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Archive for the ‘Acute coronary syndrome’ Category


Two Classes of Antithrombotic Drugs: Anticoagulants and Antiplatelet drugs

Reporter: Aviva Lev-Ari, PhD, RN
These drugs are used to treat
  • strokes,
  • myocardial infarctions,
  • pulmonary embolisms,
  • disseminated intravascular coagulation (DIC) and
  • deep vein thrombosis (DVT)
— all potentially life-threatening conditions.
THERAPEUTIC STRATEGIES
• Degrade fibrinogen/fibrin (fibrinolytic agents)
GOAL: eliminate formed clots
• Inhibit clotting mechanism (anticoagulants)
GOAL: prevent progression of thrombosis
• Interfere either with platelet adhesion and/or aggregation (antiplatelet drugs)
GOAL: prevent initial clot formation
Antithrombotic therapy has had an enormous impact in several significant ways.
  • Heparin has made bypass surgery and dialysis possible by blocking clotting in external tubing.
  • Antithrombotic therapy has reduced the risk of blood clots in leg veins (also known as deep-vein thrombosis or DVT), a condition that can lead to death from pulmonary embolism (a clot that blocks an artery to the lungs) by more than 70 percent. And most importantly,
  • it has markedly reduced death from heart attacks, the risk of stroke in people with heart irregularities (atrial fibrillation), and the risk of major stroke in patients with mini-strokes.

Antithrombotic Therapy

This article was published in December 2008 as part of the special ASH anniversary brochure, 50 Years in Hematology: Research That Revolutionized Patient Care.

Normally, blood flows through our arteries and veins smoothly and efficiently, but if a clot, or thrombus, blocks the smooth flow of blood, the result – called thrombosis – can be serious and even cause death. Diseases arising from clots in blood vessels include heart attack and stroke, among others. These disorders collectively are the most common cause of death and disability in the developed world. We now have an array of drugs that can be used to prevent and treat thrombosis – and there are more on the way – but this was not always the case.

Classes of Antithrombotic Drugs

Image Source: http://www.hematology.org/About/History/50-Years/1523.aspx

The most important components of a thrombus are fibrin and platelets. Fibrin is a protein that forms a mesh that traps red blood cells, while platelets, a type of blood cell, form clumps that add to the mass of the thrombus. Both fibrin and platelets stabilize the thrombus and prevent it from falling apart. Fibrin is the more important component of clots that form in veins, and platelets are the more important component of clots that form in arteries where they can cause heart attacks and strokes by blocking the flow of blood in the heart and brain, respectively, although fibrin plays an important role in arterial thrombosis as well.

There are two classes of antithrombotic drugs: anticoagulants and antiplatelet drugs. Anticoagulants slow down clotting, thereby reducing fibrin formation and preventing clots from forming and growing. Antiplatelet agents prevent platelets from clumping and also prevent clots from forming and growing.

Anticoagulant Drugs

The anticoagulants heparin and dicumarol were discovered by chance, long before we understood how they worked. Heparin was first discovered in 1916 by a medical student at The Johns Hopkins University who was investigating a clotting product from extracts of dog liver and heart. In 1939, dicumarol (the precursor to warfarin) was extracted by a biochemist at the University of Wisconsin from moldy clover brought to him by a farmer whose prize bull had bled to death after eating the clover.

Both of these anticoagulants have been used effectively to prevent clots since 1940. These drugs produce a highly variable anticoagulant effect in patients, requiring their effect to be measured by special blood tests and their dose adjusted according to the results. Heparin acts immediately and is given intravenously (through the veins). Warfarin is swallowed in tablet form, but its anticoagulant effect is delayed for days. Therefore, until recently, patients requiring anticoagulants who were admitted to a hospital were started on a heparin infusion and were then discharged from the hospital after five to seven days on warfarin.

In the 1970s, three different groups of researchers in Stockholm, London, and Hamilton, Ontario, began work on low-molecular-weight heparin (LMWH). LMWH is produced by chemically splitting heparin into one-third of its original size. It has fewer side effects than heparin and produces a more predictable anticoagulant response. By the mid 1980s, LMWH preparations were being tested in clinical trials, and they have now replaced heparin for most indications. Because LMWH is injected subcutaneously (under the skin) in a fixed dose without the need for anticoagulant monitoring, patients can now be treated at home instead of at the hospital.

With the biotechnology revolution has come genetically engineered “designer” anticoagulant molecules that target specific clotting enzymes. Anti-clotting substances and their DNA were also extracted from an array of exotic creatures (ticks, leeches, snakes, and vampire bats) and converted into drugs by chemical synthesis or genetic engineering. Structural chemists next began to fabricate small molecules designed to fit into the active component of clotting enzymes, like a key into a lock.

The first successful synthetic anticoagulants were fondaparinux and bivalirudin. Bivalirudin, a synthetic molecule based on the structure of hirudin (the anti-clotting substance found in leeches), is an effective treatment for patients with heart attacks. Fondaparinux is a small molecule whose structure is based on the active component of the much larger LMWH and heparin molecules. It has advantages over LMWH and heparin and has recently been approved by the FDA. Newer designer drugs that target single clotting factors and that can be taken by mouth are undergoing clinical testing. If successful, we will have safer and more convenient replacements for warfarin, the only oral anticoagulant available for more than 60 years.

Antiplatelet Drugs

Blood platelets are inactive until damage to blood vessels or blood coagulation causes them to explode into sticky irregular cells that clump together and form a thrombus. The first antiplatelet drug was aspirin, which has been used to relieve pain for more than 100 years. In the mid-1960s, scientists showed that aspirin prevented platelets from clumping, and subsequent clinical trials showed that it reduces the risk of stroke and heart attack. In 1980, researchers showed that aspirin in very low doses (much lower than that required to relieve a headache) blocked the production of a chemical in platelets that is required for platelet clumping. During that time, better understanding of the process of platelet clumping allowed the development of designer antiplatelet drugs directed at specific targets. We now have more potent drugs, such as clopidogrel, dipyridamole, and abciximab. These drugs are used with aspirin and effectively prevent heart attack and stroke; they also prolong the lives of patients who have already had a heart attack.

SOURCE 
Anticoagulation Drugs:
  • heparin (FONDAPARINUX HEPARIN (Calciparine, Hepathrom, Lipo-Hepin, Liquaemin, Panheprin)
  • warfarin – 4-HYDROXYCOUMARIN (Coumadin) WARFARIN (Athrombin-K, Panwarfin)
  • rivaroxaban (Xarelto)
  • dabigatran (Pradaxa)
  • apixaban (Eliquis)
  • edoxaban (Savaysa)
  • enoxaparin (Lovenox)
  • fondaparinux (Arixtra)
  • ARGATROBAN BIVALIRUDIN (Angiomax)
  • DALTEPARIN (Fragmin)
  • DROTRECOGIN ALFA (ACTIVATED PROTEIN C) (Xigris)
  • HIRUDIN (Desirudin)
  • LEPIRUDIN (Refludan)
  • XIMELAGATRAN (Exanta)

ANTIDOTES

  • PHYTONADIONE (Vitamin K1)
  • PROTAMINE SULFATE AMINOCAPROIC ACID (EACA) (generic, Amicar) (in bleeding disorders)
Antiplatelet Drugs
  • ACETYL SALICYLIC ACID (aspirin) 
  • clopidogrel (Plavix)
  • dipyridamole (Persantine)
  • abciximab (Centocor)
  • EPTIFIBATIDE (Integrilin)
  • TICLOPIDINE (Ticlid)
  • TIROFIBAN (Aggrastat)

THROMBOLYTICS

  1. ANISTREPLASE (APSAC; Eminase)
  2. STREPTOKINASE (Streptase, Kabikinase)
  3. TISSUE PLASMINOGEN ACTIVATORS (tPAs):
  • ALTEPLASE (Activase),
  • RETEPLASE (Retavase),
  • TENECTEPLASE (TNKase)
  • UROKINASE (Abbokinase)

Fibrinolytic Drugs

Fibrinolytic therapy is used in selected patients with venous thromboembolism. For example, patients with massive or submassive PE can benefit from systemic or catheter-directed fibrinolytic therapy. The latter can also be used as an adjunct to anticoagulants for treatment of patients with extensive iliofemoral-vein thrombosis.

Arterial and venous thrombi are composed of platelets and fibrin, but the proportions differ.

  • Arterial thrombi are rich in platelets because of the high shear in the injured arteries. In contrast,
  • venous thrombi, which form under low shear conditions, contain relatively few platelets and are predominantly composed of fibrin and trapped red cells.
  • Because of the predominance of platelets, arterial thrombi appear white, whereas venous thrombi are red in color, reflecting the trapped red cells.

SOURCE

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

A heart-healthy diet has been the basis of atherosclerotic cardiovascular disease (ASCVD) prevention and treatment for decades. The potential cardiovascular (CV) benefits of specific individual components of the “food-ome” (defined as the vast array of foods and their constituents) are still incompletely understood, and nutritional science continues to evolve.

 

The scientific evidence base in nutrition is still to be established properly. It is because of the complex interplay between nutrients and other healthy lifestyle behaviours associated with changes in dietary habits. However, several controversial dietary patterns, foods, and nutrients have received significant media exposure and are stuck by hype.

 

Decades of research have significantly advanced our understanding of the role of diet in the prevention and treatment of ASCVD. The totality of evidence includes randomized controlled trials (RCTs), cohort studies, case-control studies, and case series / reports as well as systematic reviews and meta-analyses. Although a robust body of evidence from RCTs testing nutritional hypotheses is available, it is not feasible to obtain meaningful RCT data for all diet and health relationships.

 

Studying preventive diet effects on ASCVD outcomes requires many years because atherosclerosis develops over decades and may be cost-prohibitive for RCTs. Most RCTs are of relatively short duration and have limited sample sizes. Dietary RCTs are also limited by frequent lack of blinding to the intervention and confounding resulting from imperfect diet control (replacing 1 nutrient or food with another affects other aspects of the diet).

 

In addition, some diet and health relationships cannot be ethically evaluated. For example, it would be unethical to study the effects of certain nutrients (e.g., sodium, trans fat) on cardiovascular disease (CVD) morbidity and mortality because they increase major risk factors for CVD. Epidemiological studies have suggested associations among diet, ASCVD risk factors, and ASCVD events. Prospective cohort studies yield the strongest observational evidence because the measurement of dietary exposure precedes the development of the disease.

 

However, limitations of prospective observational studies include: imprecise exposure quantification; co-linearity among dietary exposures (e.g., dietary fiber tracks with magnesium and B vitamins); consumer bias, whereby consumption of a food or food category may be associated with non-dietary practices that are difficult to control (e.g., stress, sleep quality); residual confounding (some non-dietary risk factors are not measured); and effect modification (the dietary exposure varies according to individual/genetic characteristics).

 

It is important to highlight that many healthy nutrition behaviours occur with other healthy lifestyle behaviours (regular physical activity, adequate sleep, no smoking, among others), which may further confound results. Case-control studies are inexpensive, relatively easy to do, and can provide important insight about an association between an exposure and an outcome. However, the major limitation is how the study population is selected or how retrospective data are collected.

 

In nutrition studies that involve keeping a food diary or collecting food frequency information (i.e., recall or record), accurate memory and recording of food and nutrient intake over prolonged periods can be problematic and subject to error, especially before the diagnosis of disease.

 

The advent of mobile technology and food diaries may provide opportunities to improve accuracy of recording dietary intake and may lead to more robust evidence. Finally, nutrition science has been further complicated by the influences of funding from the private sector, which may have an influence on nutrition policies and practices.

 

So, the future health of the global population largely depends on a shift to healthier dietary patterns. Green leafy vegetables and antioxidant suppliments have significant cardio-protective properties when consumed daily. Plant-based proteins are significantly more heart-healthy compared to animal proteins.

 

However, in the search for the perfect dietary pattern and foods that provide miraculous benefits, consumers are vulnerable to unsubstantiated health benefit claims. As clinicians, it is important to stay abreast of the current scientific evidence to provide meaningful and effective nutrition guidance to patients for ASCVD risk reduction.

 

Available evidence supports CV benefits of nuts, olive oil and other liquid vegetable oils, plant-based diets and plant-based proteins, green leafy vegetables, and antioxidant-rich foods. Although juicing may be of benefit for individuals who would otherwise not consume adequate amounts of fresh fruits and vegetables, caution must be exercised to avoid excessive calorie intake. Juicing of fruits / vegetables with pulp removal increases calorie intake. Portion control is necessary to avoid weight gain and thus cardiovascular health.

 

There is currently no evidence to supplement regular intake of antioxidant dietary supplements. Gluten is an issue for those with gluten-related disorders, and it is important to be mindful of this in routine clinical practice; however, there is no evidence for CV or weight loss benefits, apart from the potential caloric restriction associated with a gluten free diet.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/28254181

 

https://www.sciencedirect.com/science/article/pii/S0735109713060294?via%3Dihub

 

http://circ.ahajournals.org/content/119/8/1161

 

http://refhub.elsevier.com/S0735-1097(17)30036-0/sref6

 

https://www.scopus.com/record/display.uri?eid=2-s2.0-0031709841&origin=inward&txGid=af40773f7926694c7f319d91efdcd40c

 

https://www.magonlinelibrary.com/doi/10.12968/hosp.2000.61.4.1875

 

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2548255

 

https://pharmaceuticalintelligence.com/2018/05/31/supplements-offer-little-cv-benefit-and-some-are-linked-to-harm-in-j-am-coll-cardiol/

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Acute Coronary Syndrome (ACS): Strategies in Anticoagulant Selection: Diagnostics Approaches – Genetic Testing Aids vs. Biomarkers (Troponin types and BNP)

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 8/7/2018

Siemens’ high-sensitivity Troponin I (TnIH) assaysgot FDA clearance for use in diagnosing acute myocardial infarction. (Cardiovascular Business) The first high-sensitivity Troponin T test was cleared last year, as MedPage Today reported.

SOURCE

https://www.medpagetoday.com/cardiology/prevention/74423?xid=nl_mpt_cardiobreak2018-08-06&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CardioBreak_080618&utm_term=SM%20CardioBreak%20Alert

UPDATED on 3/17/2018

An NT-proBNP <300 pg/ml strongly excludes the presence of acute HF.

J Am Coll Cardiol. 2018 Mar 20;71(11):1191-1200. doi: 10.1016/j.jacc.2018.01.021.

N-Terminal Pro-B-Type Natriuretic Peptide in the Emergency Department: The ICON-RELOADED Study

 

A breakthrough in emergence of

  • Genetic Testing Aids as a Personalized approach, genomics-based approach to selecting antiplatelet therapy, for reduction in ischemic and bleeding events, and
  • Biochemical Biomarker approaches for dosing anti-thrombotic drugs are presented here.

“This study fills in a part of the puzzle of genomic testing,” said Craig Beavers, PharmD, of the University of Kentucky in Lexington. “It shows we can use genomic information in clinical decision making. It was interesting that there appeared to be a change in prescribing based on genomics.”

SOURCE

https://www.medpagetoday.com/meetingcoverage/acc/71722?xid=nl_mpt_DHE_2018-03-13&eun=g99985d0r&pos=3&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%202018-03-13&utm_term=Daily%20Headlines%20-%20Active%20User%20-%20180%20days

At 12 months, 25.9% of patients receiving standard care had experienced the trial’s primary composite endpoint — cardiovascular death, non-fatal MI or stroke, and Bleeding Academic Research Consortium (BARC) 3-5 major bleeding — compared with 15.8% of patients receiving an anticoagulant drug on the basis of genetic testing (P<0.001), reported Diego Ardissino, MD, of Azienda Ospedaliero-Universitaria di Parma in Italy, and colleagues.

PHARMCLO is the first trial to combine clinical characteristics with genetic information to inform the choice of P2Y12 receptor antagonist in patients with ACS, Ardissino said in a presentation at the American College of Cardiology annual meeting. The study was simultaneously published in the Journal of the American College of Cardiology.

“Selecting treatment on the basis of genetic data in addition to considerations concerning the patients’ clinical characteristics may lead to a more personalized, and therefore more efficient, antiplatelet therapy, thus reducing both ischemic and bleeding risk,” he said. “PHARMCLO is the first step of a new approach that will see a shift in emphasis away from trying to discover ever-more potent anti-thrombotic drugs, and toward ensuring that the right therapy is given to each individual patient.”

However, PHARMCLO was halted after about a fourth of the intended population was recruited. The Ethics Committee of Modena (Italy) required the trial to be prematurely stopped because of a lack of in vitro diagnosis certification for the testing instruments. The original patients were still followed, Ardissino stated.

The authors enrolled 888 patients, and randomly assigned them to be tested for

  • three genes associated with resistance to clopidogrel (Plavix), and then were assigned a
  • treatment based on clinical data informed by the testing results.
  • Tested genes were ABCB1, 2C19*2 and 2C19*17 with the STQ3 system.
  • Another group was assigned to treatment without reference to genetic testing.
  • Standard of care treatment was with Clopidogrel, Ticagrelor (Brilinta), or Prasugrel (Effient).
  1. Clopidogrel was more frequently used in the standard arm (50.7% versus 43.3%), while
  2. Ticagrelor in the pharmacogenomic arm (42.6% versus 32.7%, P<0.05) and
  3. Prasugrel were used equally in both.

The primary endpoint hazard ratio was 0.58 versus the standard arm (95% CI 0.43-0.78, P<0.001).

Previous studies have shown Prasugrel and Ticagrelor to be superior to Clopidogrel at preventing ischemic events. However, prasugrel and ticagrelor, which are more potent, are also known to increase the risk of bleeding. The findings suggest that having more information about a specific patient’s likely response to clopidogrel can help doctors weigh this trade-off, Ardissino said.

 SOURCES

The STANDARD OF CARE in Diagnosis of Acute Coronary Syndrome (ACS) using BioMarkers in serum blood relays of values of Troponin types and BNP for dosing anti-thrombotic drugs.

The team at LPBI Group published the following articles on this topic:

A search into our Journal Archive for “Acute Coronary Syndrome” yielded 210 articles

https://pharmaceuticalintelligence.com/?s=Acute+Coronary+Syndrome

  1. High Sensitivity Troponin (hs cTn) Assays 

  • Previously undiscerned value of hs-troponin

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/06/18/previously-undiscerned-value-of-hs-troponin/

  • Recent Insights into the High Sensitivity Troponins for Acute Coronary Syndromes

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/09/08/recent-insights-into-the-high-sensitivity-troponins-for-acute-coronary-syndromes/

  • Dealing with the Use of the High Sensitivity Troponin (hs cTn) Assays: Preparing the United States for High-Sensitivity Cardiac Troponin Assays

Author and Curator: Larry H Bernstein, MD, FCAP and Author and Curator: Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2013/05/18/dealing-with-the-use-of-the-hs-ctn-assays/

  • Preparing the United States for High-Sensitivity Cardiac Troponin Assays

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/06/13/high-sensitivity-cardiac-troponin-assays/

 

2. BNP and proBNP

Brain natriuretic peptide (BNP), also known as B-type natriuretic peptide, is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume, decrease in systemic vascular resistance and central venous pressure as well as an increase in natriuresis. The net effect of these peptides is a decrease in blood pressure due to the decrease in systemic vascular resistance and, thus, afterload. Additionally, the actions of both BNP and ANP result in a decrease in cardiac output due to an overall decrease in central venous pressure and preload as a result of the reduction in blood volume that follows natriuresis and diuresis.

SOURCE

Maisel A, Krishnaswamy P, Nowak R, McCord J, Hollander J, Duc P, Omland T, Storrow A, Abraham W, Wu A, Clopton P, Steg P, Westheim A, Knudsen C, Perez A, Kazanegra R, Herrmann H, McCullough P (2002). “Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure“. N Engl J Med347 (3): 161–7. 

 

The team at LPBI Group published the following articles on this topic:

  • Effect of Coronary Atherosclerosis and Myocardial Ischemia on Plasma Levels of High-Sensitivity Troponin T and NT-proBNP in Patients With Stable Angina

https://pharmaceuticalintelligence.com/2016/02/17/effect-of-coronary-atherosclerosis-and-myocardial-ischemia-on-plasma-levels-of-high-sensitivity-troponin-t-and-nt-probnp-in-patients-with-stable-angina/

  • More on the Performance of High Sensitivity Troponin T and with Amino Terminal Pro BNP in Diabetes

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/20/more-on-the-performance-of-high-sensitivity-troponin-t-and-with-amino-terminal-pro-bnp-in-diabetes/

  • Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker

Co-Author of the FIRST Article: Larry H. Bernstein, MD, FCAP. Reviewer and Curator of the SECOND and of the THIRD Articles: Larry H. Bernstein, MD, FCAP and Article Architecture Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/10/epo-as-therapeutics-for-anemia-in-chf/

  • Highlights of LIVE Day 1: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017  BOSTON, MA • UNITED STATES

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/01/highlights-of-live-day-1-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma-%E2%80%A2-united-states/

 

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