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Summary of Genomics and Medicine: Role in Cardiovascular Diseases
Author: Larry H. Bernstein, MD, FCAP
The articles within Chapters and Subchapters you have just read have been organized into four interconnected parts.
Genomics and Medicine
Epigenetics – Modifyable Factors Causing CVD
Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Individualized Medicine Guided by Genetics and Genomics Discoveries
The first part established the
rapidly evolving science of genomics
aided by analytical and computational tools for the identification of nucleotide substitutions, or combinations of them
that have a significant association with the development of
cardiovascular diseases,
hypercoagulable state,
atherosclerosis,
microvascular disease,
endothelial disruption, and
type-2DM, to name a few.
These may well be associated with increased risk for stroke and/or peripheral vascular disease in some cases,
essentially because the involvement of the circulation is systemic in nature.
Part 1
establishes an important connection between RNA and disease expression. This development has led to
the necessity of a patient-centric approach to patient-care.
When I entered medical school, it was eight years after Watson and Crick proposed the double helix. It was also
the height of a series of discoveries elucidating key metabolic pathways.
In the period since then there have been treatments for some of the important well established metabolic diseases of
carbohydrate,
protein, and
lipid metabolism,
such as – glycogen storage disease, and some are immense challenges, such as
Tay Sachs, or
Transthyretin-Associated amyloidosis.
But we have crossed a line delineating classical Mendelian genetics to
multifactorial non-linear traits of great complexity and
involving combinatorial program analyses to resolve.
The Human Genome Project was completed in 2001, and it has opened the floodgates of genomic discovery. This resulted in the identification of
genomic alterations in
cardiovascular disease,
cancer,
microbial,
plant,
prion, and
metabolic diseases.
This has also led to
the identification of genomic targets
that are either involved in transcription or
are involved with cellular control mechanisms for targeted pharmaceutical development.
In addition, there is great pressure on the science of laboratory analytics to
codevelop with new drugs,
biomarkers that are indicators of toxicity or
of drug effectiveness.
I have not mentioned the dark matter of the genome. It has been substantially reduced, and has been termed dark because
this portion of the genome is not identified in transcription of proteins.
However, it has become a lightning rod to ongoing genomic investigation because of
an essential role in the regulation of nuclear and cytoplasmic activities.
Changes in the three dimensional structure of these genes due to
changes in Van der Waal forces and internucleotide distances lead to
conformational changes that could have an effect on cell activity.
Part 2
is an exploration of epigenetics in cardiovascular diseases. Epigenetics is
the post-genomic modification of genetic expression
by the substitution of nucleotides or by the attachment of carbohydrate residues, or
by alterations in the hydrophobic forces between sequences that weaken or strengthen their expression.
This could operate in a manner similar to the conformational changes just described. These changes
may be modifiable, and they
may be highly influenced by environmental factors, such as
smoking and environmental toxins,
diet,
physical activity, and
neutraceuticals.
While neutraceuticals is a black box industry that evolved from
the extraction of ancient herbal remedies of agricultural derivation (which could be extended to digitalis and Foxglove; or to coumadin; and to penecillin, and to other drugs that are not neutraceuticals).
The best examples are the importance of
n-3 fatty acids, and
fiber
dietary sulfur (in the source of methionine), folic acid, vitamin B12
arginine combined with citrulline to drive eNOS
and of iodine, which can’t be understated.
In addition, meat consumption involves the intake of fat that contains
the proinflammatory n-6 fatty acid.
The importance of the ratio of n-3/n-6 fatty acidsin diet is not seriously discussed when
we look at the association of fat intake and disease etiology.
Part 2 then leads into signaling pathways and proteomics.The signaling pathways are
critical to understanding the inflammatory process, just as
dietary factors tie in with a balance that is maintained by dietary intake,
possibly gut bacteria utilization of delivered substrate, and
proinflammatory factors in disaease.
These are being explored by microfluidic proteomic and metabolomic technologies that were inconceivable a half century ago.
This portion extended into the diagnosis of cardiovascular disease, and
elucidated the relationship between platelet-endothelial interaction in the formation of vascular plaque.
It explored protein, proteomic, and genomic markers
for identifying and classifying types of disease pathobiology, and
for following treatment measures.
Part 3
connected with genetics and genomic discoveries in cardiovascular diseases.
Part 4
is the tie between life style habits and disease etiology, going forward with
the pursuit of cardiovascular disease prevention.
The presentation of walking and running, and of bariatric surgery (type 2DM) are fine examples.
It further discussed gene therapy and congenital heart disease. But the most interesting presentations are
in the pharmacogenomics for cardiovascular diseases, with
volyage-gated calcium-channels, and
ApoE in the statin response.
This volume is a splendid example representative of the entire collection on cardiovascular diseases.
Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases
Author and Curator: Larry H Bernstein, MD, FCAP
This introduction is to a thorough evaluation of a rich source of research literature on the genomic influences, which may have variable strength in the biological causation of atherosclerosis, microvascular disease, plaque formation, not necessarily having expressing, except in a multivariable context that includes the environment, dietary factors, level of emotional stress, sleep habits, and the daily activities of living for affected individuals. The potential of genomics is carried in the DNA, copied to RNA, and this is most well studied in the micro RNAs (miRNA). The miRNA has been explored for the appearance in the circulation of specific miRNAs that might be associated with myocyte or endothelial cell injury, and they are also being used as targets for therapeutics by the creation of silencing RNAs (siRNA). The extent to which there is evidence of success in these studies is limited, but is being translated from animal studies to human disease. There is also a long history of the measurement of circulating enzymes and isoenzymes (alanine amino transferase, creatine kinase, and lactate dehydrogenase, not to leave out the adenylate kinase species specific to myocardium), and more recently the release of troponins I and T, and the so far still not fully explored ischemia modified albumin, or of miRNAs for the diagnosis of myocardial infarction.
There is also a significant disagreement about the value of measuring high sensitivity C reactive protein (hs-CRP), which has always been a marker for systemic inflammatory disease, in both chronic rheumatic and infectious diseases having a broad range, so that procalcitonin has appeared to be better for that situation, and for early diagnosis of sepsis. The hs-CRP has been too easily ignored because of
1. the ubiquitous elevations in the population
2. the expressed concerns that one might not be inclined to treat a mild elevation without other risk factors, such as, LDL cholesterolemia, low HDL, absent diabetes or obesity. Nevertheless, hs-CRP raises an reasonable argument for preventive measures, and perhaps the use of a statin.
There has been a substantial amount of work on the relationship of obesity to both type 2 diabetes mellitus (T2DM) and to coronary vascular disease and stroke. Here we bring in the relationship of the vascular endothelium, adipose tissue secretion of adiponectin, and platelet activation. A whole generation of antiplatelet drugs addresses the mechanism of platelet activation, adhession, and interaction with endothelium. Very interesting work has appeared on RESISTIN, that could bear some fruit in the treatment of both obesity and T2DM.
It is important to keep in mind that epigenomic gene rearrangements or substitutions occur throughout life, and they may have an expression late in life. Some of the known epigenetic events occur with some frequency, but the associations are extremely difficult to pin down, as well as the strength of the association. In a population that is not diverse, epigenetic changes are passed on in the population in the period of childbearing age. The establishment of an epigenetic change is diluted in a diverse population. There have been a number of studies with different findings of association between cardiovascular disease and genetic mutations in the Han and also in the Uyger Chinese populations, which are distinctly different populations that is not part of this discussion.
This should be sufficient to elicit broad appeal in reading this volume on cardiovascular diseases, and perhaps the entire series. Below is a diagram of this volume in the series.
PART 1 – Genomics and Medicine
Introduction to Genomics and Medicine (Vol 3)
Genomics and Medicine: The Physician’s View
Ribozymes and RNA Machines
Genomics and Medicine: Genomics to CVD Diagnoses
Establishing a Patient-Centric View of Genomic Data
VIDEO: Implementing Biomarker Programs P Ridker
PART 2 – Epigenetics – Modifiable
Factors Causing CVD
Diseases Etiology
Environmental Contributors
Implicated as Causing CVD
Diet: Solids and Fluid Intake
and Nutraceuticals
Physical Activity and
Prevention of CVD
Psychological Stress and
Mental Health: Risk for CVD
Correlation between
Cancer and CVD
PART 3 Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Introduction
Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)
Functional Characterization of CV Genomics: Disease Case Studies @ 2013 ASHG
Leading DIAGNOSES of CVD covered in Circulation: CV Genetics, 3/2010 – 3/2013
Commentary on Biomarkers for Genetics and Genomics of CVD
PART 4 Individualized Medicine Guided by Genetics and Genomics Discoveries
Medical Etiologies: EBM – LEADING DIAGNOSES, Risks
Pharmacogenomics for Cardio-
vascular Diseases
Signaling Pathways
Response to Rosuvastatin in
Patients With Acute Myocardial Infarction:
Hepatic Metabolism and Transporter Gene
Variants Effect http://pharmaceuticalintelligence.com/2014/
01/02/response-to-rosuvastatin-in-patients-
with-acute-myocardial-infarction-hepatic-
metabolism-and-transporter-gene-variants-effect/
Proteomics and Metabolomics
Voltage-Gated Calcium Channel and Pharmaco-
genetic Association with Adverse Cardiovascular
Outcomes: Hypertension Treatment with Verapamil
SR (CCB) vs Atenolol (BB) or Trandolapril (ACE) http://pharmaceuticalintelligence.com/2014/01/02/
voltage-gated-calcium-channel-and-pharmacogenetic-
association-with-adverse-cardiovascular-outcomes-
hypertension-treatment-with-verapamil-sr-ccb-vs-
atenolol-bb-or-trandolapril-ace/
These presentations covered several views of the utilization of cardiac markers that have evolved for over 60 years. The first stage was the introduction of enzymatic assays and isoenzyme measurements to distinguish acute hepatitis and acute myocardial infarction, which included lactate dehydrogenase (LD isoenzymes 1, 2) at a time that late presentation of the patient in the emergency rooms were not uncommon, with the creatine kinase isoenzyme MB declining or disappeared from the circulation. The world health organization (WHO) standard definition then was the presence of two of three:
1. Typical or atypical precordial pressure in the chest, usually with radiation to the left arm
2. Electrocardiographic changes of Q-wave, not previously seen, definitive; ST- elevation of acute myocardial injury with repolarization;
T-wave inversion.
3. The release into the circulation of myocardial derived enzymes –
creatine kinase – MB (which was adapted to measure infarct size), LD-1,
both of which were replaced with troponins T and I, which are part of the actomyosin contractile apparatus.
The research on infarct size elicited a major research goal for early diagnosis and reduction of infarct size, first with fibrinolysis of a ruptured plaque, and this proceeded into the full development of a rapidly evolving interventional cardiology as well as cardiothoracic surgery, in both cases, aimed at removal of plaque or replacement of vessel. Surgery became more imperative for multivessel disease, even if only one vessel was severely affected.
So we have clinical history, physical examination, and emerging biomarkers playing a large role for more than half a century. However, the role of biomarkers broadened. Patients were treated with antiplatelet agents, and a hypercoagulable state coexisted with myocardial ischemic injury. This made the management of the patient reliant on long term followup for Warfarin with the international normalized ratio (INR) for a standardized prothrombin time (PT), and reversal of the PT required transfusion with thawed fresh frozen plasma (FFP). The partial thromboplastin test (PPT) was necessary in hospitalization to monitor the heparin effect.
Thus, we have identified the use of traditional cardiac biomarkers for:
1. Diagnosis
2. Therapeutic monitoring
The story is only the beginning. Many patients who were atypical in presentation, or had cardiovascular ischemia without plaque rupture were problematic. This led to a concerted effort to redesign the troponin assays for high sensitivity with the concern that the circulation should normally be free of a leaked structural marker of myocardial damage. But of course, there can be a slow leak or a decreased rate of removal of such protein from the circulation, and the best example of this would be the patient with significant renal insufficiency, as TnT is clear only through the kidney, and TNI is clear both by the kidney and by vascular endothelium. The introduction of the high sensitivity assay has been met with considerable confusion, and highlights the complexity of diagnosis in heart disease. Another test that is used for the diagnosis of heart failure is in the class of natriuretic peptides (BNP, pro NT-BNP, and ANP), the last of which has been under development.
While there is an exponential increase in the improvement of cardiac devices and discovery of pharmaceutical targets, the laboratory support for clinical management is not mature. There are miRNAs that may prove valuable, matrix metalloprotein(s), and potential endothelial and blood cell surface markers, they require
1. codevelopment with new medications
2. standardization across the IVD industry
3. proficiency testing applied to all laboratories that provide testing
4. the measurement on multitest automated analyzers with high capability in proteomic measurement (MS, time of flight, MS-MS)
Platelet Endothelial Aggregation Receptor-1 (PEAR1) Gene to be most strongly associated with Dual Antiplatelet Therapy Response: Genetic Determinants of Variable Response to Aspirin (alone and in combination with Clopidogrel)
Reporter: Aviva Lev-Ari, PhD, RN
4 Genetic Variation in PEAR1 is Associated with Platelet Aggregation and Cardiovascular Outcomes
1University of Maryland School of Medicine, Baltimore, MD
2Sinai Hospital of Baltimore, Baltimore, MD
3Johns Hopkins University School of Medicine, Baltimore, MD
4Sinai Hospital of Baltimore & Johns Hopkins University School of Medicine, Baltimore, MD
5University of Florida College of Pharmacy, Gainesville, FL
6University of Florida College of Medicine, Gainesville, FL
7University of Maryland School of Medicine & Veterans Administration Medical Center, Baltimore, MD
↵* University of Maryland School of Medicine & Veterans Administration Medical Center, Baltimore, MD ashuldin@medicine.umaryland.edu
Abstract
Background-Aspirin or dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard therapy for patients at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known.
Methods and Results-We measured ex-vivo platelet aggregation before and after DAPT in individuals (n=565) from the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study and conducted a genome-wide association study (GWAS) of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in two independent aspirin-treated cohorts: 227 percutaneous coronary intervention (PCI) patients, and 1,000 patients of the International VErapamil SR/trandolapril Study (INVEST) GENEtic Substudy (INVEST-GENES). GWAS revealed a strong association between single nucleotide polymorphisms on chromosome 1q23 and post-DAPT platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with DAPT response (P=7.66×10-9). In Caucasian and African American patients undergoing PCI, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared to GG homozygotes (hazard ratio = 2.62, 95%CI 0.96-7.10, P=0.059 and hazard ratio = 3.97, 95%CI 1.10-14.31, P=0.035 respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared to GG homozygotes (OR=2.03, 95%CI 1.01-4.09, P=0.048).
Conclusions – Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin, alone and in combination with clopidogrel.
Clinical Trial Registration Information-clinicaltrials.gov; Identifiers:NCT00799396 and NCT00370045
This article is a segment in several articles about platelets, platelet function, and advances in applying the surge of knowledge to therapy. In acute coronary syndromes, plaque rupture leads to thrombotic occlusion. We have also seen that the development of a plaque occurs in 3 stages, only the last of which involves plaque rupture. Platelets interact with the vascular endothelium, and platelet-endothelial as well as platelet-platelet interactions are known to be important in atherogenesis. We learned that platelets are derived from megakaryocytes that break up and these elements are released into the blood stream. It has recently been discovered that platelets can replicate in the circulation. The turnover of platelets is rapid, and platelets sre stored at room temperature with shaking, and are viable for perhaps only 3-4 days once they are received in the blood bank for use. In cardiology, the identification, isolation, and characterization of GPIIb/IIIa from the platelet was a huge advance in the potential for coronary intervention, and that potential became of paramount importance with the introduction of GPIIb/IIIa inhibitors as a standard in coronary vascular therapeutic procedures. The following manuscript by Barry Coller, at Rockefeller University, is a presentation of the GPIIb/IIIa story as an excellent example of Translational Medicine.
Search for GPIIb/IIIa inhibitor of the (anti-αIIb133 (GPIIb/IIIa) receptor)
The deliberate search for drugs to inhibit the αIIb133 (GPIIb/IIIa) receptor ushered in the era of rationally designed antiplatelet therapy and thus represents an important milestone in the evolution of antiplatelet drug development. The selection of the αIIb133 receptor as a therapeutic target rested on a broad base of basic and clinical research conducted by many investigators in the 1960s and 1970s working in the fields of platelet physiology, the rare bleeding disorder Glanzmann thrombasthenia, platelet membrane glycoproteins, integrin receptors, coronary artery pathology, and experimental thrombosis. Thus, αIIb133 was found to mediate platelet aggregation by virtually all of the physiology agonists (e.g., ADP, epinephrine, and thrombin) through a mechanism in which platelet activation by these agents results in a change in the conformation of the receptor. This is followed by increased affinity of the receptor for the multivalent ligands fibrinogen and von Willebrand factor, both of which are capable of binding to receptors on two platelets simultaneously, producing platelet crosslinking and aggregation. At about the same time, experimental studies demonstrated platelet thrombus formation at sites of vascular injury, and biochemical studies in humans demonstrated evidence of platelet activation during acute ischemic cardiovascular events.
Our own studies initially focused on platelet-fibrinogen interactions using an assay in which normal platelets agglutinated fibrinogen-coated beads. The agglutination was enhanced with platelet activators. Platelets from patients with Glanzmann thrombasthenia, who lack the αIIb133 receptor, did not agglutinate the beads. We adapted this assay to a microtiter plate system to identify monoclonal antibodies that inhibited platelet-fibrinogen interactions and then demonstrated that these antibodies bound to αIIb133. They were also more potent inhibitors of platelet aggregation than any known antiplatelet agent and produced a pattern of aggregation that was virtually identical to that found using platelets from patients with Glanzmann thrombasthenia.
I recognized the theoretical potential of using an antibody to inhibit platelets in vivo but also recognized the challenges and limitations. Since experimental models of thrombosis had been developed in the dog, and since the antibody we initially worked with did not react with dog platelets, we had to go back to our original samples to identify an antibody (7E3) that reacted with dog platelets in addition to human platelets. Since coating platelets with immunoglobulins results in their rapid elimination of the platelets from the circulation, and since the clearance is mediated by the immunoglobulin Fc region, we prepared F(ab’)2 fragments of 7E3 for our in vivo studies. Additional challenges included preparing large quantities of antibody on a very limited budget and purifying the antibodies so they contained only minimal amounts of endotoxin. With the small amount of 7E3-F(ab’)2 we initially prepared, we were able to show dose response inhibition of platelet aggregation in three dogs, achieving greater inhibition than with aspirin or ticlopidine, the only antiplatelet agents approved for human use at that time. We also devised an assay using radiolabeled 7E3 to quantify the percentage of platelet αIIbβ3 receptors that were blocked when a specific dose of 7E3-F(ab’)2 was administered in vivo. This allowed us to directly measure the effect of the agent on its target receptor on its target cell.
I considered two criteria most important in selecting the initial animal models in which to test the efficacy and safety of administering 7E3-F(ab’)2:
1) the model had to convincingly simulate a human vascular disease, and
2) aspirin had to have failed to produce complete protection from thrombosis.
The latter criterion was particularly important because I planned to stop this line of research if the 7E3-F(ab’)2 was not more efficacious than aspirin.
Ultimately, we collaborated with Dr. John Folts of the University of Wisconsin, who had developed a dog model of unstable angina by attaching a short cylindrical ring to partially occlude a coronary artery and using a hemostat to induce vascular injury. Pretreatment of the animal with 7E3-F(ab’)2 was more effective than aspirin or any other compound Dr. Folts had previously tested in preventing platelet thrombus formation,as judged by its effects on the characteristic repetitive cycles of platelet deposition and embolization. Electron microscopy of the vessels confirmed the reduction in platelet thrombi by 7E3-F(ab’)2, with only a monolayer of platelets typically deposited.
Dr. Chip Gold and his colleagues at Massachusetts General Hospital had developed a dog model to assess the effects of tissue plasminogen activator (t-PA) on experimental thrombi induced in the dog coronary artery. Although t-PA was effective in lysing the thrombi, the blood vessels rapidly reoccluded with new thrombi that were rich in platelets. Aspirin could not prevent reocclusion, whereas 7E3-F(ab’)2 not only prevented reocclusion, but also increased the speed of reperfusion by t-PA.
The next steps in drug development could not be performed in my laboratory because they required resources far in excess of those in my grant from the National Heart, Lung, and Blood Institute to study basic platelet physiology. As a result, in 1986 the Research Foundation of the State University of New York licensed the 7E3 antibody to Centocor, Inc., a new biotechnology company specializing in the diagnostic and therapeutic application of monoclonal antibodies.
Subsequent Development of 7E3
The subsequent development of 7E3 as a therapeutic agent required extensive collaboration among myself, a large number of outstanding scientists at Centocor, and many leading academic cardiologists. Many decisions and hurdles remained for us, including the decision to develop a mouse/human chimeric 7E3 Fab (c7E3 Fab); the design and execution of the toxicology studies; the assessment of the potential toxicity of 7E3 crossreactivity with αVβ3; the development of sensitive and specific assays to assess immune responses to c7E3 Fab; the design, execution, and analysis of the Phase I, II, and III studies; and the preparation, submission, and presentation of the Product Licensing Application to the Food and Drug Administration, and comparable documents to European and Scandinavian agencies.
Based on the results of the 2,099 patient EPIC trial, in which conjunctive treatment with a bolus plus infusion of c7E3 Fab significantly reduced the risk of developing an ischemic complication (death, myocardial infarction, or need for urgent intervention) after coronary artery angioplasty or atherectomy in patients at high risk of such complications, the Food and Drug Administration approved the conjunctive use of c7E3 Fab (generic name, abciximab) in high-risk angioplasty and atherectomy on December 22, 1994. Since then it has been administered to more than 2.5 million patients in the U.S., Europe, Scandinavia, and Asia. Its optimal role in treating cardiovascular disease continues to evolve in response to the introduction of new anticoagulants, antiplatelet agents, stents, and procedures.
Extended Investigations
We have also been able to apply the monoclonal antibodies we prepared to αIIb33 to the prenatal detection of Glanzmann thrombasthenia, and have used the antibodies as probes for characterizing both the biogenesis of the receptor and the conformational changes that the receptor undergoes with activation. We have been able to precisely map the 7E3 epitope on 33, providing additional insights into the mechanism by which it prevents ligand binding. We have also exploited the ability of another antibody to αIIb33 to stabilize the receptor complex in order to facilitate production of crystals of the αIIb33 headpiece; the x-ray diffraction properties of these crystals were studied in collaboration with Dr. Timothy Springer’s group at Harvard and provide the first structural information on the receptor.
In landmark studies in the 1980s, Pierschbacher and Ruoslahti demonstrated the importance of the arginine-aspartic acid (RGD) sequence in the interaction of the integrin α531 with fibronectin, and they went on to show that peptides with the RGD sequence could inhibit this interaction. Subsequent studies by many groups demonstrated that these peptides could also inhibit the interaction of platelet αIIb33 with fibrinogen and von Willebrand factor. Dr. David Phillip and Dr. Robert Scarbrough led the team at Cor Therapeutics that made a cyclic pentapeptide with high selectivity for αIIb33 over αV33 by patterning their compound on the KGD sequence in the snake venom barbourin. The resulting antiplatelet agent, eptifibatide, received FDA approval in May 1998. At Merck, Dr. Robert Gould led the team that developed the nonpeptide RGD-mimetic tirofiban, which also is selective for αIIb33 compared to αV33. It also received FDA approval in May 1998. Our recent x-ray crystallographic studies in collaboration with Dr. Springer’s group provided structural information on the mechanisms and sites of binding of these drugs with αIIb33.
Translation of Basic Science into Therapy
Many important elements and an enormous amount of good fortune were needed for the translation of the basic science information about platelet aggregation into the drug abciximab, including, but not limited to:
1) the support of basic studies of platelet physiology by the National Institutes of Health in my laboratory and many other laboratories,
2) the creation and ongoing funding of a core facility available to all faculty members to prepare monoclonal antibodies at the State University of New York at Stony Brook under the direction of Dr. Arnold Levine,
3) the 1988 Bayh-Dole Act and its subsequent amendments, and the expertise of the Technology Transfer Office at Stony Brook in licensing 7E3 to Centocor, which then provided the capital and additional expertise required for its development, and
4) the expert and enthusiastic collaboration by two large and disciplined cooperative groups of interventional cardiologists (TAMI, EPIC) under the dynamic leadership of Drs. Eric Topol and Rob Califf,
tirofiban, that were eager to test the safety and efficacy of the 7E3 derivatives. Although the translation of each new scientific discovery into improved health via novel preventive, diagnostic, or therapeutic strategies requires the blazing of a unique path, optimizing these elements and similar ones may allow the path to be shorter and/or to be traversed more easily, at a lower cost, or in a shorter period of time.
Attend this session if you want:
To take part in an informative, lively and balanced debate about the two most burning unresolved questions in interventional medicine today
Coronary bioresorbable scaffolds: what is their role in today’s clinical practice?
Dual antiplatelet therapy. Which drug? For which patient? For which stent? For how long?
Aspirin-clopidogrel combination no better than aspirin alone.
Antiplatelet drugs such as aspirin are routinely prescribed to help prevent new strokes in people with a history of lacunar stroke. The Secondary Prevention of Small Subcortical Strokes (SPS3) trial was designed to determine if adding clopidogrel to aspirin would offer better protection than aspirin alone. The results appear in the Aug. 30th New England Journal of Medicine.* They show that the aspirin-clopidogrel combination was about equal to aspirin in reducing the risk of any type of stroke, but it almost doubled the risk of gastrointestinal bleeding.
“For all stroke therapeutics, there is a need to balance the potential benefits against the risks. The SPS3 findings establish that for lacunar stroke, dual therapy with aspirin and clopidogrel carries significant risk and minimal benefit,” said Walter Koroshetz, M.D., deputy director of National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
In addition to comparing dual antiplatelet therapy with aspirin, the trial was designed to test two levels of blood pressure control. After an interim data analysis in August 2011, the antiplatelet component of the trial was stopped. NIH also issued a clinical alert, warning that there was “little likelihood of benefit in favor of aspirin plus clopidogrel [for] recurrent stroke should the study continue to conclusion.” The blood pressure component of the trial is ongoing, and the trial participants have been encouraged to continue taking aspirin without clopidogrel.
Strokes occur when blood vessels that supply the brain rupture or become blocked, such as by a blood clot. Antiplatelet drugs interfere with the formation of blood clots.
Lacunar strokes occur due to chronic high blood pressure, which in turn leads to progressive narrowing and finally blockage of small arteries that supply deep brain structures. They account for up to one-fifth of all strokes and are especially common among African-Americans, Hispanics and people with diabetes. Although lacunar strokes tend to produce relatively small lesions, they can cause disability depending on where they occur in the brain.
The SPS3 trial involves more than 3,000 participants at 82 clinical centers in North and South America and in Spain. The participants are age 30 and older, and all had a recent history of lacunar stroke prior to enrollment. About 52 percent are white, 31 percent Hispanic and 17 percent black.
For the antiplatelet component of the trial, about half of the participants received 325 milligrams of aspirin and 75 milligrams of clopidogrel daily, and the other half received aspirin and placebo. The participants were also randomly assigned to receive either standard control of systolic blood pressure (less than 130 mm Hg) or aggressive control (130-149 mm Hg).
After eight years of study, the annual risk of recurrent stroke was 2.7 percent in the aspirin-only group and 2.5 percent in the aspirin plus clopidogrel group. Most of the recurrent strokes in both groups were lacunar strokes. The rate of serious or life-threatening internal bleeding was 1.1 percent in the aspirin group and 2.1 percent in the dual therapy group. The difference was due mostly to a higher number of gastrointestinal bleeds in the dual therapy group. The percentage of brain bleeds in the two groups was not significantly different. Deaths from any cause were also higher in the aspirin-clopidogrel group.
For both groups, stroke recurrence was lower than the investigators had expected. When the SPS3 trial began in 2003, another large trial that tested warfarin vs. aspirin for stroke prevention had just ended. Warfarin is an anticoagulant, another class of drugs that interferes with blood clotting. That trial, called the Warfarin vs. Aspirin Recurrent Stroke Study (WARSS), found that patients with a history of lacunar strokes who took aspirin had an annual stroke recurrence rate of about 7 percent. (Warfarin and aspirin were about equal.)
This reflects a common trend, Dr. Benavente said. “What we see more and more often in stroke prevention trials is a significant decrease in stroke risk, compared to data from 10 years ago. We have better medications now to control stroke risk factors such as high blood pressure and cholesterol, and these are clearly having an impact.”
In prior studies, antiplatelet drugs including aspirin or clopidogrel alone, or a combination of aspirin and dipyridamole, have been shown to reduce stroke risk in patients with heart disease or prior stroke. In one trial, aspirin combined with clopidogrel was more effective than aspirin alone at reducing stroke risk in patients with atrial fibrillation, a type of abnormal heart rhythm. However, other trials involving broader stroke populations found no added benefit from combining aspirin and clopidogrel. Therefore, current practice guidelines recommend aspirin alone, clopidogrel alone, or aspirin plus dipyridamole for secondary prevention after most types of stroke. The SPS3 results are consistent with those guidelines.
Researchers continue to investigate whether the clopidogrel-aspirin combination might be beneficial for patients with other types of stroke, such as transient ischemic attack (TIA). This is a type of stroke in which symptoms fade away in less than 24 hours; it is also a warning that a more damaging stroke may be imminent. The Platelet-Oriented Inhibition in New TIA (POINT) trial is testing whether aspirin plus clopidogrel are effective at preventing major strokes when given within 12 hours of a TIA. That trial is also funded by NINDS.
WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulantion and Coronary Stenting): Get Rid Of The Aspirin In Triple Therapy
According to current guidelines and clinical practice, PCI patients already taking an oral anticoagulant generally end up on triple therapy comprising the anticoagulant plus clopidogrel and aspirin. However, there is no supporting evidence base for this approach and the triple therapy regimen is known to increase bleeding complications. Now a new study– the first randomized trial to address this situation, according to the investigators– may have a large impact on clinical practice by demonstrating that the omission of aspirin in this context appears to be safe and may reduce adverse events.
Results of the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulantion and Coronary Stenting) trial were presented by Willem Dewilde at the ESC in Munich today. Investigators in the Netherlands and Belgium randomized 573 patients to triple therapy or dual therapy of an anticoagulant plus clopidogrel for at least one month after implantation of a bare-metal stent or one year after a drug-eluting stent. Two-thirds of the patients were receiving oral anticoagulation for atrial fibrillation.
The primary endpoint, the total number of bleeding events, was dramatically reduced in the dual therapy group at one year:
44.9% in the triple therapy group versus 19.5% (HR 0.36, CI 0.26-0.50)
There were 3 intracranial bleeds in each group. Most of the difference in bleeding occurred in TIMI minor and minimal bleeding. The difference in TIMI major bleeding (3.3% versus 5.8%) did not achieve statistical significance.
Clinical events, the trials’s secondary endpoint, were numerically lower in the dual therapy group. The difference in mortality achieved statistical significance.
Mortality: 7 deaths (2.6%) in the dual therapy group versus 18 deaths (6.4%) in the triple therapy group, p=0.027
MI: 3.3% versus 4.7%, p=0.382
TVR: 7.3% versus 6.8%, p=0.876
Stroke: 1.1% versus 2.9%, p=0.128)
Stent thrombosis: 1.5% versus 3.2%, p=0.165
“The WOEST study demonstrates that omitting aspirin leads to less bleedings but does not increase the risk of stent thrombosis, stroke or myocardial infarction,” said Dewilde in an ESC press release. “Although the number of patients in the trial is limited, this is an important finding with implications for future treatment and guidelines in this group of patients known to be at high risk of bleeding and thrombotic complications.”
David Holmes said the trial addressed “an incredibly important issue” and predicted that it would “change the way we practice medicine, it will change practice right away.” Keith Fox said that the evidence base prior to WOEST was extremely limited and that the trial showed that there was no hazard in doing without aspirin. The ESC discussant, Marco Valgimigli, said the trial showed it was safe to drop aspirin and provided another demonstration that “we have hit the wall” with anticoagulation.
Republished with permission from CardioExchange, a NEJM group publication.
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
MUNICH — For patients with unstable angina or non-ST-segment elevation myocardial infarction (non-STEMI) who do not undergo revascularization, increasing platelet inhibition may not improve outcomes, a randomized trial showed.
Added to a background of low-dose aspirin, prasugrel (Effient) did not significantly reduce the rate of MI, stroke, or cardiovascular death compared with clopidogrel (13.9% versus 16%, HR 0.91, 95% CI 0.79 to 1.05), according to Matthew Roe, MD, of Duke University in Durham, N.C.
The risk of severe bleeding was similar with both drugs, although minor and moderate bleeding were increased with prasugrel, Roe reported at the European Society of Cardiology meeting here. The findings were published simultaneously online in the New England Journal of Medicine.
“I think the outcome is a bit surprising because we think usually that more aggressive antiplatelet therapy, conceivably, in the face of an acute coronary syndrome and non-ST-elevation would lead to lesser adverse outcome from acute myocardial infarction or death,” said William Zoghbi, MD, from Methodist DeBakey Heart Center in Houston and president of the American College of Cardiology.
But he said clinicians need to respect the data “and start thinking about pathogenesis and what we’re trying to do with any of our new interventions.”
In patients with unstable angina or non-STEMI, practice guidelines call for angiography within 48 to 72 hours with provisional revascularization. Many of these patients do not ultimately undergo revascularization, placing them at greater risk compared with those who have their arteries opened with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG).
Recommended medical therapy is with clopidogrel and aspirin, which is an approach that will not change from the current findings, Zoghbi said.
The purpose of the TRILOGY ACS trial was to explore whether using a more powerful platelet inhibitor — prasugrel — would improve outcomes compared clopidogrel (Plavix) in this high-risk patient subset.
The primary analysis involved 7,243 patients younger than 75 (mean age 62) who were receiving aspirin and were randomized to prasugrel 10 mg daily (or 5 mg daily for those weighing less than 132 pounds) or to clopidogrel 75 mg daily. The researchers recommended a daily aspirin dose of 100 mg or less.
A secondary, exploratory analysis involved 2,083 patients, 75 or older, who were randomized to prasugrel 5 mg daily or to clopidogrel 75 mg daily.
The lack of efficacy seen in the primary analysis of patients younger than 75 remained when patients of all ages were combined. There were no between-group differences for any of the components of the primary endpoint.
A prespecified secondary analysis taking multiple recurrent ischemic events into consideration showed a lower risk of MI, stroke, and cardiovascular death with prasugrel in the younger patients (HR 0.85, 95% CI 0.72 to 1.00, P=0.04), a finding consistent with the main results of the TRITON-TIMI 38 trial, which involved patients treated with PCI. The apparent benefit appeared after 12 months of treatment.
“Although this observation is exploratory, it raises the question of whether investigation of the multiplicity of ischemic events is warranted in future secondary-prevention trials, rather than solely analyzing the time to the first event, as has been traditional in studies involving patients who have had an acute coronary event,”the researchers wrote.
Rates of GUSTO severe or life threatening bleeding and TIMI major bleeding — as well as intracranial hemorrhage — were similar in the two groups in both the younger patients and in the overall study population. When minor and moderate bleeding events were added, the bleeding rate was higher with prasugrel.
There were no widespread differences between the groups in rates of nonhemorrhagic serious adverse events, but heart failure was more frequent with clopidogrel (1.8% versus 1.3%, P=0.045).
Douglas Weaver, MD, of Henry Ford Health System, said that he does not think the findings will have any impact on the use of prasugrel, which is not indicated for the patient population included in the study.
“It just doesn’t pass muster in improving value over clopidogrel,” said Weaver, a past president of the American College of Cardiology.
From a clinical perspective, he said, an important message from the study is the evidence of the safety of a reduced dose of prasugrel in the patients 75 and older, which is a consideration when prescribing prasugrel for patients undergoing PCI.
In comments following Roe’s presentation, Raffaele De Caterina, MD, PhD, of the G. d’Annunzio University in Chieti, Italy, provided context about how the findings fit in with the rest of the literature.
He compared the current results to those of a substudy of the PLATO trial, which involved ticagrelor (Brilinta).
In that trial, ticagrelor significantly reduced vascular death, MI, and stroke (HR 0.85, 95% CI 0.73 to 1.00, P=0.045) — the primary endpoint — and all-cause death (HR 0.75, 95% CI 0.61 to 0.93).
He then highlighted the ESC guidelines on treating patients with acute coronary syndromes without persistent ST-segment elevation.
In those, ticagrelor is recommended for all patients at moderate-to-high risk of ischemic events, regardless of initial treatment strategy and including those pre-treated with clopidogrel, and prasugrel is recommended for those who have not taken another P2Y12 inhibitor, who have a known coronary anatomy, and who are proceeding to PCI.
“I believe such statements and recommendations of the guidelines should not be changed,” De Caterina said.
Roe reported relationships with Daiichi Sankyo, Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck, Hoffmann-La Roche, and sanofi-aventis. The other authors reported numerous relationships with industry.
Prematurely halted ALTITUDE trial showed When added to monotherapy with either an ACE inhibitor or an angiotensin receptor blocker (ARB), aliskiren (Tekturna) did not improve outcomes in patients with type 2 diabetes who had high cardiovascular and renal risk
ESC: Aliskiren Onboard No Help in T2D
By Todd Neale, Senior Staff Writer, MedPage Today
Published: August 26, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
MUNICH — When added to monotherapy with either an ACE inhibitor or an angiotensin receptor blocker (ARB), aliskiren (Tekturna) did not improve outcomes in patients with type 2 diabetes who had high cardiovascular and renal risk, the prematurely halted ALTITUDE trial showed.
Through an average follow-up of 32 months, a composite of various cardiovascular and renal outcomes occurred in 17.9% of patients receiving the direct renin inhibitor and 16.8% of those receiving placebo (HR 1.08, 95% CI 0.98 to 1.20), according to Hans-Henrik Parving, MD, DMSc, of the University of Copenhagen and Aarhus University in Denmark.
As a Hot Line presentation European Society of Cardiology meeting here, Parving reported that there were no significant differences on any of the individual components of the endpoint — cardiovascular death, resuscitated sudden death, MI, stroke, unplanned hospitalization for heart failure, doubling of baseline serum creatinine, and onset of end-stage renal disease — or all-cause death.
The rate of stroke — mostly ischemic stroke — was numerically higher with aliskiren, although the result fell short of statistical significance (3.4% versus 2.8%; HR 1.25, 95% CI 0.98 to 1.60,P=0.07).
Thus, Parving said, using aliskiren with ACE inhibitors or ARBs in these high-risk patients “is not recommended and may even be harmful.”
The data monitoring committee for the ALTITUDE trial decided to stop the study early in December 2011 both for futility and for adverse events. Then, earlier this year, the FDA issued a warning about using aliskiren with ACE inhibitors or ARBs and changed the drug label to reflect a contraindication for such combinations in patients with diabetes or renal impairment.
The trial included 8,561 patients with type 2 diabetes who had a high risk of cardiovascular or renal disease who were randomized to aliskiren — at 150 mg daily for 1 month followed by 300 mg daily thereafter — or placebo in addition to monotherapy with either an ACE inhibitor or an ARB (but not both).
Adding aliskiren did not improve outcomes, and in fact, may have caused harm, Parving said, as indicated by the apparent increase in stroke risk.
He said that could be explained by the impaired autoregulation of patients with diabetes or by chance, as there are no indications of a stroke risk in other studies of the drug.
Johannes Mann, of Friedrich Alexander University in Erlangen, Germany, and McMaster University in Hamilton, Ontario, who served as the discussant following Parving’s presentation, agreed that it could be a chance finding, but said that it could also be a direct effect of aliskiren itself.
He concluded that the stroke risk was not explained, however, by dual renin system inhibition, because such a signal was not seen in the ONTARGET trial, which compared the combination of ramipril (an ACE inhibitor) and telmisartan (an ARB) with each drug as monotherapy.
As noted when the trial was halted last year, adverse events were more frequent in the aliskiren group.
The percentage of patients who had a potassium level of 5.5 to less than 6.0 mmol/L was greater with active treatment (21% versus 16%), as was the percentage of those with a potassium level of 6.0 mmol/L or greater (8.8% versus 5.6%).
Aliskiren carried higher risks of hyperkalemia (38.7% versus 28.6%), hypotension (12.1% versus 8%), diarrhea (9.6% versus 7.2%), and falls (2.8% versus 2.6%). There was one death caused by hyperkalemia.
Douglas Weaver, MD, of the Henry Ford Health System in Detroit, said that the findings were disappointing, but that they likely wouldn’t change how aliskiren is used in practice.
“I don’t think this is going to have a negative or a positive effect on it,” said Weaver, who is a past president of the American College of Cardiology.
ALTITUDE was sponsored by Novartis Pharma AG.
The executive committee and other investigators or their institutions received a consultancy fee. Some of the authors are employees of Novartis and therefore eligible for stock and stock options.
Primary source: European Society of Cardiology
Source reference:
Parving H-H, et al “The Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE)” ESC 2012; Abstract 399.
Aliskiren (INN) (trade names Tekturna, U.S.; Rasilez, U.K. and elsewhere) is the first in a class of drugs called direct renin inhibitors. Its current licensed indication is essential (primary) hypertension.
In December 2011, Novartis had to halt a clinical trial of the drug after discovering increased incidence of non-fatal stroke, renal complications, hyperkalemia and hypotension in patients with diabetes and renal impairment.[4]
The following recommendations are being added to the drug labels for aliskiren-containing products as of 4/20/12:
I) A new contraindication against the use of aliskiren with ARBs or ACEIs in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia. II) A warning to avoid use of aliskiren with ARBs or ACEIs in patients with moderate to severe renal impairment (i.e., where glomerular filtration rate [GFR] < 60 mL/min).
Mechanism of Action
Renin is the first enzyme in the renin-angiotensin-aldosterone system which plays a role in blood pressure control. Renin cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) toangiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following thereby increasing plasma volume and blood pressure.
Aliskiren binds to the S3bp binding pocket of renin, essential for its activity.[5] Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I.
Many drugs control blood pressure by interfering with angiotensin or aldosterone. However, when these drugs are used chronically, the body increases renin production, which drives blood pressure up again. Therefore, doctors have been looking for a drug to inhibit renin directly. Aliskiren is the first drug to do so.[7][8]
Aliskiren may have renoprotective effects that are independent of its blood pressure−lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. According to the AVOID study, researchers found that treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). Furthermore, the AVOID trial shows that treatment with 300 mg of aliskiren daily reduces albuminuria in patients with hypertension, type 2 diabetes, and proteinuria who are receiving the recommended maximal renoprotective treatment with losartan and optimal antihypertensive therapy. Therefore, direct renin inhibition will have a critical role in strategic renoprotective pharmacotherapy, in conjunction with dual blockade of the renin−angiotensin−aldosterone system with the use of ACE inhibitors and angiotensin II–receptor blockers, very high doses of angiotensin II−receptor blockers, and aldosterone blockade.[9]
Rarely: allergic swelling of the face, lips or tongue and difficulty breathing
Contraindications
Pregnancy: other drugs such as ACE inhibitors, also acting on the renin-angiotensin system have been associated with fetal malformations and neonatal death[10]
Breast feeding: during animal studies, the drug has been found present in milk.[10]
Aliskiren has not yet been evaluated in patients with significantly impaired renal function.
Drug interactions
Aliskiren is a minor substrate of CYP3A4 and, more important, P-glycoprotein:
Atorvastatin may increase blood concentration, however no dose adjustment needed.
Possible interaction with ciclosporin (the concomitant use of ciclosporin and aliskiren is contraindicated).
Caution should be exercised when aliskiren is administered with ketoconazole or other moderate P-gp inhibitors (itraconazole, clarithromycin, telithromycin, erythromycin, amiodarone).
Doctors should stop prescribing aliskiren-containing medicines to patients with diabetes (type 1 or type 2) or with moderate to severe kidney impairment who are also taking an ACE inhibitor or ARB, and should consider alternative antihypertensive treatment as necessary.[11]
References
^ Gradman A, Schmieder R, Lins R, Nussberger J, Chiang Y, Bedigian M (2005). “Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients”. Circulation111 (8): 1012–8. doi:10.1161/01.CIR.0000156466.02908.ED. PMID15723979.
^ Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. “Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy,” N Engl J Med 2008;358:2433-46.
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