Advertisements
Feeds:
Posts
Comments

Archive for the ‘Pharmacotherapy of Cardiovascular Disease’ Category


@Cleveland Clinic – Serial measurements of high-sensitivity C-reactive protein (hsCRP) post acute coronary syndrome (ACS) may help identify patients at higher risk for morbidity and mortality

 

Reporter: Aviva Lev-Ari, PhD, RN

 

Original Investigation
March 6, 2019

Association of Initial and Serial C-Reactive Protein Levels With Adverse Cardiovascular Events and Death After Acute Coronary Syndrome, A Secondary Analysis of the VISTA-16 Trial

Key Points

Question  Are initial and serial increases in high-sensitivity C-reactive protein levels after acute coronary syndrome in medically optimized patients associated with increased risk of a major cardiac event, cardiovascular death, and all-cause death?

Findings  In this secondary analysis of the VISTA-16 randomized clinical trial that included 5145 patients, baseline and longitudinal high-sensitivity C-reactive protein levels were independently associated with increased risk of a major adverse cardiac event, cardiovascular death, and all-cause death during the 16-week follow-up.

Meaning  Monitoring high-sensitivity C-reactive protein levels in patients after acute coronary syndrome may help better identify patients at greater risk for recurrent cardiovascular events or death.

Abstract

Importance  Higher baseline high-sensitivity C-reactive protein (hsCRP) levels after an acute coronary syndrome (ACS) are associated with adverse cardiovascular outcomes. The usefulness of serial hsCRP measurements for risk stratifying patients after ACS is not well characterized.

Objective  To assess whether longitudinal increases in hsCRP measurements during the 16 weeks after ACS are independently associated with a greater risk of a major adverse cardiac event (MACE), all-cause death, and cardiovascular death.

Results  Among 4257 patients in this study, 3141 (73.8%) were men and the mean age was 60.3 years (interquartile range [IQR], 53.5-67.8 years). The median 16-week low-density lipoprotein cholesterol level was 64.9 mg/dL (IQR, 50.3-82.3 mg/dL), and the median hsCRP level was 2.4 mg/L (IQR, 1.1-5.2 mg/L). On multivariable analysis, higher baseline hsCRP level (hazard ratio [HR], 1.36 [95% CI, 1.13-1.63]; P = .001) and higher longitudinal hsCRP level (HR, 1.15 [95% CI, 1.09-1.21]; P < .001) were independently associated with MACE. Similar significant and independent associations were shown between baseline and longitudinal hsCRP levels and cardiovascular death (baseline: HR, 1.61 per SD [95% CI, 1.07-2.41], P = .02; longitudinal: HR, 1.26 per SD [95% CI, 1.19-1.34], P < .001) and between baseline and longitudinal hsCRP levels and all-cause death (baseline: HR, 1.58 per SD [95% CI, 1.07-2.35], P = .02; longitudinal: HR, 1.25 per SD [95% CI, 1.18-1.32], P < .001).

Conclusions and Relevance  Initial and subsequent increases in hsCRP levels during 16 weeks after ACS were associated with a greater risk of the combined MACE end point, cardiovascular death, and all-cause death despite established background therapies. Serial measurements of hsCRP during clinical follow-up after ACS may help to identify patients at higher risk for mortality and morbidity.

SOURCE

https://jamanetwork.com/journals/jamacardiology/fullarticle/2725734

 

Inflammation’s role in residual risk

Residual risk of cardiovascular events or death remains high following ACS, despite coronary revascularization and optimal guideline-directed treatment with antiplatelet and LDL cholesterol-lowering agents. Inflammation is thought to drive this risk, but no effective treatment for such inflammation is commercially available. The secretory phospholipase A2 inhibitor varespladib was developed to meet this need, and it was evaluated in VISTA-16.

VISTA-16 was an international, multicenter clinical trial that randomized 5,145 patients in a double-blind manner to varespladib or placebo on a background of atorvastatin treatment within 96 hours of presentation with ACS. The trial was terminated early due to futility and likely harm from the drug, which was subsequently pulled from development.

Implications for practice

The association of increasing CRP levels with residual cardiovascular risk may prompt more intensive treatment to lower this risk. In particular, a secondary analysis showed that use of antiplatelet agents (clopidogrel, ticlopidine and prasugrel) was associated with stable or decreasing hsCRP levels.

“Monitoring not only lipids but also hsCRP after ACS may help us better identify patients at increased risk for recurrent cardiovascular events or death,” notes Dr. Puri. “High or increasing CRP levels could be an indication to optimize dual antiplatelet therapy post-ACS, along with high-intensity statin therapy (and possibly PCSK9 inhibitors) and antihypertensive therapy, in addition to instituting measures that are globally beneficial, such as dietary modifications and cardiac rehabilitation/exercise.”

SOURCE

https://consultqd.clevelandclinic.org/increasing-inflammation-correlates-with-residual-risk-after-acute-coronary-syndrome/amp/?__twitter_impression=true

 

Other related articles published in this Open Access Online Scientific Journal, include the following:

 

Biomarkers and risk factors for cardiovascular events, endothelial dysfunction, and thromboembolic complications

Larry H Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/09/09/biomarkers-and-risk-factors-for-cardiovascular-events-endothelial-dysfunction-and-thromboembolic-complications/

 

A Concise Review of Cardiovascular Biomarkers of Hypertension

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/04/25/a-concise-review-of-cardiovascular-biomarkers-of-hypertension/

 

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

https://pharmaceuticalintelligence.com/2018/03/13/acute-coronary-syndrome-acs-strategies-in-anticoagulant-selection-diagnostics-approaches-genetic-testing-aids-vs-biomarkers-troponin-types-and-bnp/

 

In Europe, BigData@Heart aim to improve patient outcomes and reduce societal burden of atrial fibrillation (AF), heart failure (HF) and acute coronary syndrome (ACS).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/10/in-europe-bigdataheart-aim-to-improve-patient-outcomes-and-reduce-societal-burden-of-atrial-fibrillation-af-heart-failure-hf-and-acute-coronary-syndrome-acs/

 

Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN, 2006 – 4/2018

https://pharmaceuticalintelligence.com/2014/04/17/cardiovascular-diseases-and-pharmacological-therapy-curations-by-aviva-lev-ari-phd-rn/

 

 

Advertisements

Read Full Post »


Cardiovascular (CV) Disease and Diabetes: New ACC Guidelines for use of two major new classes of diabetes drugs — sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) for reduction of adverse outcomes

Reporter: Aviva Lev-Ari, PhD, RN

 

“The main aim for this report is to educate cardiologists, who might not otherwise think about prescribing diabetes drugs, about these two new classes of medications that have important cardiovascular benefits for their patients,” cochair of the writing committee for the new consensus document, Brendan Everett, MD, assistant professor of medicine, Brigham and Women’s Hospital, Boston, commented to theheart.org | Medscape Cardiology.

We hope to help them understand which of their patients might benefit, and to help them understand how to prescribe these new drugs appropriately to their patients with both atherosclerotic cardiovascular disease and diabetes.”

The document is published online November 26 in the Journal of the American College of Cardiology, and is endorsed by the American Diabetes Association.

Journal of the American College of Cardiology

2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease

A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways Writing Committee: 

4 Pathway Summary Graphic

Figure 1 provides an overview of what is covered in the Expert Consensus Decision Pathway. See each section for more detailed considerations and guidance.

Figure 1

Summary Graphic

Figure 2 offers 1 approach to deciding which drug to use in which patient, Table 11 outlines patient and clinician preferences to consider when selecting an SGLT2 inhibitor or GLP-1RA. Table 12 provides an overview of considerations for initiating and monitoring an SGLT2 inhibitor. Table 13 provides an overview of considerations for initiating and monitoring a GLP-1RA.

Figure 2

Approach to Managing Patients With Established ASCVD and T2D

SOURCE

Read Full Post »


The HFE H63D variant confers an increased risk for hypertension, no increased risk for adverse cardiovascular events or substantial left ventricular remodeling

Reporter: Aviva Lev-Ari, PhD, RN

Conclusion:

The HFE H63D variant confers an increased risk for hypertension per allele and, given its frequency, accounts for a significant number of cases of hypertension. However, there was no increased risk for adverse cardiovascular events or substantial left ventricular remodeling.

 

HFE H63D Polymorphism and the Risk for Systemic Hypertension, Myocardial Remodeling, and Adverse Cardiovascular Events in the ARIC Study

Originally publishedHypertension. 2018;0:HYPERTENSIONAHA.118.11730

H63D has been identified as a novel locus associated with the development of hypertension. The quantitative risks for hypertension, cardiac remodeling, and adverse events are not well studied. We analyzed white participants from the ARIC study (Atherosclerosis Risk in Communities) with H63D genotyping (N=10 902). We related genotype status to prevalence of hypertension at each of 5 study visits and risk for adverse cardiovascular events. Among visit 5 participants (N=4507), we related genotype status to echocardiographic features. Frequencies of wild type (WT)/WT, H63D/WT, and H63D/H63D were 73%, 24.6%, and 2.4%. The average age at baseline was 54.9±5.7 years and 47% were men. Participants carrying the H63D variant had higher systolic blood pressure (P=0.004), diastolic blood pressure (0.012), and more frequently had hypertension (P<0.001). Compared with WT/WT, H63D/WT and H63D/H63D participants had a 2% to 4% and 4% to 7% absolute increase in hypertension risk at each visit, respectively. The population attributable risk of H63D for hypertension among individuals aged 45 to 64 was 3.2% (95% CI, 1.3–5.1%) and 1.3% (95% CI, 0.0–2.4%) among individuals >65 years. After 25 years of follow-up, there was no relationship between genotype status and any outcome (P>0.05). H63D/WT and H63D/H63D genotypes were associated with small differences in cardiac remodeling. In conclusion, the HFE H63D variant confers an increased risk for hypertension per allele and, given its frequency, accounts for a significant number of cases of hypertension. However, there was no increased risk for adverse cardiovascular events or substantial left ventricular remodeling.

Footnotes

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.118.11730.

Correspondence to Scott D. Solomon, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. Email 

Read Full Post »


Live 12:00 – 1:00 P.M  Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health : October 19, 2018

Reporter: Stephen J. Williams, Ph.D.

12.00 The Italian Mediterranean Diet as a Model of Identity of a People with a Universal Good to Safeguard Health?

Prof. Antonino De Lorenzo, MD, PhD.

Director of the School of Specialization in Clinical Nutrition, University of Rome “Tor Vergata”

It is important to determine how our bodies interacts with the environment, such as absorption of nutrients.

Studies shown here show decrease in life expectancy of a high sugar diet, but the quality of the diet, not just the type of diet is important, especially the role of natural probiotics and phenolic compounds found in the Mediterranean diet.

The WHO report in 2005 discusses the unsustainability of nutrition deficiencies and suggest a proactive personalized and preventative/predictive approach of diet and health.

Most of the noncommunicable diseases like CV (46%) cancer 21% and 11% respiratory and 4% diabetes could be prevented and or cured with proper dietary approaches

Italy vs. the US diseases: in Italy most disease due to environmental contamination while US diet plays a major role

The issue we are facing in less than 10% of the Italian population (fruit, fibers, oils) are not getting the proper foods, diet and contributing to as we suggest 46% of the disease

The Food Paradox: 1.5 billion are obese; we notice we are eating less products of quality and most quality produce is going to waste;

  •  growing BMI and junk food: our studies are correlating the junk food (pre-prepared) and global BMI
  • modern diet and impact of human health (junk food high in additives, salt) has impact on microflora
  • Western Diet and Addiction: We show a link (using brain scans) showing correlation of junk food, sugar cravings, and other addictive behaviors by affecting the dopamine signaling in the substantia nigra
  • developed a junk food calculator and a Mediterranean diet calculator
  • the intersection of culture, food is embedded in the Mediterranean diet; this is supported by dietary studies of two distinct rural Italian populations (one of these in the US) show decrease in diet
  • Impact of diet: have model in Germany how this diet can increase health and life expectancy
  • from 1950 to present day 2.7 unit increase in the diet index can increase life expectancy by 26%
  • so there is an inverse relationship with our index and breast cancer

Environment and metal contamination and glyphosate: contribution to disease and impact of maintaining the healthy diet

  • huge problem with use of pesticides and increase in celiac disease

12:30 Environment and Health

Dr. Iris Maria Forte, PhD.

National Cancer Institute “Pascale” Foundation | IRCCS · Department of Research, Naples, Italy

Cancer as a disease of the environment.  Weinberg’s hallmarks of Cancer reveal how environment and epigenetics can impact any of these hallmarks.

Epigenetic effects

  • gene gatekeepers (Rb and P53)
  • DNA repair and damage stabilization

Heavy Metals and Dioxins:( alterations of the immune system as well as epigenetic regulations)

Asbestos and Mesothelioma:  they have demonstrated that p53 can be involved in development of mesothelioma as reactivating p53 may be a suitable strategy for therapy

Diet, Tomato and Cancer

  • looked at tomato extract on p53 function in gastric cancer: tomato extract had a growth reduction effect and altered cell cycle regulation and results in apoptosis
  • RBL2 levels are increased in extract amount dependent manner so data shows effect of certain tomato extracts of the southern italian tomato (     )

Antonio Giordano: we tested whole extracts of almost 30 different varieties of tomato.  The tomato variety  with highest activity was near Ravela however black tomatoes have shown high antitumor activity.  We have done a followup studies showing that these varieties, if grow elsewhere lose their antitumor activity after two or three generations of breeding, even though there genetics are similar.  We are also studying the effects of different styles of cooking of these tomatoes and if it reduces antitumor effect

please see post https://news.temple.edu/news/2017-08-28/muse-cancer-fighting-tomatoes-study-italian-food

 

To follow or Tweet on Twitter please use the following handles (@) and hashtags (#):

@ handles


@S_H_R_O 

@SbarroHealth

@Pharma_BI 

@ItalyinPhilly

@WHO_Europe

@nutritionorg

# hashtags


#healthydiet

#MediterraneanDiet

#health

#nutrition

Please see related articles on Live Coverage of Previous Meetings on this Open Access Journal

Real Time Conference Coverage for Scientific and Business Media: Unique Twitter Hashtags and Handles per Conference Presentation/Session

LIVE – Real Time – 16th Annual Cancer Research Symposium, Koch Institute, Friday, June 16, 9AM – 5PM, Kresge Auditorium, MIT

Real Time Coverage and eProceedings of Presentations on 11/16 – 11/17, 2016, The 12th Annual Personalized Medicine Conference, HARVARD MEDICAL SCHOOL, Joseph B. Martin Conference Center, 77 Avenue Louis Pasteur, Boston

Tweets Impression Analytics, Re-Tweets, Tweets and Likes by @AVIVA1950 and @pharma_BI for 2018 BioIT, Boston, 5/15 – 5/17, 2018

BIO 2018! June 4-7, 2018 at Boston Convention & Exhibition Center

LIVE 2018 The 21st Gabay Award to LORENZ STUDER, Memorial Sloan Kettering Cancer Center, contributions in stem cell biology and patient-specific, cell-based therapy

HUBweek 2018, October 8-14, 2018, Greater Boston – “We The Future” – coming together, of breaking down barriers, of convening across disciplinary lines to shape our future

Read Full Post »


The Promise of Low-Dose Aspirin on Longevity in the Geriatric Population: No Effect on Outcomes in the US and Australia

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 10/17/2018

https://www.nejm.org/doi/full/10.1056/NEJMoa1800722

Effect of Aspirin on Disability-free Survival in the Elderly

ORIGINAL ARTICLE

Effect of Aspirin on Disability-free Survival in the Healthy Elderly

J.J. McNeil and Others

    

McNeil et al. conducted the randomized, placebo-controlled Aspirin in Reducing Events in the Elderly (ASPREE) trial to investigate whether the daily use of aspirin, at a dose of 100 mg, in healthy, community-dwelling older adults would prolong a healthy life span, free from dementia and persistent physical disability. Trial participants were community-dwelling men and women from Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States).

Clinical Pearls

  Is there any evidence to support the use of aspirin for primary prevention of cardiovascular or other chronic disease in healthy older adults?

Several large, randomized trials have shown the efficacy of aspirin for the secondary prevention of cardiovascular disease among persons with a history of coronary heart disease or stroke. The evidence supporting a benefit of aspirin therapy in the primary prevention of cardiovascular or other chronic disease is less conclusive despite favorable trends suggesting that aspirin use reduces the incidence of cardiovascular events and possibly reduces the incidence of cancer and cancer-related mortality, particularly from colorectal cancer.

  Does the daily use of 100 mg of aspirin prolong a healthy lifespan in older adults without cardiovascular disease, dementia, or physical disability?

In the ASPREE trial, the daily use of 100 mg of enteric-coated aspirin did not differ significantly from placebo in influencing the rates of disability-free survival at a median of 4.7 years. The primary end point of death, dementia, or physical disability occurred in 921 participants in the aspirin group (21.5 events per 1000 person-years) and in 914 in the placebo group (21.2 events per 1000 person-years). The between-group difference was not significant (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P=0.79). Among participants who had a primary end-point event, death was the most common first event (in 911 participants [50% of the events] at a mean age of 77.5 years), dementia was the next most common (in 549 participants [30% of the events] at a mean age of 77.7 years), and persistent physical disability was the least common.

Morning Report Questions

Q. How does a daily aspirin dose of 100 mg influence rates of death from any cause and the risk of major hemorrhage in healthy older adults?

A. In the ASPREE trial, the secondary end point of death from any cause, denoting death as the first, second, or third event to occur in the primary end point, occurred in 558 participants in the aspirin group (12.7 events per 1000 person-years) and in 494 participants in the placebo group (11.1 events per 1000 person-years) (hazard ratio, 1.14; unadjusted 95% CI, 1.01 to 1.29). Because there was no adjustment for multiple comparisons of secondary end points, no inferences can be made regarding differences in mortality between the two groups. Major hemorrhage occurred in 3.8% of the participants in the aspirin group, as compared with 2.8% of those in the placebo group (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). Fatal or nonfatal hemorrhagic stroke (including subarachnoid hemorrhage) occurred in 49 participants (0.5%) in the aspirin group and in 40 (0.4%) in the placebo group.

Q. How generalizable are the results of the ASPREE trial?

A. White participants comprised 91% of the overall trial cohort. Owing to the small number of blacks and Hispanics (including participants who were younger than 70 years of age) and other nonwhites, the applicability of the main findings of the ASPREE trial to these subgroups is unclear.

 

Daily Low-Dose Aspirin Found to Have No Effect on Healthy Life Span in Older People?

According to 3 articles published online The New England Journal of Medicine (16 September 2018), daily low-dose aspirin was found to have no effect on healthy life span in older people. This large NIH-funded study examined outcomes in United States and Australia

Results showed that in a large clinical trial to determine the risks and benefits of daily low-dose aspirin in healthy older adults without previous cardiovascular events,

Aspirin did not prolong healthy, independent living (life free of dementia or persistent physical disability).

Risk of dying from a range of causes, including cancer and heart disease, varied and will require further analysis and additional follow-up of study participants. These initial findings from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, partially supported by the National Institutes of Health.

ASPREE is an international, randomized, double-blind, placebo-controlled trial that enrolled 19,114 older people (16,703 in Australia and 2,411 in the United States). The study began in 2010 and enrolled participants aged 70 and older; 65 was the minimum age of entry for African-American and Hispanic individuals in the United States because of their higher risk for dementia and cardiovascular disease. At study enrollment, ASPREE participants could not have dementia or a physical disability and had to be free of medical conditions requiring aspirin use. They were followed for an average of 4.7 years to determine outcomes.

In the total study population, treatment with 100 mg of low-dose aspirin per day did not affect survival free of dementia or disability. Among the people randomly assigned to take aspirin,

  • 90.3% remained alive at the end of the treatment without persistent physical disability or dementia, compared with 90.5% of those taking a placebo.
  • Rates of physical disability were similar, and rates of dementia were almost identical in both groups. However,
  • the group taking aspirin had an increased risk of death compared to the placebo group: 5.9% of participants taking aspirin and 5.2% taking placebo died during the study.

This effect of aspirin has not been noted in previous studies; and caution is needed in interpreting this finding. The higher death rate in the aspirin-treated group was due primarily to a higher rate of cancer deaths. A small increase in new cancer cases was reported in the group taking aspirin but the difference could have been due to chance. The authors also analyzed the ASPREE results to determine whether cardiovascular events took place. They found that

  • the rates for major cardiovascular events — including coronary heart disease, nonfatal heart attacks, and fatal and nonfatal ischemic stroke — were similar in the aspirin and the placebo groups. In the aspirin group, 448 people experienced cardiovascular events, compared with 474 people in the placebo group.

Significant bleeding — a known risk of regular aspirin use — was also measured. The authors noted that

  • aspirin was associated with a significantly increased risk of bleeding, primarily in the gastrointestinal tract and brain. Clinically significant bleeding — hemorrhagic stroke, bleeding in the brain, gastrointestinal hemorrhages or hemorrhages at other sites that required transfusion or hospitalization — occurred in 361 people (3.8%) on aspirin and in 265 (2.7%) taking the placebo.
  • As would be expected in an older adult population, cancer was a common cause of death, and 50% of the people who died in the trial had some type of cancer.
  • Heart disease and stroke accounted for 19% of the deaths and major bleeding for 5%.

The ASPREE team is continuing to analyze the results of this study and has implemented plans for monitoring participants. As these efforts continue, the authors emphasized that older adults should follow the advice from their own physicians about daily aspirin use. It is important to note that the new findings do not apply to people with a proven indication for aspirin such as stroke, heart attack or other cardiovascular disease. In addition, the study did not address aspirin’s effects in people younger than age 65. Also, since only 11% of participants had regularly taken low-dose aspirin prior to entering the study, the implications of ASPREE’s findings need further investigation to determine whether healthy older people who have been regularly using aspirin for disease prevention should continue or discontinue use.

SOURCE

From: OnTarget <ontarget@targethealth.com>

Date: September 23, 2018 at 10:47:06 PM EDT

To: avivalev-ari@alum.berkeley.edu

Subject: OnTarget Newsletter

 

Other 121 articles on ASPIRIN were published in this Open Access Online Scientific Journal, including the following:

https://pharmaceuticalintelligence.com/?s=Aspirin

Read Full Post »


UPDATED on 2/25/2019

https://www.medpagetoday.com/cardiology/prevention/78202?xid=nl_mpt_SRCardiology_2019-02 25&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CardioUpdate_022519&utm_term=NL_Spec_Cardiology_Update_Active

 

ICER announced plans to look at icosapent ethyl (Vascepa) and rivaroxaban (Xarelto) as add-on therapies in cardiovascular disease.

Heart attack risk is rising among young women. But NHANES data show women are still ahead of men on control of hypertension, diabetes, and cholesterol. (Circulation)

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

Read Full Post »


A new mechanism of action to attack in the treatment of coronary artery disease (CAD), Novartis developed Ilaris (canakinumab), a human monoclonal antibody targeting the interleukin-1beta innate immunity pathway

Reporter: Aviva Lev-Ari, PhD, RN

 

Speaking at an ESC press briefing, Ridker said, “This is what personalized predictive medicine is all about.” Once a patient has experienced an MI, there is always residual risk of recurrence. Thus, he suggested that residual risk can be divided into

  • residual lipid-driven risk and
  • residual inflammatory-driven risk.

canakinumab might prove to be most useful if it were given to an identified high-responder group. Findings in the hs-CRP responders:

Patients whose hs-CRP declined to 1.8 mg/L or less had a much more robust response. In that subgroup, the number needed to treat to prevent a primary endpoint event was 50 at 2 years and 30 at 3.7 years.

He noted that after a single injection responders have a significant reduction in highly sensitive-CRP and it is those patients who would benefit from continuing on treatment.

“Maybe that first dose could be free,” Ridker added.

Co-investigator, Peter Libby, MD, of Massachusetts General Hospital, put it this way: 30 days after an MI, when a patient is on statin therapy and stable,

  • physicians could check LDL and then initiate more aggressive statin therapy if it is not well-controlled. Similarly,
  • physicians should check hs-CRP, and if it is elevated — 2.0 mg/L or higher — initiating anti-inflammatory therapy targeting interleukin-1 beta would be an option

Interestingly, the treatment had no effect on lipids, which suggests that the benefit was all attributable to the anti-inflammatory activity. 

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), 150 mg of canakinumab every 3 months reduced high-sensitivity C-reactive protein (hs-CRP) levels by an average of 37% compared with placebo and achieved a 15% reduction in cardiovascular events — mostly MIs — compared with placebo, Paul Ridker, MD, reported here at the European Society of Cardiology 2017 congress.

The CANTOS findings were simultaneously published online by the New England Journal of Medicine.

After a median follow-up of 3.7 years, the event rate was 4.5 per 100 person-years in the placebo group versus 3.86 events per 100 person-years in the canakinumab 150 mg group. Two other arms — canakinumab 50 mg and 300 mg — also achieved reductions in events (4.11 and 3.90 per 100 person-years, respectively) but only the 150-mg dose achieved a statistically significant reduction.

There was no reduction in mortality. The trial recruited patients who had a history of MI and a hs-CRP level of 2.0 mg/L or higher.

  • There was no significant difference in all-cause mortality (HR for all canakinumab doses versus placebo, 0.94; 95% CI 0.83-1.06; P=0.31).

Benefits of Anti-inflammatory Canakinumab

although there was no cardiovascular mortality benefit, there was 30% reduction in need for bypass surgery, angioplasty, and heart failure — all of which means a significant improvement in quality of life. And treatment was also associated with a reduction in gout, rheumatoid arthritis, and osteoarthritis, he said.

Cancer Benefit

There was an apparent decrease in risk of cancer, a finding that was elucidated in a Lancet paper also published today. In the cancer analysis, also authored by Ridker, total cancer mortality was lower only in the 300-mg group, but “[i]ncident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0.61 [95% CI 0.39–0.97]; P=0.034) and 300 mg groups (HR 0.33 [95% CI 0.18–0.59] P<0.0001.”

Negative findings

  • Canakinumab was associated with a higher incidence of fatal infection than placebo — the rate was 0.18 in the 3,344 patient placebo group versus 0.32 among the 6,717 patients who received any dose of the drug, which worked out to 23 deaths versus 78 deaths (P=0.02).
  • VIEW VIDEO

Study Author Paul M. Ridker. Interviewed by Peggy Peck, Editor-in-Chief of MedPage Today

https://www.medpagetoday.com/meetingcoverage/esc/67529

  • VIEW VIDEO

Clinical Impact or No Clinical Impact

Anthony DeMaria, MD discusses the major trials from ESC and what impact, if any, they will have on clinical practice.
Benefit vs Price
On June 28 heart failure specialist Milton Packer, MD, wrote this in his MedPage Today blog: “My prediction: [canakinumab] may cost $64,000 for a 15-20% reduction in the risk of a major cardiovascular event, without decreasing cardiovascular death by itself.
Amgen’s Repatha (evolocumab) is a PCSK9 inhibitor that aggressively lowers lipids and is approved for patients who fail statin therapy, including patients with heterozygous or homozygous familial hypercholesterolemia. But while the lipid reductions with the PCSK9 therapy are impressive, and the FOURIER trial found a 15% reduction in events with treatment, neither evolocumab nor alirocumab (Praluent), a PCSK9 inhibitor from Sanofi/Regeneron have achieved wide uptake as payers balk at the high price tags for the drugs.
Other anti-inflammatory agents:
Ridker said. For example, “we have a [National Heart, Lung, and Blood Institute] trial of methotrexate (RA agent) that is on-going. If that proves to be effective, it would be only pennies per treatment.” At the press conference, Ridker said the methotrexate trial has “randomized about 4,000 patients, and we will need to get to 7,000 so it will be a few years before we have results.”

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/67529

176 articles on monoclonal antibody

https://pharmaceuticalintelligence.com/?s=monoclonal+antibody

Read Full Post »

Older Posts »