De Heilige Anna – Beeldvorm en Verering / Saint Anne – Image and Worship, Die Liberna in der Draiflessen Collection 1/2014, contributions by Anne Margreet As-Vijvers, Iris Ellers, Thera Folmer-von Oven, Olesja Nein, Dagmar Täube, Hiltrud Westermann-Angerhausen, Mettingen (Draiflessen Collection) 2014.


text:
Q: ASP.NET FormsAuthentication.SetAuthCookie not working in custom login system I have created my custom login system, but FormsAuthentication.SetAuthCookie(user.memb___id, false); not working.
Method is:
[HttpPost]
    [ActionName("Login")]
    [ValidateAntiForgeryToken]
    public ActionResult Login(Models.UserModel user)
    {
        if (ModelState.IsValid)
        {
            if (IsValid(user.memb___id, user.memb__pwd))
            {
                FormsAuthentication.SetAuthCookie(user.memb___id, false);
                return RedirectToAction("Index", "Home");
            }
            else
            {
                ModelState.AddModelError("", "Login data is incorrect.");
            }
        }
        return View(user);
    }

And when i checking with @if (Request.IsAuthenticated) it returns false.
I have check user.memb___id is not null and in tutorial where i have seen it's working.
Have some ideas why?
P.S. I'm using Framework 4.5.1

redpajama_set_name: RedPajamaStackExchange


While it's nearly impossible to foresee and plan for every future event, there are attributes that can help a person or system to better adapt to any change, and find fulfillment in the vast range of circumstance that the world tends to offer. Because the impact of change on our lives often depends on the gap between our expectations and our reality, one could go so far as to say that lack of resilience is one of the key causes of suffering, whether starvation and disease in the wake of overtaxing the environment, or economic depression in the wake of over-sold debt.
If a system momentarily weakens or breaks down, if the individuals within it are hardy, they can rebuild. A community of weak individuals, unable to provide for themselves or others, unskilled, unhealthy and unhappy, will always struggle, even with some of the other elements in place—but should the system that supports them falter, even for a moment, it cannot be rebuilt, because the people that are a part of it cannot live even a short while without it. A resilient community depends on the resilience of its members. More actively, a resilient community will foster it. Education, health, mobility—by giving these things to our neighbors, we ensure a stronger neighborhood for ourselves.
Looking across these dynamics, it's hard to ignore the sharp contrast between the contributors to social resilience and the values often prized in our modern system. Efficiency, optimization, specialization are often the buzzwords of the day. This is not idle theorization—these values are rapidly replacing more resilient forms of social life across the world, from villages in rural Africa and China to the close-knit towns of Europe and the US. None of these are easy questions—it may well be that the capabilities gained from technological innovation or the build-up of physical capital gives us a greater ability to respond to crises than they undermine via the system necessary to create them. In other words, a program of radical economic simplification started in the 50s likely never would have seen the birth of the internet, which may ultimately offset the damage inherent in its creation. Nevertheless, if we want to create resilient communities for ourselves and our children, understanding and prizing what contributes to that resilience (and what does not) is a good place to start. We may even find that a society that's more resilient can be more beautiful too.
I encourage you to check the piece out in its entirety and think about resilience as it pertains to nature, culture, and self.
Excellent post – as usual!! Resiliency is the life blood of humanity!
Indeed, our species' ability to spread over the planet and thrive in a multitude of different environments is a testament to its inherent resiliency. It would be a shame to lose that quality.
Thanks for bringing this to my attention. Resilience is a tremendously important quality and feature for both individuals and communities.
You're very welcome. I hope it is a useful resource.
I really like your thoughts on this, although I think a more I depth definition of "resilience" is important. I believe I know what your taking about because I don't think I could be traveling the way I am and be doing the things I do without some amount of resilience. But what does it mean?
It sounds like a great defence for the Scandinavian welfare model!
Great post, and great thinking.
I must confess, I'm not familiar enough with the Nordic model to see if it truly fulfills all of these criteria, but I could see it.
Good point:-) I meant that you post is a great summary of some key points of the very long article on Joyroots, which I haven't read in all detail.
A resilient community depends on the resilience of its members. More actively, a resilient community will foster it. Education, health, mobility—by giving these things to our neighbors, we ensure a stronger neighborhood for ourselves.
'Social resilience' sounds much like the underlying idea of the Scandinavian welfare societies. There might be some variation in what these societies offers, so I'll concentrate on the Danish version, which I know intimately because I'm Danish.
– Education is free and of high quality in Denmark, including high education. The State actually pays you a salary when you study, that covers your living costs (plus a cheap study loan if you need more). If you do a PhD, you'll earn a decent salary for doing that (but not everybody get accepted, obviously). If you study abroad the Danish State still pays you the allowance so you can pay for your living costs abroad. Recently the law has changed, so the Danish state now even contributes towards paying the overseas tuition fees for Danish students. Until a few years ago, foreigners could also study for free on Danish universities. They could hardly believe it.
– A safety net with fairly solid unemployment benefits. Also, if you work as a casual worker and get sick, the State will pay you sick allowance on the days you can't work.
– Universal free health care of high quality, including advanced specialist services, institutions, many types of services such as for example in-home help and go-out companionship for disabled people to ensure they are able to take active part in society, study, go to meetings and so on.
– Effective public infrastructure & public transport of high quality – not free, but somewhat subsidised. In Copenhagen there's a strong emphasis on environment friendly transport forms (public transport and bicycles) and some parts of the city is PT and bicycles only. Bicycles is a standard means of transport, and the infrastructure of bicycle lanes is excellent compared to many other places.
– There is a strong focus on improving sustainability, ecology and social responsibility at all levels of society, and the focus isn't limited to Denmark.
My point isn't that the Scandinavian countries meet all the criteria, but that the 'social resilience' idea is an integral part of how these societies are designed.
Why give people a free and even paid education? Surely some will enrol in an expensive education just because they haven't figured out what they want to do, and then they get paid to do that and have sort of a frame of their life. Maybe they'll never use the degree in a job. However, the point is to have a resilient society of highly educated, healthy, smart people who are able and willing to work for the benefit of everybody and think about what's right and wrong, not just focussing on surviving day by day doing what they have always done, and ending up in a state of panic when their world changes.
Here is a somewhat related article: The Secret Scandinavian Ingredient that Makes Their Tech Good for the World. It is about technological development and not disaster response, and it is written by an outsider who doesn't get the ingredients of Scandinavian culture totally right, but she's got the community mentality right – that people create things just for the sake of building something, rather than for economic growth and narrow personal gains. Basically, society is a strong fabric, and whenever something unexpected happens there is plenty of calm, healthy, competent people available to work out solutions and get the best out of it.
Ps. Despite what it might sound like from the above, this isn't supposed to be a glowing/fanatic praise of the Scandinavian welfare model. I am just trying to outline the basic idea. There are plenty of downsides too.
Thanks very much for a comprehensive explanation from a Danish perspective, Mados. I learn a lot from detailed and thoughtful comments such as yours.
There's definitely a quality of resilience in emphasizing the cultivation of a well-educated citizenry that doesn't need to worry about day to day subsistence and can adapt to the challenges of a rapidly changing world. Fear and ignorance have a harder time undermining the foundations of such a society too.
Ahem… unfortunately not, it seems. Denmark is fairly xenophobic IMO (and homogenous… when I was a kid, I barely ever saw anyone in the streets who wasn't white and Danish-looking).
That's a shame. Upon reflection, it is probably much easier to stitch together a strong community fabric when everyone is from a single culture, as opposed to one with people from all over the world with different value systems. New ideas and ways of doing things, for good or for bad, probably have a harder time getting through.
Resilience is such an important subject. The word seems to have much more appeal to a broader group of people than sustainability. I'll have to check out the Joyroots.com article to read more of their view of resilience. I wrote a short book called the Seven Foundations of a Resilient Livelihood because I believe we are too short-sighted about what resilience means for ourselves and society. Thanks for your great summary!
I do think resiliency is a more readily understood and positive concept. For me, it implies a hidden and flexible strength, whereas sustainability carries with it a connotation of preservation and stasis.
But both terms are tough sells for those who still value efficiency and growth as the only qualities worth pursuing.
is your book linked on your blog? I would like to check it out.
That might play a role… I guess it is easier to design & stick to collective rules and visions when people aren't too diverse.
Also, the system's resilience relies on a certain cultural attitude, a moral commitment to not exploiting the system (too much).
There is also the perception that foreigners who haven't grown up with such a 'free goods' system haven't developed the required cultural self-discipline and respect for the system, so they just think 'wow… here I can be paid to have holiday all the time!' and totally overload the system so it breaks down. While unemployed they develop depressions, self-loathe (converted into hating Western culture and the Danish system) and family problems. I am talking about primarily Muslim immigrants from middle Eastern cultures, which seems to be the main group of non-Scandinavian immigrants in Denmark and the primary source of controversy*. The bleak picture is enforced by the fact that the immigrants often find it hard to find employment in Denmark, so they actually often do rely on Danish version of 'the dole' in many cases.


This place is linked to the following locations: Operations Room, West Stairway 1F.
50% chance of appearing here instead of Zombie Dogs.
50% chance of appearing here instead of Zombies.
50% chance of appearing on the floor next to the barricaded door instead of in the Office Corridor.


text:
641 (DCXLI) je bilo navadno leto, ki se je po julijanskem koledarju začelo na ponedeljek.

Dogodki

Arabci zasedejo Egipt.

Rojstva

Smrti

redpajama_set_name: RedPajamaWikipedia


text:
Pythian migrates company's global assets to GCP without downtime
by Krista Colby-Wheatley
Posted in: Business Insights, Technical Track
Tags: Google Cloud Platform (GCP)
Many businesses migrate to the cloud to take advantage of cost savings and improved agility. Optiva, a Canada-based company that develops software for communications service providers, recently migrated to Google Cloud Platform (GCP) with help from Pythian's team of experts. Since the migration, Optiva has seen the following benefits:
reduced its data center costs from $15 million to $1.5 million
consolidated its remaining physical servers from 10 data centers to one
reduced four support ticket management systems to one
uses only seven operating systems instead of 50
has four remote desktop protocol (RDP) systems instead of 120
pays only for resources used instead of always-on servers
deploys workloads to larger GCP data centers which are billed at lower rates
While Optiva now has a solid foundation from which to take full advantage of the cost savings and other benefits of the GCP, reaching that goal was challenging. As the company had grown and acquired other companies, it acquired 3,500 outdated machines running more than 50 operating systems in 10 data centers around the world, greatly complicating a move to the cloud.
Facing this complex prospect, Optiva asked Google for help, who referred Optiva to several different Google partners. Optiva chose Pythian because of Pythian's deep relationship with Google as well as its automation-based migration approach which includes multiple accountability checkpoints.
Optiva had a strict six-month deadline for the move. The cloud migration was successfully completed on schedule without extended downtime, allowing the company to quickly reduce costs and improve its agility. Because the company is less reliant on third-party hardware, it can also reduce its total cost of ownership (TCO), accelerate its refresh cycles and greatly simplify the IT team's tasks.
Find out how Pythian accomplished this migration by watching the webinar from Google Next or reading the full case study.
Interested in working with Krista? Schedule a tech call.
Krista Colby-Wheatley
Marketing Product Manager
Krista is an experienced Portfolio Marketing Manager with a demonstrated history of working in the information technology and services industry and supports the Cloud Business Unit at Pythian.


text:
Antonio Argibay, AIA, LEED AP, is a Featured Speaker at New York Build 2022
Feb 16, 2022 | Business
Founder of Meridian Design Associates Architects Will Discuss "Sustainable Interiors and Design" in a Panel Session
NEW YORK, NY, February 16, 2022 /24-7PressRelease/ — Meridian Design Associates Architects (http://www.meridiandesign.com) today announced that Founder and Managing Principal Antonio Argibay, AIA, LEED AP will speak at New York Build Expo 2022 on March 3rd at 3:00 PM. New York Build Expo 2022 – set for March 2nd and 3rd at New York's Javits Convention Center – is the largest construction and design show in New York and the Tri-State area. The event is free to attend. Additional information as well as registration can be found here – https://www.newyorkbuildexpo.com/MDAA.
Argibay is a featured speaker on the "Sustainable Interiors Design" panel. Fellow panelists include:
• Connor Glass, Principal, Workplace Practice Leader, NYC Interiors Studio Leader, Board Director at Perkins Eastman
• Raul Garcia-Moncada, Associate Principal at AECOM | IIDA | NCIDQ | LEED AP | WELL AP
• Brooke Horan, IIDA, ASID, WELL AP, LEED AP, EDAC – Interior Design Director at HDR
• Kimberley Petredis, Director of Residential Interiors, Senior Associate at FXCollaborative
• Ana Dudarenko, Project Manager at Gilbane Building Company
Together, they will address topics such as:
• what specific principles fellow architects and designers must follow for sustainable interior design
• how climate change awareness and net zero carbon goals impact interior design; and
• offer recommendations to limit carbon emissions to within net zero goals
"These topics are life-long passions of mine," says Argibay. "As such, I am so honored that I was invited to speak – and with such stellar co-panelists – and have the opportunity to contribute in a meaningful manner on a subject that is critical in everyone's lives, regardless of their industry."
Lilian Ho, the organizer of New York Build Expo at Oliver Kinross who is responsible for the conference agenda, is equally enthusiastic. "We asked Antonio to participate because he has been such a draw in the past," she says, noting that Argibay has spoken previously at New York Build Expo. "His dedication to the industry and breadth of knowledge is appreciated by all who attend his sessions. Antonio is always a delight, and we're glad he is able to join once again."
About Meridian Design Associates Architects
Founded in 1981, Meridian Design Associates Architects, P.C. is an award-winning global company headquartered in New York City, with offices in Miami and Seville, Spain. The firm's portfolio of work runs the gamut from media and entertainment to commercial interiors to retail to residential to healthcare. Meridian Design Associates offers an array of design-related services to a broad range of clients in the United States and around the world. Members of the firm are committed to providing elegant and inspiring design solutions in a practical and efficient fashion.
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Liebesgeschichten und Heurathssachen ist eine Posse mit Gesang in Drey Acten von Johann Nestroy. Das Stück wurde 1843 verfasst und hatte am 23. März dieses Jahres als Benefizvorstellung für den Dichter seine Uraufführung.

Inhalt
Im "Silbernen Rappen" treffen einander alte Freunde: der mittellose Kaufmannssohn Anton Buchner, der nach 2 Jahren Herumreisen seine Geliebte Fanny, die Tochter des ehemaligen Fleischselchers und nunmehr reichen Partikuliers Florian Fett, heiraten will und Alfred, der Sohn des Marchese Vincelli, der inkognito als Sekretär bei Fett arbeitet. Alfred ist in Ulrike verliebt und befürchtet, sein Vater werde aus Standesdünkel nicht in die Hochzeit einwilligen. Um die ledige ältliche Schwägerin des Herrn von Fett, Lucia Distel, bemüht sich der schwer verschuldete, arbeitsscheue Spitzbube Nebel, jedoch allein ihrer Mitgift wegen.
"[…] wenn man aber nix glernt, und nirgends gut gethan hat, wenn man dabei eine spezielle Abneigung gegen die Arbeit und einen Universal-Hang zur Gaudée in sich trägt, und dennoch die Idee nicht aufgiebt ein vermöglicher Kerl zu wer'n, darin liegt was Grandioses." (I. Act, 5te Scene)
Durch ein Missverständnis hält Fett Nebel für einen hohen Sprössling und schließlich sogar für den Sohn des Marchese Vincelli. Dieser vermeintlich Adelige wäre ihm als Bräutigam für seine Tochter sehr recht. Nebel intrigiert heftig, um Anton und Fanny zu entzweien.

Als sich alle Verwechslungen schließlich aufklären, willigt der Marchese in die Verbindung seines Sohnes ein, da er in Ulrike die Tochter seiner ehemaligen Angebeteten erkennt und Alfreds Notlüge glaubt, die Hochzeit sei bereits im Geheimen geschlossen worden. Auch Fett ist nunmehr einverstanden, dass Anton und Fanny sich verloben. Der entlarvte Nebel resigniert:
"Jetzt muss ich schau'n, dass mich der guten Wirthin ihr Mann als Oberkellner nimmt." (III. Act, 17te Scene)

Werksgeschichte
Die Handlung wurde der englischen Posse Patrician and Parvenu (Patrizier und Parvenu) von John Poole (1786–1872) nachgebildet. Dieses Stück hatte am 21. März 1835 im Theatre Royal Drury Lane von London Premiere. Es wurde von Nestroy zu einem Stück umgestaltet, das adeligen Standesdünkel einerseits und neokapitalistischen Hochmut andrerseits mit scharf karikierender Satire beschreibt. Eine zweite, nicht verifizierbare Quelle nannte Nestroy bei den Vorarbeiten mit dem Vermerk "Scene nach Ogl" (= Original) ohne nähere Angaben; es könnte sich dabei um eine zeitgenössische (Zeitungs-)Anekdote gehandelt haben. Das Werk wurde nur wenige Monate nach dem nicht sehr erfolgreichen Stück Die Papiere des Teufels (Uraufführung am 17. November 1842) verfasst.

Nach dem Theaterzettel der Premiere spielte Johann Nestroy den Nebel, Wenzel Scholz den Particulier Florian Fett, Alois Grois den Marchese Vincelli, Ignaz Stahl den Wirten, Eleonore Condorussi das Stubenmädchen Philippine.

Ein Originalmanuskript in Nestroys Handschrift ist ebenso wie die Reinschrift von Nebels Couplets im II. Act, 8te Scene erhalten. Das Rollenheft von Nebels Couplets (Singstimme und Text) im II. Act, 8te Scene und im III. Act, 8te Scene ist lediglich in einer Aufzeichnung von fremder Hand erhalten.

Zeitgenössische Rezeption
Die zeitgenössische Kritik war vorwiegend positiv, so schrieb Der Sammler am 25. März 1843 (S. 190 f.):
"Zieht man nun noch in Anbetracht, dass dem Dialog eine Fülle von Witz, Satyre, pikanter Einfälle und komischen Pointen innewohnt, und dies besonders in jenen Szenen, wo Hr. Nestroy selbst mitwirkend ist, dass ferner die neuesten Kouplets dieses Abends zu den gelungensten gehören, die der Feder des genialen Volksdichters entflossen, und dass endlich die Hauptrollen in den besten Händen waren, so wird es jedem unserer freundlichen Leser leicht erklärlich sein, dass diese Novität einen glänzenden Succeß hatte, und eine sehr beifällige Aufnahme erfuhr."
Weder in dieser Rezension, noch in der am gleichen Tag erschienenen im Wanderer (S. 190 f.) wurde – vermutlich aus Unkenntnis – erwähnt, dass die Vorlage eine englische comedy sei. Der Wanderer nennt Nestroy den "Alleinherrscher im Reiche des Jokus".

Anders urteilte der allen Possen stets sehr kritische gegenüberstehende Rezensent der Sonntagsblätter, Dr. Wagner, der am 26. März (S. 301 f.) konstatierte, es lohne sich nicht, die zeitgenössische "Possen-Seichtigkeit", von der auch Nestroys Stück keine Ausnahme mache, zu besprechen. Der Inhalt sei "ganz haltlos", ein "fadenscheiniger Stoff", an den der Dichter eine "unerschöpfliche Fülle seines Witzes und seiner Laune" verschwendet habe – immerhin letztlich ein Kompliment für Nestroy.

Die Kritik in Adolf Bäuerles Wiener Theaterzeitung vom 27. März (S. 331) war wie fast immer voller Lob. Als erster und einziger nannte Bäuerle den korrekten Namen der englischen Quelle, er stieß sich lediglich am für die Hauptperson Nebel unglücklichen Ausgang, der tatsächlich bei Nestroy sonst kaum je vorkam:
"Das Publikum sieht es nicht gerne, wenn der komische Hauptheld des Stückes am Ende so spurlos verschwindet, wenn er mit langer Nase abziehen muss, wenn er gleichsam verstoßen wird, und untergeht, indeß die Nebenpersonen mit Glück und Freude überschüttet werden. Referent hätte dem lustigen Kauz Nebel ohne Anstand die Mamsell Lucie Distel mit ihren 40.000 fl. an den Hals geworfen."
Dagegen nannte die Wiener Zeitschrift vom 27. März (S. 485 f.) Nebel einen "Lumpen", dem "der Sieg des Besseren" fehle und störte sich auch an der "Verhöhnung des Adels".

Spätere Interpretation
Fritz Brukner und Otto Rommel war 1928 die englische Quelle noch nicht bekannt. Sie weisen darauf hin, dass die einzelnen Motive des Stückes in der Tradition des Altwiener Volkstheaters unzählige Male wiederkehren. Der große Erfolg beim Publikum wird ebenso erwähnt, wie die "merkwürdig farblose" Art der zeitgenössischen Zeitungsrezensionen. Sogar die "Verwegenheit der Belauschungsszene" bleibe dabei unerwähnt, der Protest über die Persiflierung des Adels knüpfe sich besonders an die outrierende Gestaltung des Marchese Vincelli durch Herrn Grois. Nestroys Vorzensuranmerkungen sei zu entnehmen, dass er einige ihm gefährlich erscheinende Passagen bereits selbst gestrichen habe.

Nach Franz H. Mautner mache Nestroy aus der Vorlage von John Pool eine breit angelegten Aussage gegen kapitalistische Einstellung und Standesdünkel. Das Stück zeige speziell den Virtuosen der Sprache in genialen Wortschöpfungen und des Witzes, der Verstrickung, Verknüpfung und Entwirrung zahlreicher nebeneinander laufender Handlungen, die auf die Spitze getrieben würden. Unzart sei freilich die Behandlung der alten Jungfer Lucia Distel, neu bei Nestroy der Ausschluss der zynischen Hauptfigur Nebel vom allgemeinen Happy End.

Helmut Ahrens weist darauf hin, dass diese Posse mit all ihren bösen Sätzen über Liebe, Ehe und Zuneigung dennoch "keineswegs Eingeständnis einer glücklosen eheähnlichen Gemeinschaft" (Zitat) mit seiner Lebensgefährtin Marie Weiler sei, sie richte sich vielmehr gegen Adelsdünkel und die großsprecherische G'schaftelhuberei der nouveaux riches (Neureichen). Da im Publikum gar nicht so wenige der von ihm apostrophierten Kreise saßen, sei der große Beifall umso bemerkenswerter gewesen. Die egoistische menschliche Natur geißelt der Dichter im Monolog des von ihm gespielten Opportunisten Nebel:
"Ich werd' mich jetzt auf den Eh'stand verlegen und dabei allen Anforderungen der Ästhetik entsprechen; meine Auserwählte is nämlich reich und dabei nicht ohne Unliebenswürdigkeit, ich schließe also eine Vernunftheirat, eine Geldheirat und zugleich eine Heirat aus Inklination, weil ich eine unendliche Inklination zum Geld hab'." (I. Act, 5te Scene)

Literatur
Helmut Ahrens: Bis zum Lorbeer versteig ich mich nicht. Johann Nestroy, sein Leben. Societäts-Verlag, Frankfurt am Main 1982, ISBN 3-7973-0389-0.
Fritz Brukner/Otto Rommel: Johann Nestroy, Sämtliche Werke. Historisch-kritische Gesamtausgabe, elfter Band, Verlag von Anton Schroll & Co., Wien 1928.
Jürgen Hein (Hrsg.): Johann Nestroy; Stücke 19. In: Jürgen Hein/Johann Hüttner: Johann Nestroy, Sämtliche Werke, Historisch-kritische Ausgabe. Jugend und Volk, Wien/München 1988, ISBN 3-224-16901-X; S. 1–84, 113–234.
Franz H. Mautner (Hrsg.): Johann Nestroys Komödien. Ausgabe in 6 Bänden, Insel Verlag, Frankfurt am Main 1979, 2. Auflage 1981, IV. Band.
Otto Rommel: Nestroys Werke, Auswahl in zwei Teilen, Goldene Klassiker-Bibliothek, Deutsches Verlagshaus Bong & Co., Berlin/Leipzig/Wien/Stuttgart 1908; 1. Teil S. 313–381, 2. Teil S. 357–358.

Weblinks
Inhalt auf nestroy.at/nestroy-stuecke/47

Einzelnachweise

Literarisches Werk
Literatur (19. Jahrhundert)
Alt-Wiener Volkstheater
Literatur (Deutsch)
Posse
Werk von Johann Nepomuk Nestroy
Literatur (Österreich)
Michael Hebenstreit


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The Vedensky okrug was a district (okrug) of the Terek Oblast of the Caucasus Viceroyalty of the Russian Empire. The area of the Vedensky okrug made up part of the North Caucasian Federal District of Russia. The district was eponymously named for its administrative centre, Vedeno.

Administrative divisions
The subcounties (uchastoks) of the Vedensky okrug were as follows:

Demographics

Kavkazskiy kalendar
According to the 1917 publication of Kavkazskiy kalendar, the Vedensky okrug had a population of 127,718 on , including 67,444 men and 60,274 women, 125,801 of whom were the permanent population, and 1,917 were temporary residents:

Notes

References

Bibliography

Okrugs of Terek Oblast


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3. DEEP WATERS
Historians of the social life of the later Roman Empire speak of a certain young man of Ariminum, who would jump into rivers and swim in 'em. When his friends said, 'You fish!' he would answer, 'Oh, pish! Fish can't swim like me, they've no vim in 'em.'
Just such another was George Barnert Callender.
On land, in his land clothes, George was a young man who excited little remark. He looked very much like other young men. He was much about the ordinary height. His carriage suggested the possession of an ordinary amount of physical strength. Such was George--on shore. But remove his clothes, drape him in a bathing-suit, and insert him in the water, and instantly, like the gentleman in The Tempest, he 'suffered a sea-change into something rich and strange.' Other men puffed, snorted, and splashed. George passed through the ocean with the silent dignity of a torpedo. Other men swallowed water, here a mouthful, there a pint, anon, maybe, a quart or so, and returned to the shore like foundering derelicts. George's mouth had all the exclusiveness of a fashionable club. His breast-stroke was a thing to see and wonder at. When he did the crawl, strong men gasped. When he swam on his back, you felt that that was the only possible method of progression.
George came to Marvis Bay at about five o'clock one evening in July. Marvis Bay has a well-established reputation as a summer resort, and, while not perhaps in every respect the paradise which the excitable writer of the local guide-book asserts it to be, on the whole it earns its reputation. Its sands are smooth and firm, sloping almost imperceptibly into the ocean. There is surf for those who like it, and smoother water beyond for those whose ideals in bathing are not confined to jumping up and down on a given jelly-fish. At the northern end of the beach there is a long pier. It was to this that George made his way on his arrival.


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Expand high technology maritime sector at Port of Palm Beach
Music and Marketing September 4, 2022 3 min read
W. Bradford Gary
We should commend the Port of Palm Beach Commission for the successful establishment and expansion of the super yacht facility Berth One.
Everything I have seen in the maritime world suggests that super yachts will dominate the "new build" category of ship construction for many years to come. The port is well equipped to handle the new marine business, while other docking facilities lower in the Lake Worth Lagoon may have difficulty with large vessel length, depth and channel restrictions.
The port also has exciting opportunities for clean environment business activity. A large cruise ship operation has been retrofitted with a business model designed by Jimmy Buffett. The expanded cruise facility has the potential to provide additional revenues, but also attract cruise tourists to the other attractions of the county. Unfortunately, for many years, the port was utilized as a remote staging point and export shipping platform for heavy industrial composites. Today, our valuable county waterfront is better suited for tourism and high-technology activity — platforms for new marine technology.
Storage of large commodity and construction items should be located in less-expensive areas outside the near shore area of Lake Worth. Lockheed Martin, a leading U.S. maritime warfare defense contractor is a major DoD contractor based on the north side of the port. Lockheed technology is leading the way for new maritime weapons systems. Lockheed tests underwater drones off the Lake Worth Inlet, [and] our Gulf Stream location serves as a near shore weapons range. Almost every week test drones are towed out to the Lake Worth Inlet for sea trials.
Lockheed's history in Palm Beach is instructive; original work on civilian and government submersibles occurred in the 1950s at Perry Submersibles in Riviera Beach. The U.S. government — through the work of former U.S. Rep. Paul Rogers of Palm Beach — established a large shoreside base in West Palm for the Navy's Underwater Weapons Range in the Atlantic tongue in the lower Bahamas chain. U.S. Navy contractor flights to and from the range now depart daily from Palm Beach International Airport. The Bahamas Underwater Range and associated West Palm activity are major employers and bring government science assets to the area.
Because the Lake Worth Inlet has secure all-weather access for ocean-going vessels, the port is uniquely qualified for expansion of the high technology maritime sector. No U.S. port facility is similarly situated. We should take further advantage of our superior oceanic location to build a world-class maritime location to include research institutions, specialized submersible ship sites and university programs in the ocean sciences.
Many U.S. and foreign jurisdictions establish local tax incentives for new technology employment. Perhaps Palm Beach County should review the desirability of establishing a new county "wage credit" that would provide a partial credit for specifically qualified new marine research facilities.
Some years ago Palm Beach established numerous local incentives for a biotechnology cluster. I believe that marine technology has better prospects for our county employment growth compared to the pharmaceutical/biotechnology sector.
Our future prospects are clearly better served today if we engage with the world of high maritime technology. Let's start to work.
W. Bradford Gary of Palm Beach is a director at the Southern Ocean Research Company.
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Golisano Children's Hospital implements new technology to enhance procedural communication
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Collection Videos
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More than 30,000 Jews were murdered near Kiev over a two-day period during the Holocaust. Why are Ukrainians, Russians, and Germans only now beginning to come to terms with this black chapter in their histories?
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In 1961, 24 brave men gave their lives in a superhuman effort to save the the Soviet Union's first ballistic missile submarine - and the world - from environmental catastrophe. This is their story.
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(2015) Double First Cousin Marriage and Genetic Disorders in South of IRAN. American Journal of Life Science Researches.
Abstract: Marriage between persons biologically related as second cousins are known as consanguineous. Double first cousins arise when siblings of one family reproduce with siblings of another family. A consanguineous couple especially double cousin couple is at increased risk for both autosomal recessive disorders and several congenital malformations. This study is designed in order to illustrate the prevalence of first double cousin marriage and its outcomes in Hormozgan province in south of IRAN. This is a cross-sectional study. Participants are 68 couples who came to medical genetic counseling center because of first double cousin marriage between 2003 to 2013. In 10 years from 2003-2013 genetic counseling was done for 4800 couples. 2856 couples (59.5%) had consanguineous marriage. 68 couples were double first cousin (1.4%). Double first cousin marriage is high risk for offspring to have genetic disorders. Counseling and giving knowledge and information to couples could encourage them to avoid high risk marriages like double first cousin.


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Home	Cardiology	Guidelines, Clinical Evidence, and Real-Life Practice: How to Find…
Guidelines, Clinical Evidence, and Real-Life Practice: How to Find Your Way in Managing Hypercholesterolaemia
11 October 2018 | Cardiology Download as	| PDF
This satellite symposium took place on 28th August 2018, as part of the European Society of Cardiology (ESC) Congress in Munich, Germany
Chairpeople:
Erik Stroes1,2
Lluis Masana,3 Michel Farnier4
1. Faculty of Medicine, University of Amsterdam, Amsterdam, Netherlands
2. AMC Medical Research BV, Amsterdam, Netherlands
3. Vascular Medicine and Metabolism Unit, Sant Joan University Hospital, Institut d'Investigació Sanitaria Pere Virgili (IISPV), Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Universitat Rovira i Virgili, Reus, Spain
4. Lipid Clinic, Point Médical and Department of Cardiology, Centre Hospitalier Universitaire (CHU) Dijon-Bourgogne, Dijon, France
Prof Stroes has received fees to his institution for lectures and advisory boards for Amgen, Sanofi, Novartis, Athera, Mylan, Akcea, and Regeneron. Prof Masana received fees for lectures and advisory boards from Amgen, Sanofi, MSD, and Mylan. Prof Farnier has research contracts with Amgen, Sanofi/Regeneron; has undertaken consulting work for Abbott, Akcea/Ionis, Amarin, Amgen, AstraZeneca, Eli Lilly, Kowa, Merck and Co., Mylan, Pfizer, Sanofi/Regeneron, and Servier; and has participated in clinical trials including ODYSSEY (Sanofi/Regeneron), TESLA/TAUSSIG (Amgen), and Anacetrapib (Merck and Co.).
Medical writing assistance was provided by Janet Fricker.
The symposium and this article were funded by Mylan.
EMJ Cardiol. 2018;6[1]:38-46.
Meeting Summary
Prof Masana presented evidence that low-density lipoprotein (LDL) cholesterol is a causal factor for atherosclerosis and that cardiovascular disease (CVD)-relative risk (RR) is reduced proportionally to LDL reductions, regardless of the type of monotherapy used. Combination therapy offers the advantage of increased lipid-lowering efficacy and a reduction in the side effects associated with high-intensity statins. The rationale thus exists for replacing high-intensity statin therapy with high-intensity cholesterol-lowering therapy.
Prof Farnier gave an in-depth description of the results of the IMPROVE-IT, FOURIER, and ODYSSEY-Outcomes trials, demonstrating that the magnitude of clinical benefit is independent of whether it is achieved by statins, ezetimibe, or PCSK9 inhibitors. The IMPROVE-IT study also showed that the magnitude of benefit is proportionate to the absolute decrease in LDL cholesterol. This is consistent with the conclusions of a meta-analysis of randomised controlled statin trials, showing that patients achieving very low LDL cholesterol levels have a reduced risk of major cardiovascular (CV) events compared with those achieving moderately low levels. The greatest benefits for reductions in major adverse CV events from lowering LDL cholesterol occur in patients with diabetes.
The above studies have led the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) taskforce on PCSK9 inhibitors to outline a strategy for additional treatment, with patients on maximally-tolerated statin doses failing to achieve LDL cholesterol goals at 4 weeks being considered for ezetimibe treatment, and those failing to achieve goals after a further 4 weeks being considered for PCSK9 inhibitors.
Votes from the audience, collected at the start and end of each presentation, showed that the speakers convinced delegates that the lower the LDL cholesterol level achieved the better the outcome for patients would be, that combination therapy is as effective as single dose high-intensity statins, and that statins plus ezetimibe should be considered as standard treatment in high-risk patients, particularly in Type II diabetes mellitus (T2DM) patients.
From Guidelines to Real Life: Practical Considerations for Patients with Hypercholesterolaemia. Combination Therapy
Professor Lluis Masana
The audience were asked to consider the case of a 71-year-old ex-smoker with hypertension treated with angiotensin-converting-enzyme inhibitors, calcium inhibitors, and hydrochlorothiazide, who was admitted to hospital with acute myocardial infarction (MI). The patient had untreated moderate hypercholesterolaemia (total cholesterol: 213 mg/dL; high-density lipoprotein [HDL] cholesterol: 43 mg/dL; LDL cholesterol: 140 mg/dL; and triglycerides [TG]: 150 mg/dL) and had been prescribed omeprazole.
In the first vote, 62%, 4%, and 6% of delegates said LDL cholesterol therapy targets should be <70 mg/dL, <50 mg/dL, and <30 mg/dL, respectively (NB. 1 mg/dL cholesterol=0.02586 mmol/L). Eight percent said that a 50% reduction should be achieved, 8% indicated that no target was necessary if a high-intensity statin was used, and 11% said that the lowest possible LDL cholesterol level should be aimed for. The LDL cholesterol target for such a patient is <70 mg/dL.1
In the second vote, 51% and 23% of delegates indicated that the patient should be started on atorvastatin 80 mg or rosuvastatin 20 mg, respectively. Fourteen percent said they would start on atorvastatin 40 mg/ezetimibe 10 mg, 3% voted for atorvastatin 80 mg/ezetimibe 10 mg, 1% decided on rosuvastatin 10 mg/ezetimibe 10 mg, and 7% chose rosuvastatin 20 mg/ezetimibe 10 mg.
Such responses demonstrated that three-quarters of the audience were aware of the ESC/EAS and the American College of Cardiology (ACC)/American Heart Association (AHA) 2013 guidelines on blood cholesterol treatment recommending that hypercholesterolaemic patients who have experienced a MI should receive high-intensity statins before being considered for combination therapy. For patients at higher risk for side effects, moderate-intensity statins can be started and, if this fails, statins should be increased to the highest intensity tolerable; only if this approach does not work should combination therapy be considered.1,2
Guidelines were developed after several trials showed no CV benefits for non-statin lipid-modifying agents used in combination with statins versus statin monotherapy. Negative trials included ILLUMINATE (torcetrapib),3 HPS2-THRIVE (niacin),4 DAL-OUTCOMES (dalcetrapib),5 AIM-HIGH (niacin),6 and ACCELERATE (evacetrapib).7 Positive outcomes were observed in two studies, FIELD8 and ACCORD,9 for the fenofibrate/statin combination in patient subsets with high TG and low HDL cholesterol but not in overall diabetic subjects. Following these findings, the AHA and ACC 2013 cholesterol treatment guidelines recommended high-intensity statins as the preferred option for established CVD or hyperlipidaemia.2
Notably, in 2017, a EAS comprehensive review of scientific studies concluded that LDL cholesterol is not just a CV risk biomarker but also an aetiological factor in atherosclerosis.10
The LDL cholesterol level associated with CV outcomes has been established by a meta-regression analysis for statin and non-statin therapies.11 The analysis included statins (25 trials), fibrates (9 trials), ezetimibe (1 trial), niacin (3 trials), cholesteryl ester transfer protein inhibitors (3 trials), diet (4 trials), bile acid sequestrants (2 trials), ileal bypass surgery (1 trial), and PCSK9 inhibitors (2 trials). The analysis found a 23% reduction in CV events for each mmol/L reduction in LDL cholesterol when patients were treated with statins (RR: 0.77; 95% confidence interval [CI]: 0.71–0.84; p<0.001). A similar RR was reported for five non-statin therapies, including diet, bile acid sequestrant, ileal bypass, and ezetimibe (RR: 0.77; 95% CI: 0.75–0.79; p<0.001). The findings indicated that the relationship between CV event risk and LDL cholesterol levels achieved exists for both statins and certain non-statin therapies.
The IMPROVE-IT study demonstrated a relationship between incremental lowering of LDL cholesterol and improved CV outcomes when the non-statin lipid-modifying agent ezetimibe was added to simvastatin.12 This suggests that, regardless of the mechanism of action, all reductions in LDL levels are of equivalent benefit and that a high-intensity cholesterol-lowering strategy should replace high-intensity statin therapy.13
Current cholesterol-lowering drugs include statins, ezetimibe, PCSK9 inhibitors, and resins/colesevelam. TG-lowering drugs include fibrates and omega-3 fatty acids. In addition to each agent reducing CV events as a monotherapy, there is now evidence supporting the effectiveness of combining statins with ezetimibe and PCSK9 inhibitors. There is also evidence supported by post-hoc analyses that statins and fenofibrate may be useful in patients with diabetes and atherogenic dyslipidaemia. Negative results have been reported for statin–omega 3 combinations, although high-dose omega 3 fatty acids with fibrates are used to treat patients with very high TG levels.1
Cholesterol-lowering therapies are classified into four groups according to LDL cholesterol reduction intensity, with low, mild, high, and very-high-intensity cholesterol-lowering therapies reducing LDL cholesterol by <30%, 30–49%, 50–60%, and >60%, respectively.13 Very-high-intensity combinations include atorvastatin 40–80 mg/ezetimibe 10 mg and rosuvastatin 20–40 mg/ezetimibe 10 mg.12
Since 1984, randomised controlled trials have achieved progressively lower LDL cholesterol concentrations. For example, the latest FOURIER study reported LDL levels of 30 mg/dL.14 A pre-specified secondary analysis of this study demonstrated that such a concentration is more favourable, in terms of CV outcomes, than concentrations of 90 mg/dL or 70 mg/dL.15
While these data suggest that CV prevention is improved with lower LDL cholesterol levels, only 28.1% of CVD patients reach LDL cholesterol targets, according to the DYSIS targets.16
DYSIS furthermore found that, in patients at very high CV risk, the mean difference between actual levels and target levels was roughly 1 mmol/L, and that for populations failing to achieve LDL cholesterol targets the mean starting dose was equivalent to 35 mg/day of simvastatin, and only 7% received combination therapy. Such data suggests the need to address undertreatment.
Treatment options for patients taking medium or standard doses of statins who are not exhibiting the desired response include doubling their dose, switching to a more powerful statin, and starting combination therapy.1
A study that compared LDL cholesterol reductions for a range of statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, and rosuvastatin) and a second study looking at pitavastatin found that only atorvastatin and rosuvastatin at daily doses of ≥20 mg produced reductions >40%.17,18 Furthermore, when the atorvastatin dose was doubled, from 40 mg to 80 mg, the LDL lipid-lowering effect increased by only 6%, from 44% to 50%. Reductions in LDL cholesterol achieved from doubling doses are less pronounced than those observed following the addition of other agents. Combining two different lipid-lowering drugs provides a greater LDL cholesterol decrease; however, this does not simply correspond to the addition of each individual drug effect. For example, rosuvastatin 20 mg/day and ezetimibe 10 mg/day lowered LDL by 50% and 20%, respectively, but the two agents combined lower LDL cholesterol by 60%.19
Generally, the following LDL cholesterol reductions can be achieved with therapy: ezetimibe: -20%; moderate-intensity statin: -40%; high-intensity statin: -50%; PCSK9 inhibitor: -60%; high-intensity statin plus ezetimibe: -60%; moderate intensity statin plus PCSK9 inhibitor: -76%; high-intensity statin plus PCSK9 inhibitor: -80%; moderate-intensity statin plus ezetimibe plus PCSK9 inhibitor: -81%; and high-intensity statin plus ezetimibe plus PCSK9 inhibitor: -84%.20 Thus, maximum LCL cholesterol lipid lowering can be achieved with combinations of high intensity statins plus ezetimibe plus PCSK9 inhibitors. Notably, the difference between high-intensity and moderate-intensity statins when combined with ezetimibe and PCSK9 inhibitors is just 3% (Figure 1).19
Figure 1: The lipid-lowering difference between high-intensity and moderate-intensity statins when combined with ezetimibe and PCSK9 is 3%.
EZE: ezetimibe; HI-St: high-intensity statin; inh: inhibitor; MI-St: moderate-intensity statin.
Adapted from Masana et al.19
Benefits of statins, including CVD reduction and increased survival, need to be balanced against risks such as developing muscle symptoms, T2DM, and transaminases elevation. Evidence from studies, including PROVE-IT, A-Z, TNT, IDEAL, and SEARCH, suggests that the diabetogenic effects of statins are dose- related.21 According to a EAS panel, factors influencing the risk of statin-associated muscle symptoms include pre-existing risk factors and comorbidities, high-dose statin therapy, polypharmacy, and drug–drug interactions (including concomitant use of gemfibrozil, macrolides, azole antifungal agents, protease inhibitors, and immunosuppressive drugs such as cyclosporine and inhibitors of CYP450 isoenzymes).22
To conclude, LDL cholesterol can be considered a causal factor for atherosclerosis, with the RR of CVD reduced proportionally to LDL cholesterol decreases regardless of the therapy used. The benefits of combination therapy, such as statins plus ezetimibe and statins plus PCSK9 inhibitors, have a scientific evidence base. Combination therapy increases lipid-lowering efficacy and reduces side effects associated with high-intensity statins, improving adherence and CV event reduction. Thus, the rationale exists for replacing high-intensity statin therapy with high-intensity cholesterol-lowering therapy.
In a repeat of the original vote, 39%, 4%, and 0% of the audience said LDL cholesterol therapy targets should be <70 mg/dL, <50 mg/dL, and <30 mg/dL, respectively. Eleven percent said that a 50% reduction should be achieved, 17% indicated there is no target when high intensity statins are used, and 29% that the lowest possible level should be aimed for.
Regarding the second vote on treatments, 51% choose atorvastatin 80 mg, 14% voted for rosuvastatin 20 mg, 20% for atorvastatin 40 mg plus ezetimibe, 10% for atorvastatin 80 mg plus ezetimibe, 5% for rosuvastatin 10 mg plus ezetimibe, and 15% for rosuvastatin 20 mg plus ezetimibe.
The feedback from the audience demonstrated that the presentation had been successful in convincing delegates that the lower the LDL cholesterol level achieved the more favourable the outcome for patients and that use of combination therapy was as effective as single-dose high-intensity statins.
Interpretation of Recent Trial Outcomes and Considerations for Daily Practice
Professor Michel Farnier
At the start of Prof Farnier's presentation, the audience was asked to consider the case of a 62-year-old male with T2DM treated with coronary artery bypass graft who had a lipid profile on rosuvastatin 20 mg of an LDL cholesterol level of 81 mg/dL, TG levels of 180 mg/dL, and HDL-C levels of 40 mg/dL.
In the first vote, 6% of the delegates opted for no change to treatment, 27% for increasing the dose of rosuvastatin to 40 mg, 55% for adding ezetimibe, 4% for adding a PCSK9 inhibitor, and 7% for adding fenofibrate.
A number of trials have shown benefits from adding LDL therapies to statins, including IMPROVE-IT (ezetimibe),12 REVEAL (anacetrapib), FOURIER (evolocumab),15 SPIRE-1 and 2 (bococizumab),23 and ODYSSEY-Outcomes (alirocumab).24 Bococizumab and anacetrapib have since been withdrawn due to antidrug antibodies, which caused the LDL-lowering effect to wear off in bococizumab trials and accumulation in adipose tissue with anacetrapib.
In the IMPROVE-IT study, 18,144 patients with post-acute coronary syndrome for <10 days with LDL cholesterol of 50–100 mg/dL (on lipid-lowering therapy) or 50–125 mg/dL (without lipid-lowering therapy) were randomised to simvastatin 40 mg plus ezetimibe 10 mg or simvastatin 40 mg plus placebo.12 Results at a median follow-up of 6 years showed that the primary endpoint (CV death, MI, documented unstable angina requiring rehospitalisation, coronary revascularisation for >30 days, or stroke) occurred in 32.7% of patients in the simvastatin plus ezetimibe group versus 34.7% in the simvastatin plus placebo group (hazard ratio [HR]: 0.936; 95% CI: 0.89–0.99; p=0.016).12
In the FOURIER trial,25 27,564 stable patients with established CVD (prior MI [81%], prior stroke [19%], or symptomatic peripheral artery disease [PAD] [13%]), 69% of whom were on high-intensity statins, who had either LDL cholesterol >70 mg/dL or non-HDL cholesterol >100 mg/dL were randomised to evolocumab every 2 weeks (or every 4 weeks) versus placebo. At a median follow-up of 2.2 years the primary efficacy endpoint (CV death, MI, stroke, hospitalisation for unstable angina, or coronary revascularisation) occurred in 11.3% of patients taking placebo versus 9.8% taking evolocumab (HR: 0.85; 95% CI: 0.79–0.92; p<0.001). The RR reduction was 15% and absolute risk reduction 1.5%.
Finally, in the ODYSSEY Outcomes trial, 18,924 patients were randomised to alirocumab or placebo plus background high-intensity statins starting 1–12 months after acute coronary syndrome. All participants had baseline LDL cholesterol levels of ≥70 mg/dL despite intensive statin treatment. The specific strategy was to obtain LDL cholesterol targets between 25 and 50 mg/dL, with some subjects needing up-titration of alirocumab, others down-titration of alirocumab, and a few switching to placebo when cholesterol became too low (<15 mg/dL).
Results at a median of 2.8 years showed the primary endpoint (a composite of coronary heart disease death, nonfatal MI, ischaemic stroke, or unstable angina requiring hospitalisation) occurred in 9.5% of alirocumab patients versus 11.1% of placebo patients (HR: 0.85; 95% CI: 0.78–0.93; p=0.0003). The study was presented by Prof Gabriel Steg at the 2018 ACC meeting.24
Taking the IMPROVE-IT, FOURIER, and ODYSSEY-Outcomes studies together, the magnitude of LDL cholesterol lowering benefit is independent of whether it is achieved by statins, PCSK9 inhibitors, or ezetimibe. This conclusion is in alignment with studies showing genetic mutations affecting LDL metabolism that decrease LDL cholesterol results in dose-dependent decreases in atherosclerotic cardiovascular disease (ASCVD) risk.10 The magnitude of benefit is proportional to the absolute decrease in LDL cholesterol, which is demonstrated by the IMPROVE-IT study showing that reductions in LDL cholesterol are directly related to reductions in event rates.12 When the same durations of follow-up were used to compare PCSK9 inhibitors in the FOURIER and SPIRE trials with statin treatment in the Cholesterol Treatment Trialists meta-analysis of statin trials, a similar magnitude of risk reduction was obtained. At 1 year of treatment, for every 1 mmol/L of LDL cholesterol reduction, the RR reduction of major vascular events was 14% in SPIRE 2 and 12% in CTT with statins. At 2 years of treatment, for every 1 mmol/L of LDL cholesterol reduction, the RR reduction of major vascular events was 17% in FOURIER versus 17% in CTT with statins.26 Together with the genetic evidence, this demonstrates that therapies reduce CV event risks proportionally to absolute achieved reductions in LDL cholesterol and total durations of therapy. For non-statin therapies used for ASCVD, cost-effectiveness analyses are essential to determine whether, how, and when PCSK9 inhibitor treatment meets accepted value for financial metrics.27 The higher the risk, the higher the benefit, and this raises a key question of how to identify statin therapy patients at highest risk of recurrent disease for additional treatments.
A meta-analysis of eight randomised controlled statin trials demonstrated that patients achieving very low LDL cholesterol levels had lower risks of major CV events than those achieving moderately low levels. Compared to patients achieving LDL cholesterol >175 mg/dL, those reaching LDL cholesterol 75–100 mg/dL, 50–75 mg/dL, and <50 mg/dL had adjusted HR for major CV events of 0.56, 0.51, and 0.44, respectively.28
Similar relationships hold for events when the placebo arms in FOURIER and ODYSSEY-Outcomes were analysed. In FOURIER, 13.6% of patients with LDL cholesterol <80 mg/dL had a CV event versus 16.2% with LDL cholesterol >109 mg/dL. In the ODYSSEY-Outcomes trial, 9.5% of patients with LDL cholesterol <80 mg/dL experienced an event versus 14.9% with LDL cholesterol >100 mg/dL.
For the FOURIER placebo group, the risk of CV death, MI, or stroke was 10.8% for patients <2 years from qualifying MI versus 9.3% for patients >2 years from qualifying MI (HR: 1.19; 95% CI: 1.04–1.37; p=0.01). The risk changes to 15.0% for patients having over two prior MI versus 8.2% for patients having one prior MI (HR: 2.04; 95% CI: 1.78–2.35; p<0.001), and 12.6% for patients having multivessel disease versus 8.9% for single vessel disease (HR: 1.47; 95% CI: 1.27–1.70; p<0.001). Analysis of FOURIER placebo data showed that the risk of CV, MI, or stroke was 13.0% in patients with PAD versus 7.6% in patients without PAD (adjusted HR: 1.81; 95% CI: 1.53–2.14; p<0.001).
Among the categories of highest risk ASCVD on statin therapy (defined as around or above a benchmark of 30% of a 10-year risk) are patients with clinical atherosclerotic CVD and T2DM.29
When IMPROVE-IT was analysed according to diabetic status, in non-diabetic patients the probability of the primary endpoint at 7 years was 30.2% for patients taking simvastatin or ezetimibe versus 30.8% for patients taking simvastatin alone (HR: 0.98; 95% CI: 0.91–1.04; p=0.526). For diabetic patients it was 40.0% for patients taking simvastatin or ezetimibe versus 45.5% for patients taking simvastatin alone (HR: 0.85; 95% CI: 0.78–0.94; p<0.001).30 Such data demonstrate that patients with diabetes derived significantly greater relative and absolute benefits from the addition of ezetimibe than patients without diabetes.
A recent meta-analysis of seven trials showed the ezetimibe plus statin combination therapy was associated with a greater reduction in major adverse CV events in diabetic patients than those without diabetes (pooled RR: 0.84 versus 0.93; pheterogeneity=0.012).31 Such data raise questions about why ezetimibe delivers greater benefits to patients with T2DM. The benefit was shown in IMPROVE-IT, where there was a 3 mg/dL greater reduction in LDL cholesterol for patients with diabetes compared to those without (p=0.03).30 Furthermore, a pooled analysis of 27 clinical trials of patients with and without diabetes receiving ezetimibe plus statin or statin alone showed patients with diabetes achieved significantly larger reductions in LDL cholesterol with the combination therapy (difference of 2.5%; p<0.0001).32
Reductions in cholesterol do not fully explain the magnitude of the effect in diabetic patients, leading to suggestions that other beneficial effects may also occur, including influencing postprandial lipaemia (a condition in which TG-rich chylomicron remnants are increased during the postprandial period).33
The ESC and EAS recently updated their practical clinical guidance for the use of PCSK9 inhibitors in patients with ASCVD.34 The new guidelines recommend that in patients with clinical ASCVD, ezetimibe should be given according to clinical judgement and local guidance, and that for patients with LDL cholesterol >140 mg/dL or patients with LDL-C >100 mg/dL and additional indices of risk, a PCSK9 inhibitor should be considered. Additional risk categories include familial hypercholesterolaemia, diabetes with target organ damage or marked hypertension, severe or extensive ASCVD, and rapid progression of ASCVD.
The taskforce additionally provided a decision algorithm for PCSK9 inhibitors in familial hypercholesterolaemia in primary prevention, with patients who have no additional indices being considered for PCSK9 inhibitors when they have LDL cholesterol levels >180 mg/dL and for patients with additional indices of risk severity being considered with LDL cholesterol levels >140 mg/dL. Here, additional risk indices are defined as diabetes with target organ damage, lipoprotein (a) >50 mg/dL, major risk factors such as smoking, marked hypertension, >40 years of age without treatment, and premature ASCVD (<55 years in males and <60 years in females) in first-degree relatives and imaging indicators.
The taskforce recommendation is to first place patients on the maximally tolerated statin doses and assess their response at 4 weeks. Those failing to achieve LDL cholesterol goals should be considered for ezetimibe, with their response assessed again after 4 weeks. Those found to be above LDL cholesterol thresholds should then be considered for a PCSK9 inhibitor. Patients prescribed the PCSK9 inhibitors should have their LDL cholesterol-lowering response assessed 2 weeks after the first injection.
A recent analysis of the DYSIS II study found that, among 631 Italian patients with coronary heart disease receiving lipid lowering treatment, 64.6% had LDL cholesterol levels >70 mg/dL and 25.1% had LDL cholesterol levels >100 mg/dL. In a model, the addition of ezetimibe reduced the percentage of patients with LDL cholesterol >70 mg/dL and >100 mg/dL from 64.6–37.9% and from 25.1–11.8%, respectively.35
A simulation model involving a cohort of 105,269 patients was undertaken to estimate the percentage of patients with ASCVD that would require a PCSK9 inhibitor.36 The USA database revealed that only 25.2% achieved LDL cholesterol levels <70 mg/dL, with 51.5% of the database using statin monotherapy and 1.7% statins plus ezetimibe. The model showed that following treatment intensification, 99.3% could achieve LDL cholesterol levels <70 mg/dL including 67.3% with statin monotherapy, 18.7% with statins plus ezetimibe, and 14% with add-on PCSK9 inhibitors. In conclusion, combining statins with ezetimibe represents the logical first choice of therapy when LDL cholesterol is uncontrolled by statin monotherapy, with PCSK9 inhibitors considered for the highest risk categories on maximally tolerated statin plus ezetimibe therapies.
When the vote was returned to the audience, 2% said they would not change the treatment, 9% would use rosuvastatin 40 mg, 85% would add ezetimibe, 3% would add a PCSK9 inhibitor, and 2% would add a fibrate. The second vote showed that the vast majority of the audience agreed with the rationale given in the presentation to add ezetimibe and consider statin plus ezetimibe in secondary prevention of high-risk patients with T2DM.
In summary, the symposium's take-home messages are that clinicians should move away from thinking about high-intensity statin therapy and instead consider high-intensity lipid- lowering therapy. Furthermore, patients that do not achieve the LDL cholesterol target with residual LDL cholesterol burden and high absolute risk require combination therapy, preferably with high-intensity statin and ezetimibe.
Catapano AL et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016;37(39):2999-3058. Stone NJ et al. 2013 ACC/AHA guidelines on the treatment of blood cholesterol to educe atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25):S1-45. Barter PJ et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109-22. The HPS2-THRIVE Collaborative Group. Effects of extended release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371: 203-12. Schwarz GG et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089-99. The AIM-HIGH Investigators. Niacin in patients with low LDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-67. Lincoff AM et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933-42. Keech A; FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with Type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet. 2005;366(9500):1849-61. Elam M et al. The ACCORD-Lipid study: Implications for treatment of dyslipidemia in Type 2 diabetes mellitus. Clin Lipidol. 2011;6(1):9-20. Ference BA et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32): 2459-72. Silverman MG et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA. 2016;316:1289-97. Cannon CP et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-97. Masana L et al. IMPROVE-IT clinical implications. Should the 'high-intensity cholesterol-lowering therapy' strategy replace the 'high intensity statin therapy'? Atherosclerosis. 2015;240(1):161–2. Masana L et al. Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels-The zero-LDL hypothesis. J Clin Lipidol. 2018;12(2):292-9. Giugliano RP et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: A prespecfified secondary analysis of the FOURIER trial. Lancet. 2017;390(10106):1962-71. Gitt AK et al. Cholesterol target value attainment and lipid-lowering therapy in patients with stable or acute coronary heart disease: Results from the Dyslipidemia International Study II. Atherosclerosis. 2017;266:158-66. Weng TC et al. A systematic review and meta-analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. 2010;35(2):139-51. Mukhtar RY et al. Pitavastatin. Int J Clin Pr. 2005;59(5):239-52. Masana L et al. Maximum low-density lipoprotein cholesterol lowering capacity achievable with drug combinations. When 50 plus 20 equals 60. Rev Esp Cardiol. 2016;69(3):342-3. Masana L et al. Máxima reducción de cholesterol unido a lipoproteinas de baja densidad alcanzable con combinaciones farmacológicas. Cuando 50 más 20 suma 60. Rev Esp Cardiol. 2016;69(3):342-3. Sattar NA et al. The use of statins in people at risk of developing diabetes mellitus: Evidence and guidance for clinical practice. Atheroscler. 2014;15(1):1-15. Stroes ES et al. Statin-associated muscle symptoms: Impact on statin therapy - European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17);1012-22. Ridker PM. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376:1527-39. Steg P. Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab - ODYSSEY OUTCOMES. American College of Cardiology Annual Scientific Session (ACC 2018). Available at: https://www.acc.org/latest-in-cardiology/clinical-trials/2018/03/09/08/02/odyssey-outcomes. Last accessed: 25 September 2018. Sabatine MS et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-22. Ference BA et al. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: An analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. 2018;39:2540-5. Annemans L et al. 'Highest risk benefit' strategy: A pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. Eur Heart J. 2018;39(17):2546-50. Boekholdt SM et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. JACC. 2014;64(5):485-94. Annemans L. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: An analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. 2018;39(27):2540-45. Giugliano RP et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: Results from IMPROVE-IT. Circulation. 2017;137(15):1571-82. Hong N et al. Comparison of the effects of ezetimibe-statin combination therapy on major adverse cardiovascular events in patients with and without diabetes: A meta-analysis. Endocrinol Metab. 2018;33(2):219-27. Leiter LA et al. Lipid-altering efficacy and safety profile of combination therapy with ezetimibe/ stain vs. statin monotherapy in patients with and without diabetes: An analysis of pooled data from 27 clinical trials. Diab Obes Metab. 2011;13(7):615-28. Farnier M. Ezetimibe/statin combination therapy to treat patients with type 2 diabetes. Atheroscler. 2015;17:2-8. Landmesser U et al. 2017 Update of ESC/EAS Task Force on Practical Clinical Guidance for proprotein convertase subtilisin/ kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J. 2018;39(14):1131-43. De Ferrari GM et al. Available oral lipid-lowering agents could bring most high-risk patients to target: An estimate based on the Dyslipidemia International Study II-Italy. J Cardiovas Med. 2018;19(9):485-90. Cannon CP et al. Simulation of lipid-lowering therapy intensification in a population with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017;2(9):959-66.
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