Bleeding Risk Reduction
Guest
|
Studies
May 24, 2015 8:02:28 GMT -6
Post by Bleeding Risk Reduction on May 24, 2015 8:02:28 GMT -6
New Data on Bleeding Risk Reduction Strategies in Anticoagulation Therapy Data from 3 separate trials presented at an American Heart Association Late-Breaking Session focused on potential ways to reduce the risk for bleeding in patients who require anticoagulation therapy. Newly published data were presented for the EU-PACT and COAG trials, which examined the use of genetic tests to optimize warfarin dosing, and the ENGAGE TIMI-AF 48 study for the factor Xa inhibitor edoxaban versus warfarin. Approximately 25 million Americans take warfarin. Maintaining patients’ dosing within a narrow therapeutic range is critical to optimizing its safety and effectiveness. Dosing that is too low puts patients at increased risk for clots, but too high dosing creates an increased risk for bleeding. Genetics-Guided Dosing “The problem with warfarin is that we can’t determine what the individual dose should be,” said trial investigator Munir Pirmohamed, MD, PhD, lead author of the EU-PACT study and NHS chair of pharmacogenetics, University of Liverpool. Various factors determine the individual dosing requirements for warfarin. About 50% to 55% of the daily dosing requirement can be explained by 2 genetic factors, CYP2C9 and VKORC1, Dr Pirmohamed said. The US Food and Drug Administration changed the labels in 2010 to include recommendations concerning dosing that are based on these factors, he said; however, current guidelines do not recommend genotyping for warfarin dosing. EU Pharmacogenetics of Anticoagulant Therapy (EU-PACT)1 The European study compared the use of genetics to guide warfarin dosing with usual dosing methods, which depend on frequent blood testing to measure the therapeutic range. A total of 455 patients were randomized to either the genotype-guided dosing arm or standard dosing and were followed for 3 months. Most patients were males (61%) with a mean age of 67 years. The majority of patients had atrial fibrillation (AF; 72%). Primary end point results showed that genotyping was associated with a 7% increase in the time patients were within therapeutic range (67.4% vs 60.3% for the genotyping and standard arms, respectively; P <.001). Genotyping was also associated with a reduction in over-coagulation, time to reach the therapeutic range, and time to reach a stable dose. “Our study very much fits in with the concept of personalized medicine, which aims to get the right drug, at the right dose, to the right patient,” Dr Pirmohamed said. The Clarification of Optimal Anticoagulation Through Genetics (COAG) Trial2 “Warfarin has served as a model for pharmacogenetics,” said lead COAG investigator Stephen Kimmel, MD, professor of medicine and epidemiology, University of Pennsylvania School of Medicine. In the COAG trial, researchers randomized 1015 patients with histories of stroke, venous thrombosis, and AF to 1 of 2 groups to determine the incremental effect of using genetic information to guide dosing. One group had dosing adjustments based on both genetic information and clinical information (eg, age, weight, and smoking status), while the other group’s dosing decisions were based only on clinical information. Patients were followed for up to 6 months. Patients’ average age was 57 years; 51% were male; 27% were African American; 22% had AF; and 58% had deep vein thrombosis in the legs or lungs. Results showed no differences in the primary end point of percent time within therapeutic range (approximately 45% for both groups). There were significant differences, however, for African Americans. In this population, those receiving therapy based on genetics didn’t do as well as those who did not use genetics (35.2% vs 34.1%, respectively; P = .01). “There is huge potential in the cardiovascular field for personalizing therapy on the basis of genetic or non-genetic tests,” Dr Kimmel said. “For genetic testing, in some cases it may be possible to undertake the testing at the bedside or in surgery, so called point-of-care tests as we did in this trial. We need evidence from randomized controlled trials to show the utility of genetic testing.” Novel Oral Anticoagulant Alternative3 The ENGAGE-TIMI 48 inferiority trial included 21,105 patients with AF who were randomized to 1 of 3 groups: warfarin, the factor Xa inhibitor edoxaban 30 mg/day, or edoxaban at 60 mg/day. The primary end point was a composite of stroke, systemic embolic events (SEEs), and major bleeding, according to lead trial investigator Robert P. Giugliano, MD, SM, FAHA, FACC of Brigham and Women’s Hospital, who presented the results. The data showed that both doses of edoxaban met the primary end point for noninferiority. The higher dose was associated with a 21% reduction in stroke and SEE (P <.001). With the secondary efficacy end points, both doses were associated with significant reductions in hemorrhagic stroke (P <.001). For the primary safety end point, International Society of Thrombosis and Hemostasis (ISTH) major bleeding, the high dose was associated with a 20% reduction, and the low dose a 53% reduction. Both the high and low doses of edoxaban were also associated with significant reductions in intracranial hemorrhaging (53% and 70%, respectively; P <.001). “Atrial fibrillation is a common problem among the elderly, and as Americans live longer we need safer, yet effective treatments,” Dr Giugliano said. Currently, edoxaban is approved only in Japan. All 3 studies were published online ahead of print in the New England Journal of Medicine to coincide with this late-breaking session. References: 1. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin [published online November 19, 2013]. N Engl J Med. doi:10.1056/NEJMoa1311386. 2. Kimmel SE, French, B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing [published online November 19, 2013]. N Engl J Med. doi:10.1056/NEJMoa1310669. 3. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban vs warfarin in patients with atrial fibrillation [published online November 19, 2013]. N Engl J Med. doi:10.1056/NEJMoa1310907. www.ajmc.com/conferences/AHA2013/New-Data-on-Bleeding-Risk-Reduction-Strategies-in-Anticoagulation-Therapy |
|
Personalized Medicine
Guest
|
Studies
May 24, 2015 8:03:41 GMT -6
Post by Personalized Medicine on May 24, 2015 8:03:41 GMT -6
Personalized Medicine a Cost-Effective Way to Tailor Drug Therapy After Stents
Computer Simulation Shows that Knowing Patients’ Genetic Profiles Can Save Money, Improve Outcomes
By Pete Farley on February 19, 2014
Genetic testing can help doctors choose the most effective and economical drugs to prevent blood clots in the half a million patients in the U.S. who receive coronary stents each year, according to a new study led by a UC San Francisco researcher.
The work, reported in the February 18, 2014 Annals of Internal Medicine, demonstrates that genetically guided personalized medicine, often perceived as pricier than traditional approaches, can both lower costs and increase the quality of health care.
Dhruv Kazi, MD, MSc, MS
“Our results counter the general perception that personalized medicine is expensive,” said Dhruv Kazi, MD, MSc, MS, assistant professor of medicine at UCSF and first author of the new study. “What we have shown is that individualizing care based on genotype may in fact be very cost-effective in some settings, because it allows us to target the use of newer, more expensive drugs to the patients who are most likely to benefit from them.”
According to the American Heart Association, about 500,000 patients per year in the U.S. receive stents to open up coronary arteries after experiencing unstable angina or a heart attack. These patients routinely begin a one-year regimen of aspirin taken daily in combination with a prescription antiplatelet medication, a dual therapy that can significantly reduce the risk of stent-clogging clots by preventing blood cells known as platelets from sticking together.
Historically, most patients have taken aspirin in combination with clopidogrel (trade name Plavix), but the effectiveness of that drug in preventing clotting and recurrent cardiovascular problems varies considerably among patients. One cause of this variability is that clopidogrel is a “pro-drug”: to work it must first be activated by a liver enzyme known as CYP2C19, and it is therefore less effective in patients who carry genetic variations that reduce the activity of the CYP2C19 gene. Approximately 28 percent of the population carries these genetic variations, which are known as loss-of-function alleles.
Two newer drugs, prasugrel (Effient) and ticagrelor (Brilinta), prevent clotting more reliably than clopidogrel in most patients, but they are considerably more expensive, and they can have troublesome side effects. Prasugrel can cause fatal bleeding in some patients, and ticagrelor can cause uncomfortable shortness of breath.
Juggling these variables of effectiveness, expense, side effects, and genetic factors has made it challenging for doctors to choose the right drug for their patients, particularly since neither the benefit of genetic testing forCYP2C19 variants nor the relative advantages of prasugrel versus ticagrelor have been tested in randomized clinical trials.
In the new research, Kazi and colleagues built a computer simulation based on 100,000 hypothetical 65-year-old patients receiving stents for heart problems. The model incorporated more than 100 quantitative parameters that might affect the choice of anti-platelet therapy, including clinical data from the medical literature and Medicare claims, procedure and hospitalization costs from national datasets, as well as actuarial information from published life tables.
Taking all this information into account, the model showed that, in most health care settings, genotyping for the loss-of-function CYP2C19 allele before prescribing either prasugrel or ticagrelor would be more cost-effective than treating all patients with either of these drugs or with clopidogrel. Of all treatment strategies evaluated in the model, the targeted use of ticagrelor for patients with loss-of-function alleles, and generic clopidogrel for other patients appears to be the most cost-effective at a population level.
But Kazi emphasizes that one of the model’s greatest strengths is its flexibility in accommodating differences in clinical settings. “The way we’ve constructed our model allows patients and institutions to make decisions based on their own numbers rather than national averages,” he explained. “An institution can say, ‘This is what the drugs cost us, and this is our cost of genotyping,’ and decide whether genotyping makes sense in their own ecosystem.”
For example, if an institution buys ticagrelor in bulk at a relatively low cost, it may make sense for that institution to use that drug in all patients without additional expenditures for genotyping. Likewise, because loss-of-function alleles in CYP2C19 are much more frequent in patients with ancestry in South and East Asia and Oceania than in those of European or African ancestry, in health care settings with large populations of such patients genotype-guided treatment may be less cost-effective than simply treating all patients with ticagrelor.
“Current trends suggest that we can expect the cost of genotyping to go down, and the cost of newer therapies to go up in the future,” said Kazi, who is affiliated with the Division of Cardiology at San Francisco General Hospital. “So personalized medicine may become even more economically attractive in years to come.”
In addition to Kazi and senior author Mark A. Hlatky, MD, professor of health policy and of medicine at Stanford University School of Medicine, researchers from Harvard University, Harvard Medical School, the University of Pittsburgh Medical Center, Stanford Graduate School of Business, and the Veterans Affairs Palo Alto Health Care System took part in the study.
Funding for the research was from the American Heart Association, the U.S. Department of Veterans Affairs, Stanford University, and UCSF.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital.
|
|
|
|
Studies
May 24, 2015 8:04:50 GMT -6
Post by Plavix Suits on May 24, 2015 8:04:50 GMT -6
Insight & Intelligence™ : Apr 3, 2014
Plavix Suits Target Personalized Medicine
States sue BMS, Sanofi over drug’s effects on subpopulations.
Alex Philippidis
Drug developers have long trumpeted the potential of personalized medicine to revolutionize disease treatment by targeting new drugs to patients most likely to benefit. Now, the tangle of lawsuits nationwide over Plavix (clopidrogel) threatens to turn personalized medicine into a weapon against the biopharma industry.
In addition to plaintiffs from 24 states and the District of Columbia filing dozens of lawsuits linking Plavix to injuries or wrongful deaths, attorneys general in five U.S. states—California, Hawaii, Louisiana, Mississippi, and West Virginia—have sued Plavix co-developers Bristol-Myers Squibb (BMS) and Sanofi, accusing the companies of lying to authorities about the blockbuster blood thinner’s ability to treat specific subpopulations.
While many state lawsuits cite elderly users as being at-risk, Hawaii and its Attorney General David M. Louie accuse BMS and Sanofi of promoting the drugs despite research showing diminished effect on two key segments of the Aloha State’s population—East Asians (38.6% of Hawaii’s population in the 2010 U.S. Census) and Pacific Islanders (10%); another 23.6% are of mixed race.
BMS and Sanofi refuse comment on the Hawaii suit while touting Plavix’ track record: “Plavix is one of the most studied medicines with over a decade of real-world experience in patients with acute coronary syndrome, recent stroke, recent heart attack, and peripheral arterial disease (PAD). Plavix has been prescribed to more than 115 million patients worldwide, including more than 50 million in the United States.”
Plavix generated 2013 sales of $2.811 billion, most of it overseas. In the U.S., where patent protection ended in 2012, sales plummeted from $2.5 billion in 2012 to $258 million last year.
Additional billions are at stake, if the percentage of Hawaii’s population that was prescribed Plavix equals the 16% of all Americans. Hawaii seeks civil penalties of up to $31,000 per patient, including $10,000 per elderly patient for “repeated and willful violation” of UDAP. Multiply that by 16% of Hawaii’s population of 1,360,301, and you get $6.8 billion—not counting the unspecified punitive damages and disgorgement of profits also sought by the state.
The Plavix lawsuits are unlikely to slow down personalized medicine by making biopharma companies reconsider developing new drugs for subsets of the general population. “It may even have a positive impact because the pharmaceutical companies will understand that it is in their collective interests to share noncompetitive data,” Edward Abrahams, Ph.D., president of the Personalized Medicine Coalition, told GEN.
“How pharmaceutical companies share data with each other and the public on nonresponders, that is an ongoing issue that the industry faces. It’s an extremely competitive industry and they’re not conditioned to easily just share information,” Dr. Abrahams acknowledged, adding that “they are moving in that direction” through research consortia and clinical collaborations.
Raju Kucherlapati, Ph.D., Paul C. Cabot professor in the Harvard Medical School Department of Genetics, notes that industry has long ago changed its drug development paradigm toward addressing targeted populations.
“Many drugs are now approved for subsets of patients who are most likely to respond to such a drug. Examples of this include herceptin in breast cancer, tarceva in lung cancer, zalkori in lung cancer, vemurafinib in melanoma and so on,” said Dr. Kucherlapati, also a professor in the Department of Medicine at Brigham and Women’s Hospital, and a member of the Presidential Commission for the Study of Bioethical Issues. “It is my understanding that most of the new cancer drugs that are in development are associated with the use of one or more biomarkers. This trend will continue.”
Alleles and Ethnicity
Hawaii argued that BMS and Sanofi “have known or should have known of additional information regarding Plavix’ diminished or complete lack of effectiveness in many patients since at least March 1998,” when the companies began marketing the drug.
Several studies have linked diminished response to Plavix in some patients with alleles of the Cytochrome P450 2C19 (CYP2C19) liver enzyme. A team led by David A. Flockhart, M.D., Ph.D., of Indiana University School of Medicine published a 2002 study in Clinical Pharmacokinetics finding that CYP2C19*2 was the most frequent CYP2C19 allele (95%), with LOF alleles seen in 40% of blacks and more than 55% of East Asians, compared with about 30% of whites.
Those percentages differ somewhat from earlier studies showing 33% of African Americans and 51% of Asians populations with at least one copy of CYP2C19*2—and are well below figures printed on Plavix’ product label, stating that “published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites, 4% for blacks, and 14% for Chinese,” unaccompanied by a footnote—though the Chinese figure matches that of a 2000 study by Hong-Guang Xie, M.D., Ph.D., in the journal Life Sciences.
Should the Plavix cases advance beyond procedural arguments, BMS and Sanofi can be expected to play up differences in the percentages, to suggest lack of consensus or shortcomings in the research. Plaintiffs will likely argue the variation reflects study differences. Or they could take the tack of a 2012 meta-analysis of 16 studies including 7,035 patients carrying more than one CYP2C19 loss-of-function allele, and 13,750 patients with the wild-type genotype.
Kyoung-Im Cho, M.D., Ph.D., led a team that found higher odds of adverse clinical events in Asians with LOF variants of CYP2C19, while acknowledging differences in clinical significance according to patient ethnicity. But those differences didn’t diminish the study’s key finding that associated carrier status for LOF CYP2C19 with an increased risk of adverse clinical events in Plavix users with coronary artery disease.
A team led by Jessica L. Mega, M.D., and Marc S. Sabatine, M.D., concluded that *2 and other common polymorphisms in the CYP2C19 gene “significantly diminish both the pharmacokinetic and pharmacodynamic responses to clopidogrel by approximately one quarter to one third.” Those findings were published January 2009 in the New England Journal of Medicine.
Seven months later in Journal of the American Medical Association, a study linked CYP2C19*2 to diminished platelet response to Plavix and poorer cardiovascular outcomes: “The strength of effect of CYP2C19*2 genotype on clopidogrel response may depend on other factors such as genetic background or environmental exposures, which may differ among ethnic groups,” Alan R. Shuldiner, M.D., and colleagues concluded.
By 2009, the FDA added to Plavix’ label a caution that the drug’s effectiveness was diminished in poor metabolizers. That caution was strengthened in 2010 to a black box warning that advises doctors to “consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.”
Hawaii and other states have cited the black box warning and CYP2C19 studies as part of their complaints, which allege that BMS and Sanofi mismarketed Plavix and covered up unfavorable safety and efficacy data, thus putting profits ahead of patients, a contention the companies have denied.
Effect on Elderly
Several of the lawsuits have linked elderly patients to increased risk of problems associated from Plavix. A “master” complaint filed by dozens of New York plaintiffs faulted the companies for burying within the product label statistics on the population percentage experiencing major bleeding events after taking a Plavix-aspirin combination—2.5% in patients under age 65; 4.1% in patients ages 65–74; and 5.9% from age 75 onward. The percentages for placebo-aspirin patients were 2.1% for <65 years, 3.1% for ≥65 to <75 years, and 3.6% for ≥75 years.
Yet as the product label notes, the rate of major bleeding events “was dose-dependent on aspirin,” rising from 2.6% for patients taking less than 100 mg, to 4.9% for patients taking more than 200 mg.
Those findings come from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. CURE results published in the New England Journal of Medicine in 2001 indicated that larger percentages of patients older than age 65 also had increased risks of a first primary outcome, specifically death from cardiovascular causes, nonfatal myocardial infarction, or stroke—though that was true of both Plavix and placebo users. For the 6,208 patients older than 65, 15.3% of placebo users and 13.3% of Plavix users had an event, compared with 7.6% of placebo users and 5.4% of Plavix users among the 6,354 patients 65 or younger.
Courts hearing the Plavix cases will decide whether the CURE results reflect specific harm to elderly patients. Interestingly, the study published from the single Phase III trial that underpinned FDA’s 1997 approval of Plavix—Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE)—did not detail how many patients were over age 65; patients were grouped by stroke, recent heart attack, or peripheral arterial disease.
How courts decide harm to subpopulations attributable to Plavix could affect how much further study of subpopulations drug developers will need for new treatments, potentially raising costs and timeframes for new medicines, two measures that personalized medicine is designed to reduce.
© 2013 Genetic Engineering & Biotechnology News, All Rights Reserved
|
|
|
|
Studies
May 24, 2015 8:05:51 GMT -6
Post by Racial disparity on May 24, 2015 8:05:51 GMT -6
Am Heart J. 2013 Aug;166(2):266-72. doi: 10.1016/j.ahj.2013.04.008. Epub 2013 May 23.
Racial disparity with on-treatment platelet reactivity in patients undergoing percutaneous coronary intervention.
Pendyala LK1, Torguson R, Loh JP, Devaney JM, Chen F, Kitabata H, Minha S, Barbash IM, Suddath WO, Satler LF, Pichard AD, Waksman R.
Abstract
BACKGROUND:
On-treatment platelet reactivity to clopidogrel is variable and in part genetic dependent. In African American (AA) patients, the relation between on-treatment platelet reactivity to clopidogrel and the factors that influence this interaction is unknown. The present study aims to evaluate on-treatment platelet reactivity to clopidogrel in AA patients and its interaction to race and CYP2C19*2 loss of function mutation.
METHODS:
The study cohort included 289 consecutive patients presenting for percutaneous coronary intervention who were entered into a prospective observational registry. High on-treatment platelet reactivity (HTPR) was defined as P2Y12 reaction units (PRU) ≥208 with VerifyNow P2Y12 assay and >50% by vasodilator-stimulated phosphoprotein phosphorylation assay platelet reactivity index (VASP PRI) measured 6 to 24 hours postprocedure. CYP2C19*2 (rs4244285) genotype was analyzed by real-time polymerase chain reaction.
RESULTS:
The prevalence of HTPR by both PRU (56% vs 35%, P = .003) and VASP PRI (67% vs 45%, P = .002) is more common in AAs compared with whites, respectively. African American patients had higher on-treatment mean PRU (207 ± 110 vs 160 ± 102, P = .002) and VASP PRI (49 ± 26 vs 38 ± 26, P = .004). African Americans also had a higher prevalence of CYP2C19*2 allele carrier status compared with whites (43% vs 29%, P = .04). African American race (P = .008) and CYP2C19*2 allele status (P = .02) independently had significant effects on PRU and VASP. Multivariable logistic regression analysis has shown that both CYP2C19*2 allele carrier status and AA race were independent correlates of HTPR for PRU ≥208.
CONCLUSIONS:
African American patients undergoing percutaneous coronary intervention not only have a higher prevalence of HTPR to clopidogrelbut also have higher CYP2C19*2 allele carrier status compared with whites. Careful selection of antiplatelet agents should be considered in an AA population at higher risk for ischemic complications.
Copyright © 2013 Mosby, Inc. All rights reserved.
|
|
Launches Genetic-Testing Progr
Guest
|
Studies
May 24, 2015 8:06:51 GMT -6
Post by Launches Genetic-Testing Progr on May 24, 2015 8:06:51 GMT -6
UMMC Launches Genetic-Testing Program for Cardiac Stent Patients Source: UMMC Launches Genetic-Testing Program for Cardiac Stent Patients | University of Maryland Medical Center umm.edu/news-and-events/news-releases/2013/genetic-testing-program#ixzz3IA8eQjzw University of Maryland Medical Center New personalized medicine initiative enables doctors to tailor drug therapies to individual patients based on genetic profile Patients with coronary artery disease who undergo treatment at the University of Maryland Medical Center now can receive long-term therapy based on information found in their genes. As part of a new personalized medicine initiative, the medical center is offering genetic testing to help doctors determine which medication a patient should take after a stenting procedure in order to prevent blood clots that could lead to serious – and potentially fatal – heart attacks and strokes. Patients with suspected heart disease undergo coronary catheterization to identify blocked or narrow arteries. Tiny tubes, or stents, are often placed in the arteries to keep them open, and, after surgery, patients typically take antiplatelet drugs, such as clopidogrel (Plavix), to prevent platelets – blood cells produced in bone marrow – from sticking together and forming clots. Now, patients who undergo coronary catheterization at UMMC and the Baltimore VA Medical Center, both of which are affiliated with the University of Maryland School of Medicine, can elect to be tested for variations in a gene called CYP2C19. Up to one-fourth of the U.S. population carries at least one abnormal copy of the CYP2C19 gene, and research has shown that as a result, these individuals do not metabolize the standard anti-clotting medication clopidogrel effectively. “There is strong clinical data to support pharmacogenetic testing in regard to antiplatelet therapy,” says Alan R. Shuldiner, M.D., the John L. Whitehurst Endowed Professor of Medicine, associate dean for personalized medicine and director of the Program in Personalized and Genomic Medicine at the University of Maryland School of Medicine. “It’s time to incorporate genetics into the complex medical decisions that we make on behalf of our patients.” In 2009, Dr. Shuldiner led a University of Maryland study, published in JAMA, which showed that patients with a CYP2C19 gene variation exhibited reduced clinical benefit from taking clopidogrel. Based on growing clinical evidence reported in Dr. Shuldiner’s study and others, the U.S. Food and Drug Administration issued a warning about the reduced efficacy of clopidogrel in people with the genetic variation. “Pharmacogenetic testing enables us to tailor drug treatments to individual patients based on their unique genetic makeup, or genotype,” says Dr. Shuldiner, an endocrinologist and geneticist. “With genotype-directed therapy, we have the ability to change the ‘one size fits all’ approach to prescribing medication and ultimately improve the quality of care we provide to our patients. Patients want personalized and individualized medicine. They seek it out.” The test is performed by analyzing the patient’s DNA, isolated from a blood sample, in a new state-of-the-art translational genomics laboratory at the University of Maryland School of Medicine. The tests are being conducted as part of a National Institutes of Health (NIH)-funded study to determine the best way to implement genetic-testing programs. Tests are free, and because of the partnership between UMMC and the University of Maryland School of Medicine, results are available within a few hours. Dr. Shuldiner explains that the ability to provide test results within hours is crucial because cardiac stent patients are at risk for developing blood clots and other complications soon after they have the procedure. “This rapid turnaround time sets our program apart from other programs and commercial laboratories, where results may not be available for up to two weeks,” he adds. Pharmacogenomics – how genes affect a person’s response to drugs – is a burgeoning area of research, but only a small number of hospitals in the United States have programs to offer routine genetic testing as part of their clinical practice. This new approach to patient care is part of the University of Maryland School of Medicine’s pursuit of more individualized, or personalized, medical treatment. E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine, says, “Personalized medicine is the future of health care, and we want to be at the forefront of not only advancing the science of genomics, but also using that knowledge in a clinical setting for the benefit of patients. Our Program in Personalized and Genomic Medicine, under Dr. Shuldiner’s direction, is helping to lead the way with this new genetic-testing initiative, created in partnership with the University of Maryland Medical Center and the Baltimore VA Medical Center.” The University of Maryland launched its initiative in conjunction with a multi-center implementation study, the Translational Pharmacogenetics Project, funded by the NIH Pharmacogenomics Research Network (U01HL105198). Five other major hospitals across the United States are taking part in the study to evaluate the process for building such pharmacogenetic-testing programs. “We plan to share lessons learned at our respective sites and to develop best practices for implementation of pharmacogenetics in everyday clinical practice. We are putting together a toolbox that will be useful to other institutions,” says Dr. Shuldiner, who is leading the multi-center study. Cardiologists Mark R.Vesely, M.D., and Shawn W. Robinson, M.D., assistant professors of medicine at the School of Medicine who care for patients at UMMC and the Baltimore VA Medical Center, are co-investigators. It is expected that the test for the CYP2C19 gene variation will become standard care for all patients who receive stents at both medical centers once the initial research phase is completed. Cardiologists receive guidelines on how to interpret the test results and recommendations for choosing medications. It is up to them to determine the most appropriate treatment for their patients, who might have other medical conditions that need to be considered. The test results also are entered in the electronic medical record, where they can be accessed by other physicians. “Knowing a patient’s genotype is helping us to make more informed decisions for our patients,” Dr. Vesely says. “A combination of aspirin and clopidogrel is the routine choice of medications many physicians will prescribe for their stent patients. But patients who are likely to have a poor or moderate response may be better protected by other medications or possibly a higher dose of clopidogrel. It comes down to what is best for each patient." According to Dr. Vesely, limitations for the alternative medications include their association with higher bleeding rates. “The cost of the medications could also be a factor if patients cannot afford alternative medications or will not take them as prescribed.” Newer anti-clotting medications, such as prasugrel (Effient) and ticagrelor (Brilinta), are more expensive than Plavix, which has been available as a generic since May 2012. Dr. Robinson notes that the response from patients to genetic testing has been positive. “Patients have been very receptive to discovering this new information about themselves that can possibly have a positive impact on their future cardiovascular health,” he says. Dr. Shuldiner anticipates that the initiative will be expanded to include tests for other genes that may affect how patients respond to medications such as warfarin, an anticoagulant; simvastatin, a cholesterol-lowering drug; and codeine, a pain reliever. “Providing tailored therapy will better meet the health needs of patients and reduce the harmful side effects that can occur when a person is taking the wrong medication,” he says. The University of Maryland School of Medicine’s Personalized and Genomic Medicine Program was established in April 2011 to help facilitate the pace of discovery in personalized and genomic medicine; to accelerate the translation of these new discoveries to improve patient care; and to enhance the training and education of future generations of physicians and scientists. The program is funded jointly by the School of Medicine and University of Maryland Medical Center. |
|
|
|
Studies
May 24, 2015 8:07:44 GMT -6
Post by Variability on May 24, 2015 8:07:44 GMT -6
J Am Coll Cardiol. 2014 Jul 29;64(4):361-8. doi: 10.1016/j.jacc.2014.03.051.
Variability of individual platelet reactivity over time in patients treated with clopidogrel: insights from the ELEVATE-TIMI 56 trial.
Hochholzer W1, Ruff CT2, Mesa RA2, Mattimore JF2, Cyr JF2, Lei L3, Frelinger AL 3rd4, Michelson AD4, Berg DD2, Angiolillo DJ5, O'Donoghue ML2, Sabatine MS2, Mega JL6.
Abstract
BACKGROUND:
The degree of antiplatelet response to clopidogrel has been associated with clinical outcomes. Studies have investigated whether adjustment of antiplatelet therapies based on a single platelet function test is beneficial.
OBJECTIVES:
The aim of the study was to test the stability of platelet reactivity measurements over time among patients treated with standard and double doses of clopidogrel.
METHODS:
The ELEVATE-TIMI 56 (Escalating Clopidogrel by Involving a Genetic Strategy-Thrombolysis In Myocardial Infarction 56) investigators genotyped 333 patients with coronary artery disease and randomized them to various clopidogrel regimens. Patients with at least 2 platelet function results on the same maintenance dose of clopidogrel (75 mg or 150 mg) were analyzed. Platelet aggregation was measured using P2Y12 reaction units (PRU).
RESULTS:
In total, the mean platelet reactivity and the total number of nonresponders (PRU ≥230) with clopidogrel did not change between 2 periods for the 75-mg (22.4% vs. 21.9%; p = 0.86) and 150-mg doses of clopidogrel (11.5% vs. 11.5%; p = 1.00). In contrast, when evaluating each patient individually, 15.7% of patients taking clopidogrel 75 mg and 11.4% of patients taking 150 mg had a change in their responder status when tested at 2 different time points (p < 0.001). Despite being treated with the same dose of clopidogrel, >40% of patients had a change in PRU >40 on serial sampling, which approximates the average PRU difference caused by increasing the clopidogrel dose from 75 mg to 150 mg.
CONCLUSIONS:
Measurements of platelet reactivity vary over time in a significant proportion of patients. Thus, treatment adjustment according to platelet function testing at a single time point might not be sufficient for guiding antiplatelet therapy in clinical or research settings. (Escalating Clopidogrel by Involving a Genetic Strategy-Thrombolysis In Myocardial Infarction 56 [ELEVATE-TIMI 56]; NCT01235351).
Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
|
|
Warfarin genotyping
Guest
|
Studies
May 24, 2015 8:08:45 GMT -6
Post by Warfarin genotyping on May 24, 2015 8:08:45 GMT -6
J Am Coll Cardiol. 2010 Jun 22;55(25):2804-12
Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study).
Epstein RS1, Moyer TP, Aubert RE, O Kane DJ, Xia F, Verbrugge RR, Gage BF, Teagarden JR.
Abstract
OBJECTIVES:
This study was designed to determine whether genotype testing for patients initiating warfarin treatment will reduce the incidence of hospitalizations, including those due to bleeding or thromboembolism.
BACKGROUND:
Genotypic variations in CYP2C9 and VKORC1 have been shown to predict warfarin dosing, but no large-scale studies have prospectively evaluated the clinical effectiveness of genotyping in naturalistic settings across the U.S.
METHODS:
This national, prospective, comparative effectiveness study compared the 6-month incidence of hospitalization in patients receiving warfarin genotyping (n = 896) versus a matched historical control group (n = 2,688). To evaluate for temporal changes in the outcomes of warfarin treatment, a secondary analysis compared outcomes for 2 external control groups drawn from the same 2 time periods.
RESULTS:
Compared with the historical control group, the genotyped cohort had 31% fewer hospitalizations overall (adjusted hazard ratio
: 0.69, 95% confidence interval [CI]: 0.58 to 0.82, p < 0.001) and 28% fewer hospitalizations for bleeding or thromboembolism (HR: 0.72, 95% CI: 0.53 to 0.97, p = 0.029) during the 6-month follow-up period. Findings from a per-protocol analysis were even stronger: 33% lower risk of all-cause hospitalization (HR: 0.67, 95% CI: 0.55 to 0.81, p < 0.001) and 43% lower risk of hospitalization for bleeding or thromboembolism (HR: 0.57, 95% CI: 0.39 to 0.83, p = 0.003) in patients who were genotyped. During the same period, there was no difference in outcomes between the 2 external control groups.
CONCLUSIONS:
Warfarin genotyping reduced the risk of hospitalization in outpatients initiating warfarin. (The Clinical and Economic Impact of Pharmacogenomic Testing of Warfarin Therapy in Typical Community Practice Settings [MHSMayoWarf1]; NCT00830570).
Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
|
|
|
|
Studies
May 24, 2015 8:12:31 GMT -6
Post by Opioid therapy on May 24, 2015 8:12:31 GMT -6
|
|
|
|
Studies
May 24, 2015 8:14:53 GMT -6
Post by Warfarin on May 24, 2015 8:14:53 GMT -6
|
|
|
|
Studies
May 24, 2015 8:16:48 GMT -6
Post by cyp2C9 and VKORC1 on May 24, 2015 8:16:48 GMT -6
|
|
lab analysis guidelines
Guest
|
Studies
May 24, 2015 8:18:32 GMT -6
Post by lab analysis guidelines on May 24, 2015 8:18:32 GMT -6
|
|
|
|
Studies
May 24, 2015 8:20:19 GMT -6
Post by pain management on May 24, 2015 8:20:19 GMT -6
|
|
|
|
Studies
May 24, 2015 8:21:37 GMT -6
Post by asthma on May 24, 2015 8:21:37 GMT -6
|
|
|
|
Studies
May 24, 2015 8:23:07 GMT -6
Post by pain medicine on May 24, 2015 8:23:07 GMT -6
|
|
Pharmacogenomics of Pain Manag
Guest
|
Studies
May 24, 2015 8:25:32 GMT -6
Post by Pharmacogenomics of Pain Manag on May 24, 2015 8:25:32 GMT -6
|
|
