THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS
& AMERICAN COLLEGE OF CARDIOLOGY
MAY 2010 I VOL 3, NO 3 I SPECIAL ISSUE
ACC 2010: PAYER’S PERSPECTIVES
Applying Comparative Effectiveness Atrial Fibrillation Annual National Research in Cardiology
Costs Estimated at $26 Billion
By Caroline Helwick
Presidential Address Focused on PatientCentered Care By Wayne Kuznar
he American College of Cardiology (ACC) has designated 2010 as the Year of the Patient, a designation designed to ensure that every initiative undertaken by the ACC is focused on the best interests of patients with cardiovascular disease (CVD). ACC President Alfred A. Bove, MD, PhD, Emeritus Professor of Medicine, and Chief, Section of Cardiology, Temple University, Philadelphia, PA, devoted much of his presidential address at the ACC 2010 annual meeting to patient-centered care in the ambulatory and prevention care settings. “We should be in the ambulatory care environment, managing chronic disease and providing guidelines and therapies for cardiovascular disease prevention, in addition to managing advanced interventional and imaging tools,” said Dr Bove. Continued on page 4
panel of cardiologists and administrators discussed the emerging demand for comparative effectiveness data, concurring that such information is still lacking and is long
overdue in cardiology, but it may be challenging to apply. A new study shows that comparative effectiveness evidence is lacking in 66% of studies published in high-
atients with atrial fibrillation (AF) cost this country $26 billion a year, largely because of hospitalizations for the condition, reported Michael H. Kim, MD, an electrophysiologist at Northwestern University, Chicago. Dr Kim and colleagues conducted a large retrospective cohort analysis to provide an up-to-date, comprehensive estimate of the national cost of treating patients with AF, compared with matched controls without AF. “The unique aspect of our design was the propensity analysis, which matched patients very well according to all other criteria besides AF,” he said. “We wanted to determine the dif-
Continued on page 12
Continued on page 4
What Will Healthcare Reform Look Like? Policy Experts Offer Perspectives on Cost-Containment, Government Control By Caroline Helwick
wo Capitol Hill standouts elucidated their perspectives on healthcare reform to a packed session during ACC.10. Congressman Paul Ryan (RWisconsin and Chris Jennings, former White House Health Policy Advisor in the Clinton administration and CoDirector of the Bipartisan Policy Center’s “Leaders’ Project on the State of American Health Care,” expressed fervent and mostly opposing opinions. They debated current challenges of and potential solutions for healthcare reform just before the passage of the Patient Protection and Affordable Care Act. Other physician leaders also weighed in. They all united around one
issue: “We have problems to fix. The United States spends 2.5 times more per person on healthcare than other industrialized countries, but we still have problems, and costs are going through the roof,” said Congressman Ryan. Mr Jennings emphasized that the United States spends >$2 trillion on healthcare services that do not improve outcomes. Don’t Federalize Healthcare But Rep Ryan said he sees major flaws in the healthcare reform legisla-
tion. “The current bill federalizes the healthcare system,” he said. “It creates a new open-ended entitlement rivaling Continued on page 5
Inside Clopidogrel cost-effective for stroke prevention, Page 6 Postdischarge HF management cuts costs, Page 11 Less-intensive MI therapy for women explains 50% mortality excess, Page 14 ©2010 Engage Healthcare Communications, LLC
Angioedema higher with ACE inhibitors than ARBs, Page 15 Adding ACE or ARB reduces edema from CCB, Page 16 Genotyping identifies who will respond to statins, Page 18 Low vitamin D linked to MI outcomes, Page 21
Copyright ÂŠ2009, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.
ACC 2010: PAYER’S PERSPECTIVES
THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN
MAY 2010 I VOL 3, NO 3 I SPECIAL ISSUE
FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS
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15 Rethinking Aggressive Blood Pressure Control
Practice Innovation Can Reduce Cost, Enhance Quality 11 Statin Prophylaxis Cost-Effective for People with Low LDL-C and Elevated CRP
16 High Calcium Channel Blockers Discontinuation
Postdischarge HF Management Reduces Costs Patient’s Financial Burden May Affect Outcomes Post-MI COMPARATIVE EFFECTIVENESS RESEARCH 12 Events Post-PCI More Frequent with Public Insurance
Editorial Assistant Jessica A. Smith
HEALTH ECONOMICS 6 Economic Analysis of ACTIVE-A
13 Ticagrelor Confers Superior Survival in CABG Surgery Compared with Clopidogrel Still No Answer on Safety, Efficacy of DrugEluting versus Bare Metal Stents for Acute MI
14 Catheter Therapy for Mitral Valve Repair Safer
in Diabetes Rate Caused by Pedal Edema PERSONALIZED MEDICINE 17 Genotyping Improves Warfarin Therapy, Reduces Costs Genetic Variant Affects Response to Clopidogrel 18 Genomic Analysis Coming Soon to a Laboratory Near You CARE: Genotyping Can Identify Which Patients Will Respond to Statins DIABETES AND CVD 19 Fenofibrate plus Statin No Better than Statin Alone in Diabetes NAVIGATOR: Lifestyle Modification Still Best Strategy to Prevent Diabetes
than Surgery Less-Invasive Treatment Post-MI May Explain 50% Excess Mortality in Women than in Men
ACC.10 HIGHLIGHTS 20 In a Shift, Women Referred More Often for Cardiac Catheterization after Noninvasive Testing
CABANA: Ablation versus Drug Therapy for Complex Atrial Fibrillation
21 Regenerative Medicine for Cardiologists:
HYPERTENSION 15 Angioedema Risk 50% Higher with ACE Inhibitors than with ARBs
Advances and Challenges Low Vitamin D Prevalent in MI Patients
22 Novel Anticoagulant Safe and Well-Tolerated
EDITORIAL BOARD CLINICAL EDITOR Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA GOVERNMENT EDITOR Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Sr. Counselor, Fleishman-Hillard Washington, DC ACTUARY David Williams Milliman Health Consultant Windsor, CT CANCER RESEARCH Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University President, ACCC Past Chair, Board of Directors, NCCN
Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems CARDIOLOGY RESEARCH Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York ENDOCRINOLOGY RESEARCH James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EMPLOYERS Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA
Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE
Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare, Sharon, MA Senior Fellow, Jefferson School of Population Health EPIDEMIOLOGY RESEARCH Joshua N. Liberman, PhD Vice President, Strategic Research CVS Caremark, Hunt Valley, MD
Nirav R. Shah, MD, MPH Assistant Professor of Medicine NYU School of Medicine, NYC Senior Investigator, Geisinger Health System, Danville, PA HEALTH INFORMATION TECHNOLOGY J.B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA HEALTH OUTCOMES RESEARCH Gordon M. Cummins, MS Director, IntegriChain
Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver
POLICY & PUBLIC HEALTH Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute
Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, Boehringer-Ingelheim Ridgefield, CT PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University, Spokane, WA PERSONALIZED MEDICINE Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation
Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality and biomedical research consultancy J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago
PHARMACOECONOMICS Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH
REIMBURSEMENT POLICY Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account Amgen, Thousand Oaks, CA
PHARMACY BENEFIT DESIGN Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ
Michael Schaffer, PharmD, MBA Director, Pharmacy Programs Sanovia Corp., Philadelphia, PA
Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA
William J. Cardarelli, PharmD Director of Pharmacy Atrius Health Harvard Vanguard Medical Associates Boston, MA
Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL
Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA
MANAGED CARE & GOVERNMENT AFFAIRS Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL
Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta
MANAGED MARKETS Jeffrey A. Bourret, MS, RPh, FASHP Senior Director, Customer Marketing & Innovation, US Specialty Customers Pfizer Specialty Business Unit, PA
Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City
RESEARCH & DEVELOPMENT Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA SPECIALTY PHARMACY Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI
Paul Anthony Polansky, BSPharm, MBA Executive VP and Chief Pharmacy Officer, Sanovia Corp., Philadelphia, PA James T. Kenney, RPh, MBA Pharmacy Operations Manager Scott R. Taylor, RPh, MBA Harvard Pilgrim Health Care Associate Director, Industry Relations Wellesley, MA Geisinger Health System, Danville, PA
Presidential Address Focused on Patient... He singled out heart failure (HF) as a chronic cardiovascular condition that would be ideal for disease management programs that incorporate home care. Home surveillance of HF could enable clinical teams to keep patients stable at home through medication adjustments. Further, educating patients about lifestyle modifications, such as salt and water restriction, exercise, weight control, and adherence to medication, can help keep patients stable. According to Dr Bove, substantial improvements in low-density lipoprotein cholesterol and blood pressure levels have been observed with programs that incorporate patient communications programs with quarterly visits to the clinic. “Physician payment has been a center of focus in this past year,” he said. Payment incentives are lacking for physicians to undertake prevention, disease management, or patient education efforts, although such efforts can reduce the overall costs associated with a disease such as CVD, Dr Bove suggests. In the case of a patient with HF, careful surveillance, individualized care to prevent fluid overload, and telemedicine to enhance communication between the
patient and physician “can reduce hospitalizations and emergency room visits, maintain a high quality of life for my patient, and possibly improve longevity.”
Dr Bove also called on cardiologists to do their part to control costs, while providing effective care. “We have an obligation…to not overutilize therapies and tests, and to consider longi-
“We have an obligation…to not overutilize therapies and tests, and to consider longitudinal care as the primary goal for these patients….As stewards of the healthcare system, we also have an obligation to consider the costs of care.”—Alfred A. Bove, MD, PhD Physician reimbursement for such efforts, however, is only a few hundred dollars, whereas the payment yield for waiting until the patient is in decompensated HF is several times higher, as more imaging procedures and catheterizations are ordered, and the likelihood of HF progression requiring implantation of a cardioverter-defibrillator increases. Dr Bove calls this paradox the “keep America sick” system. The ACC is working toward reversing this paradigm through payment reform, which would include adequate reimbursement for long-term care management.
tudinal care as the primary goal for these patients,” he said. “As stewards of the healthcare system, we also have an obligation to consider the costs of care, particularly when we deal with the end of life in the elderly.” Patient as Partner Advancing the theme of patientcentered care and improving the quality of healthcare, “The Patient as Partner” spotlight session featured several prominent speakers. Suzanne Hughes, MSN, RN, Director of Health Education and Nursing Research at Robinson Memorial Hos-
Atrial Fibrillation Annual National Costs... ferential costs associated with AF in today’s dollars.” Using the MarketScan databases, the investigators identified 89,066 patients with AF and matched them with 89,066 persons without AF according to age, sex, region, payer, and cardiovascular (CV) comorbidities.
“We found huge excess costs for AF patients, even against these well-matched controls.” —Michael H. Kim, MD Medical costs (2008 US$), including AF costs (for antiarrhythmics or for claims with a primary AF diagnosis),
Continued from page 1
other CV costs (claims with other primary CV diagnoses), and non-CV costs (all other claims) were examined over a 1-year period after the index diagnosis. National incremental costs for patients with AF were estimated based on age-/sex-specific AF prevalence projections for 2010. “We found huge excess costs for patients with AF, even against these well-matched controls,” Dr Kim reported. “The total annual cost was $26 billion.” Direct medical costs were 73% higher in patients with AF compared with matched controls—$20,670 versus $11,965 per patient, respectively. This was primarily because of higher inpatient costs resulting from more frequent hospitalizations and mortality, as well as outpatient medical costs associated with AF, Dr Kim said. “We also found the highest cost burden of AF is in men aged 60 to 64, which we speculate may be because they are young, and therefore receive relatively aggressive treatment,” he added. “Their costs may also be higher because they are not yet on Medicare. As men and women age, their AF costs decline.”
pital in Ravenna, OH, discussed strategies for educating patients, including: • Having patients repeat important information at each visit • Avoiding medical jargon by the healthcare providers • Assessing patient comprehension of instructions by asking the patient to repeat these messages. Sue Wingate, PhD, RN, a certified nurse practitioner, Heart Failure Treatment Program of Kaiser Permanente Mid-Atlantic, Rockville, MD, espoused shared decision-making as a tool to enhance quality of care. Dr Wingate said that physicians need to present patients with treatment options, as well as the outcomes and uncertainties associated with each option, and patients should be asked to communicate the relative value they place on the risks and benefits of treatment. Jane Linderbaum, MS, CNP, Assistant Professor of Medicine, Mayo College of Medicine, and Director of Cardiovascular Inpatient Operations at the Mayo Center, Rochester, explained the ACC’s Hospital-to-Home (H2H) initiative. H2H was designed with the goal of a 20% reduction in allcause hospital readmissions for HF and heart attacks by the year 2012. ■
Continued from page 1
Table National Costs for CV Care: AF Patients vs Controls National AF patients, cost Matched controls, incremental cost per patient, $ cost per patient, $ in AF patients,a (N = 89,066) (N = 89,066) $ billion
Cost type CV-related costs Total
aEstimated costs for 2010 based on AF prevalence projections. bCosts for antiarrhythmics and claims with AF diagnosis.
AF indicates atrial fibrillation; CV, cardiovascular. Adapted from Kim MH, et al. Estimation of incremental cardiovascular healthcare costs in patients with atrial fibrillation in the United States. Poster presented at the American College of Cardiology, Atlanta: GA; March 14, 2010. Abstract 1028-164.
$16 Billion CV Costs in AF Eliminating the $10 billion in nonCV costs (which were higher in patients with AF than in matched controls), the total CV-related national costs of patients with AF is estimated
at nearly $16 billion in 2010 (Table), an additional analysis by the same authors showed. Almost two thirds of the CV costs related to care primarily for non-AF CV conditions. Management strategies need to Continued on page 5
AMERICAN HEALTH & DRUG BENEFITS
What Will Healthcare Reform Look Like?... the size of Medicare and Medicaid, driving us more toward bankruptcy.” He predicts that physicians will answer to the government under this legislation. “What smart 22-year-old person would choose to spend an additional 8 to 10 years in school and accrue $300,000 in student loans to become a de facto employee of the federal government?” he questioned. “Bureaucracies will be set in place to determine reimbursements,” Rep Ryan says, suggesting that new mandates will raise the price of insurance, while government subsidies will take up the slack “at a time when government is going bankrupt.” The ultimate consequence will be a focus on cost rather than on quality of care, he insisted. Paying for reform is another big concern, says Congressman Ryan. “This bill has 10 years of tax increases and Medicare cuts to pay for years of spending,” he says. “We cannot put more money back into the same system.” The determination and achievement of value must include consumer involvement, and the emerging healthcare system must have at its “nucleus” the doctor–patient relationship. “Help patients understand what treatments cost, and see their success and failures.” Whereas the current system “rewards consumption,” reforms that alter volume can achieve savings, he predicts. Physician involvement and investment in these changes are critical, Congressman Ryan points. “The public will not trust reforms without you, and the policies will be poorly made in your absence.” No Government Takeover in Sight Mr Jennings countered these concerns, noting that far too often critics fight healthcare reform out of fear, “as though our current system is nirvana.”
“The United States spends 2.5 times more per person on healthcare than other industrialized countries, but we still have problems, and costs are going through the roof.”—Rep Paul Ryan
But “no one is talking about a government takeover,” he assured ACC attendees. “What is scary is the future without reform.” He said that the recently enacted healthcare reform bill not only contains bipartisan ideas but addresses “real issues of cost and coverage,” which are inseparable concepts.
Legal reform is the only reform that increases access to care, while decreasing cost. “On this basis alone, everyone, liberal and conservatives, should embrace it.” —Richard E. Anderson, MD, FACP Cost reforms cannot be achieved without meaningful insurance reform, he asserted. “And we cannot have meaningful insurance reform without covering every individual; otherwise people will wait until they are sick to buy insurance.” Better management of chronic illness will reduce costs, but this cannot happen with intermittent and sporadic coverage, he suggests, pointing out that >90% of dollars spent as a result of healthcare reform will “go back to private insurers.” Mr Jennings maintains that the polarizing debate about healthcare
Atrial Fibrillation... Continued from page 4 focus on the treatment of AF and nonAF CV conditions to lower total healthcare costs, Dr Kim suggests. Hospitalization Primary Cost Driver During the 12-month postindex period, twice as many patients with AF than the control patients were hospitalized for any reason (37.5% vs 17.5%, respectively; P <.001), and patients with AF had a 3-fold increased rate of multiple admissions compared with the control group (11.1% vs 3.3%, respectively; P <.001). The
Continued from page 1
proportion of patients with AF who died during hospitalization for any cause was about 20-fold greater than in the controls (2.1% vs 0.1%, respectively; P <.001), the study showed. “Less than one quarter of AF-related incremental costs were attributable primarily to AF care,” Dr Kim noted. “Hospitalization continues to be the major cost driver in AF-related disease, so, all things being equal, management interventions that might prevent readmissions probably offer the best hope for reducing the cost burden of AF,” he suggested.—CH ■
reform is a metaphor for the larger concern about the nation’s mounting debt, and that rhetoric has bypassed reasoning. When a bipartisan compromise could not be obtained, “people went back to their talking points, and I’m tired of talking points after 25 years,” he said. “It is time we all worked together. The current situation is unsustainable.” New models of healthcare delivery are emerging that offer “value over volume,” and these should contain cost, Mr Jennings predicts. “The encouraging thing is that there is a tendency to start to embrace and move toward these.” Cardiologists Applaud Tort Reform To audience applause, Richard E. Anderson, MD, FACP, Chairman and CEO of the Doctors Company, the nation’s largest physician liability insurance company, insisted that tort reform is an integral component of any healthcare reform. “I submit to you that all healthcare in the United
nomic damages, according to Dr Anderson. States that have such caps have had a stable medical malpractice marketplace for 30 years, he noted. In California, for example, the cost of medical liability insurance is half of what it was in 1976 in inflationadjusted dollars, he says, and the cost of premiums has risen <2% in absolute dollars. “Fees that are not going to plaintiffs and attorneys stay inside the healthcare system to provide care,” he pointed out. Dr Anderson told cardiologists that he is encouraged by the Obama administration’s willingness to discuss tort reform, because “there was zero progress in this over the 8 years of the past administration.” Mayo Clinic Health Policy Recommendations Cardiologist Douglas Wood, MD, FACC, described the following principles for optimal healthcare delivery and cost-containment set by the Mayo Clinic Health Policy Center: • Physicians need to create value and strive for better outcomes at a lower overall cost • New methods of healthcare delivery should be explored that will enhance value • Medical care should be coordinated • The government must find a way to pay for value that does not center around cost control alone
“No one is talking about a government takeover….What is scary is the future without reform.”—Chris Jennings
States is, in fact, a form of defensive medicine,” he said. “No healthcare decisions are made without consideration of the legal or liability ramifications, and this makes the current medical liability system enormously wasteful and destructive.” The current system devalues physician judgment and undermines the doctor–patient relationship, “which is hanging on by a thread,” according to Dr Anderson, because there is “virtually no institutional support for it.” He added that legal reform is also the only reform that increases access to care, while decreasing cost. “On this basis alone, everyone, liberal and conservatives, should embrace it,” he told the audience. The single most effective component of tort reform is a cap on noneco-
• All Americans should have health insurance, and subsidies should be provided for those who cannot afford it or who are not provided insurance by their employers. The Health Policy Center used this framework for evaluating the legislation, and concluded that the Senate bill was largely in line with its guiding principles. “I am optimistic about what we can do,” Dr Wood said, “but it will take a lot of hard work.” ■
SEE ALSO articles on cost-effective analyses and cost outcomes on pages 6 and 11, including economic analyses of ACTIVE-A and JUPITER trials.
Economic Analysis of ACTIVE-A
SEE ALSO TRITON-TIMI subtrial article on page 17.
Clopidogrel Cost-Effective in Preventing Stroke Table 2 Total Cost of Care Comparison
By Caroline Helwick
ual antiplatelet therapy with clopidogrel plus aspirin is costeffective, because of its protective effect on stroke, according to a Canadian economic analysis of data from the previously published ACTIVE-A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) study. The study was reported at ACC 2010 in the Featured Clinical Research Session by Andre Lamy, MD, of the Population Health Research Institute, Hamilton, Ontario. ACTIVE-A compared clopidogrel plus aspirin versus aspirin alone in 7554 patients with atrial fibrillation at high risk for stroke who were unsuitable for vitamin K antagonists. Although mortality was not reduced, a significant 28% reduction in stroke occurred at 4 years with the clopidogrel-aspirin combination (P = .002). The effect was seen primarily for disabling and nondisabling/fatal ischemic strokes. The combination, however, was associated with a 57% increased risk of major bleeding, mostly in the gastrointestinal tract. Results showed that, for 1000 patients treated for 3 years, clopidogrel plus aspirin will prevent 28 strokes (17 fatal/disabling), prevent 6 myocardial infarctions, and result in 20 major bleeds (3 fatal). “Most clopidogrel trials had been of 6 to 12 months’ duration, but this trial
Table 1 Unit Costs of Events Event Ischemic stroke
Unit cost, $a
8104 Transient ischemic attack Myocardial infarction 9405
Congestive heart failure Non-CNS systemic embolism Unstable angina
11,262 10,162 4814
Minor bleed requiring 7235 ≥1 unit blood 7235 GI bleeding with transfusion Angioplasty with stent 19,002 5544 Catheter/coronary angiography Coronary artery bypass 17,952 grafting Pulmonary embolism 7006
Atrial fibrillation a
2008 Canadian dollars. CNS indicates central nervous system; GI, gastrointestinal.
was for 3.6 years,” Dr Lamy noted. “We wanted to determine the potential impact on the healthcare system of adding clopidogrel to aspirin, which we believed could be very important.” Direct medical costs were analyzed for the 3.6-year study period using a Canadian healthcare perspective, with 2008 costs discounted at 3% annually. Cost components included study drug (list price, $2.52/day for clopidogrel), events (drugs, treatments, length of stay, and work-up; Table 1), procedures, and nonstudy drugs. These were put together to determine the average cost per patient.
“Costs, in fact, were reduced by $1625 with the combination, due to reductions in stroke. We are confident that we reached cost-neutrality.”—Andre Lamy, MD The cost of stroke was calculated using cost of hospitalizations, ambulatory care, physician fees, tests and procedures, all medications, assistive
Placebo + ASA Mean cost (95% CI), $
Clopidogrel + ASA Mean cost (95% CI), $
13,756 (13,032, 14,544)
14,132 (13,445, 14,842)
12,961 (12,274, 13,697)
13,308 (12,664, 13,978)
Study medication Total Total, discounted
ASA indicates aspirin; CI, confidence interval.
devices, allied health professional fees, home modifications, and caregiver expenses. Although this was a Canadian study, Dr Lamy said that the resource utilization is similar in the United States, and unit costs in Canada are comparable to Medicare costs. “The cost of clopidogrel plus aspirin was not significantly higher than for aspirin alone,” Dr Lamy reported (Table 2). “Costs, in fact, were reduced by $1625 with the combination, due to reductions in stroke. We are confident that we reached cost-neutrality.” The wide confidence intervals reflected the fact that caring for some strokes was quite expensive. “The bulk
of the cost came after the hospitalization period, for rehabilitation and chronic care facilities,” Dr Lamy noted. “You cannot look at the economics of stroke only during hospitalization. The findings support the use of this combination in patients unsuitable for vitamin K antagonist therapy,” he said. He told attendees, “You can run a similar analysis in your own hospital. The price you pay for clopidogrel will be the determining factor between cost-saving, cost-neutral, or costeffective outcomes. If the drug costs just $2 to $3 a day, it is cost-neutral, meaning it costs nothing to the healthcare system, and it should reduce the occurrence of stroke.” ■
Practice Innovation Can Reduce Cost, Enhance Quality
t a session on practice innovations, speakers provided a road map for how the adoption of health information technology (HIT), data registries, and decision-support tools for appropriate-use criteria and guidelines can come together to improve quality and outcomes. American College of Cardiology (ACC) CEO Jack Lewin, MD, noted how evidence-based care can reduce variations. He highlighted a new shared decision-making pilot program in California that aims to use the ACC’s appropriate-use criteria for coronary revascularization to reduce variations in the treatment of coronary artery disease. This shared decision-making model includes 3 phases: • Patient “pre-testing” • Diagnostic testing and cardiac catheterization • Postcatheterization counseling. If the pilot is successful, the program could expand to a larger scale. It could gather baseline data, initiate development of shared patient–physician decision-making tools, track indications, and enhance patient counseling, Dr Lewin said, noting, “We have real opportunities to leverage appro-
AMERICAN HEALTH & DRUG BENEFITS
priate-use criteria, put them into practice, and ultimately improve care.” HIT can trigger this change, said James Tcheng, MD, of Duke University Health System, Durham, NC, and cochair of ACC’s Informatics Committee. “Whether you agree or disagree with health IT, it is happening,” he said.
“We have real opportunities to leverage appropriate-use criteria, put them into practice, and ultimately improve care.”—Jack Lewin, MD A new federal electronic medical record (EMR) incentive program, which emphasizes data collection and reporting, is slated to begin in 2011. Dr Tcheng acknowledged that using EMRs is “not a natural skill” but more like “skiing,” where you need “to know your destination and you need management, supporting tools, and money.” Once uniformly adopted, however, EMRs will benefit all physicians, he said. Elected ACC President Ralph Brindis, MD, MPH, FACC, said reg-
istries can help inform guideline development, educational needs assessments, quality improvement opportunities, effectiveness of new technologies, and even public policy. As an example, the National Cardiovascular Data Registry helped to reduce door-to-balloon times in interventional cardiology. Janet Wright, MD, FACC, ACC Senior Vice President for Science and Quality, noted that the ACC is leveraging its appropriate-use criteria and guidelines, HIT efforts, and registry data to improve value. She mentioned the ACC’s Hospital to Home initiative, which is designed to reduce hospital readmissions, and the Imaging in FOCUS initiative, to help providers implement appropriate-use criteria at the point of care and reduce inappropriate imaging. Dr Wright highlighted the new PINNACLE Network, which will serve as a “frame” for all aspects of quality. “PINNACLE provides ways to connect practices in a learning community, ensure better care coordination, and embed the systemic practice of evidence-based medicine,” she said.—CH ■
BYSTOLIC. Helping patients get the blood pressure reductions they need.
Significant blood pressure reductions In a 3-month study by Lacourcière et al
BYSTOLIC provides significant BP reductions in combination with hydrochlorothiazide1 Reductions From Baseline in Mean Sitting DBP and SBP at Trough at 3 Months1, 2
BYSTOLIC 5 mg/ HCTZ 12.5 mg (n=20) SBP
BYSTOLIC 10 mg/ HCTZ 12.5 mg (n=20) DBP
BYSTOLIC 5 mg/ HCTZ 25 mg (n=20) DBP
BYSTOLIC 10 mg/ HCTZ 25 mg (n=20) DBP
Change From Baseline (mm Hg)
-6 -8 -10
-24 -26 -28 -30
P <0.0005 for all BYSTOLIC combinations vs baseline -29.0
Adapted from a 3-month, multicenter, randomized, double-blind, parallel-group, placebo-controlled, multifactorial-design study of BYSTOLIC monotherapy and BYSTOLIC in combination with hydrochlorothiazide for the treatment of mild to moderate hypertension. Primary endpoint was sitting DBP at trough. Mean values at baseline: sitting DBP at trough, 102.1 mm Hg; sitting SBP at trough, 158.1 mm Hg (N=240; n=100).
In a 3-month combination study by Neutel et al
BYSTOLIC provides significant BP reductions when added to an ACEI, ARB, and/or diuretic3,4 ■
Additional reductions from baseline in mean sitting DBP and SBP were -7.1 mm Hg and -8.2 mm Hg with BYSTOLIC 5 mg, -7.2 mm Hg and -6.0 mm Hg with BYSTOLIC 10 mg, and -8.6 mm Hg and -8.6 mm Hg with BYSTOLIC 20 mg4 Prior to receiving BYSTOLIC, patients were already receiving stable doses of one or two other antihypertensive therapies—ACEI alone, 36%; ARB alone, 19%; diuretic alone, 18%; ACEI/diuretic, 13%; ARB/diuretic, 13%4
Results from a U.S. phase III, 3-month, multicenter, randomized, double-blind, parallel-group, placebo-controlled study of BYSTOLIC for the treatment of mild to moderate hypertension in patients already taking one or two other antihypertensives (ACEI, ARB, and/or diuretic). Primary endpoint was sitting DBP at trough. Mean values at baseline: sitting DBP at trough, 96.3 mm Hg; sitting SBP at trough, 146.0 mm Hg (N=669). Number of patients by dose was as follows: placebo (n=167), BYSTOLIC 5 mg (n=168), BYSTOLIC 10 mg (n=168), and BYSTOLIC 20 mg (n=166). In the placebo arm, mean sitting DBP and SBP reductions were -3.9 mm Hg and -2.6 mm Hg.
Important Safety Information Contraindications ■
BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.
Warnings and Precautions ■
■ ■ ■
■ ■ ■ ■ ■
Do not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction, and ventricular arrhythmias have been reported following the abrupt discontinuation of therapy with beta blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other beta blockers, when discontinuation of BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily. BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. In general, patients with bronchospastic diseases should not receive beta blockers. Because beta blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta blockers should generally continue treatment throughout the perioperative period. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene are used. If beta-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The beta-blocking effects of BYSTOLIC can be reversed by beta agonists, eg, dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with beta blockers. Beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities. Beta blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta blockers in these patients may be followed by an exacerbation of symptoms or may precipitate a thyroid storm. Beta blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Because of significant negative inotropic and chronotropic effects in patients treated with beta blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure of patients treated concomitantly with these agents. Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc). When BYSTOLIC is co-administered with an inhibitor or an inducer of CYP2D6, monitor patients closely and adjust the nebivolol dose according to blood pressure response. The dose of BYSTOLIC may need to be reduced. When BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC and a 3-fold increase in Cmax for d-nebivolol).
©2010 Forest Laboratories, Inc.
Low incidence of side effects Side-effect profile3 Percentage of Adverse Events by Dose, Occurring in ≥1% of Patients Taking BYSTOLIC and More Frequently Than in Patients Taking Placebo3 Placebo (n=205) %
BYSTOLIC 5 mg (n=459) %
BYSTOLIC 10 mg (n=461) %
BYSTOLIC 20-40 mg (n=677) %
Pooled results from three U.S. phase III, 3-month, multicenter, randomized, double-blind, parallel-group, placebo-controlled studies of BYSTOLIC monotherapy for the treatment of mild to moderate hypertension (N=2016; n=1802).
Overall low discontinuation rate 3 ■
The discontinuation rate due to adverse events was 2.8% for BYSTOLIC vs 2.2% for placebo3
Low potential for drug-drug interactions3 ■ ■ ■
No significant interactions with hydrochlorothiazide, furosemide, spironolactone, losartan, or ramipril3 No significant interactions with warfarin, digoxin, atorvastatin, or simvastatin3 Drugs that inhibit CYP2D6 can be expected to increase plasma levels of BYSTOLIC. When BYSTOLIC is co-administered with an inhibitor or an inducer of this enzyme, patients should be closely monitored and the BYSTOLIC dose adjusted according to blood pressure response3
Warnings and Precautions (continued) ■ ■ ■ ■
Renal clearance of nebivolol is decreased in patients with severe renal impairment. In patients with severe renal impairment (ClCr less than 30 mL/min) the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients receiving dialysis. Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients with severe hepatic impairment and therefore it is not recommended in that population. Patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine while taking beta blockers. In patients with known or suspected pheochromocytoma, initiate an alpha blocker prior to the use of any beta blocker.
Drug Interactions ■ ■ ■
Do not use BYSTOLIC with other beta blockers. Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. BYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide.
Use in Specific Populations ■ ■ ■
Use BYSTOLIC during pregnancy only if the potential benefit justifies the potential risk to the fetus. BYSTOLIC is not recommended during nursing. The safety and effectiveness of BYSTOLIC have not been established in pediatric patients. In a placebo-controlled trial of 2128 patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with nebivolol compared to placebo. However, if heart failure worsens, consider discontinuation of BYSTOLIC.
Adverse Reactions ■
The most common adverse events with BYSTOLIC versus placebo (approximately ≥1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%), and bradycardia (0.2%).
Please see brief summary of Prescribing Information on the last page of this advertisement. References: 1. Lacourcière Y, Lefebvre J, Poirier L, Archambault F, Arnott W. Treatment of ambulatory hypertensives with nebivolol or hydrochlorothiazide alone and in combination: a randomized, double-blind, placebo-controlled, factorial-design trial. Am J Hypertens. 1994;7:137-145. 2. Data on file. Forest Laboratories, Inc. 3. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2010. 4. Neutel JM, Smith DHG, Gradman AH. Adding nebivolol to ongoing antihypertensive therapy improves blood pressure and response rates in patients with uncontrolled stage l-ll hypertension. J Hum Hypertens. 2010;24:64-73.
Patient’s Financial Burden May Affect Outcomes Post-MI By Wayne Kuznar
inancial stress may adversely influence health status after myocardial infarction (MI), according to research led by investigators at Case Western University School of Medicine, Cleveland, OH. Patients reporting insufficient money left over at the end of the month are at
increased risk of hospital readmission after MI and have worse general health, more angina, and a worse perception of their condition. The investigators analyzed data from the PREMIER (Prospective Registry Evaluating Myocardial Infarction: Event and Recovery) study, an obser-
BYSTOLIC® (nebivolol) tablets Brief Summary of full Prescribing Information Initial U.S. Approval: 2007
INDICATIONS AND USAGE: Hypertension - BYSTOLIC is indicated for the treatment of hypertension [see Clinical Studies (14.1)]. BYSTOLIC may be used alone or in combination with other antihypertensive agents [see Drug Interactions (7)]. CONTRAINDICATIONS: BYSTOLIC is contraindicated in the following conditions: Severe bradycardia; Heart block greater than first degree; Patients with cardiogenic shock; Decompensated cardiac failure; Sick sinus syndrome (unless a permanent pacemaker is in place); Patients with severe hepatic impairment (Child-Pugh >B); Patients who are hypersensitive to any component of this product. WARNINGS AND PRECAUTIONS: Abrupt Cessation of Therapy - Do not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily. Angina and Acute Myocardial Infarction - BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. Bronchospastic Diseases - In general, patients with bronchospastic diseases should not receive β-blockers. Anesthesia and Major Surgery - Because beta-blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta-blockers should generally continue treatment throughout the perioperative period. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers. Diabetes and Hypoglycemia - β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities. Thyrotoxicosis - β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm. Peripheral Vascular Disease - β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Non-dihydropyridine Calcium Channel Blockers - Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure in patients treated concomitantly with these agents. Use with CYP2D6 Inhibitors - Nebivolol exposure increases with inhibition of CYP2D6 [see Drug Interactions (7)]. The dose of BYSTOLIC may need to be reduced. Impaired Renal Function - Renal clearance of nebivolol is decreased in patients with severe renal impairment. BYSTOLIC has not been studied in patients receiving dialysis [see Clinical Pharmacology (12.4) and Dosage and Administration (2.1)]. Impaired Hepatic Function - Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. BYSTOLIC has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.4) and Dosage and Administration (2.1)]. Risk of Anaphylactic Reactions - While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Pheochromocytoma - In patients with known or suspected pheochromocytoma, initiate an α-blocker prior to the use of any β-blocker. ADVERSE REACTIONS: Clinical Studies Experience - BYSTOLIC has been evaluated for safety in patients with hypertension and in patients with heart failure. The observed adverse reaction profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse reactions reported for each of these patient populations are provided below. Excluded are adverse reactions considered too general to be informative and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. The data described below reflect worldwide clinical trial exposure to BYSTOLIC in 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. HYPERTENSION: In placebo-controlled clinical trials comparing BYSTOLIC with placebo, discontinuation of therapy due to adverse reactions was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse reactions that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%) and bradycardia (0.2%). Table 1 lists treatment-emergent adverse reactions that were reported in three 12-week, placebo-controlled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg, or 2040 mg of BYSTOLIC and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group. Table 1. Treatment-Emergent Adverse Reactions with an Incidence (over 6 weeks) ≥1% in BYSTOLIC-Treated Patients and at a Higher Frequency than PlaceboTreated Patients are listed below in the following order: System Organ Class Preferred Term [Placebo (n = 205), Nebivolol 5 mg (n = 459), Nebivolol 10 mg (n = 461), Nebivolol 20-40 mg (n = 677)] Cardiac Disorders: Bradycardia (0, 0, 0, 1); Gastrointestinal Disorders: Diarrhea (2, 2, 2, 3); Nausea (0, 1, 3, 2); General Disorders: Fatigue (1, 2, 2, 5); Chest pain (0, 0, 1, 1); Peripheral edema (0, 1, 1, 1); Nervous System Disorders: Headache (6, 9, 6, 7); Dizziness ( 2, 2, 3, 4); Psychiatric Disorders: Insomnia (0, 1, 1, 1); Respiratory Disorders: Dyspnea (0, 0, 1, 1); Skin and Subcutaneous Tissue Disorders: Rash (0, 0, 1, 1). Listed below are other reported adverse reactions with an incidence of at least 1% in the more than 4300 patients treated with BYSTOLIC in controlled or open-label trials except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or adverse reactions unlikely to be attributable to drug because they are common in the population. These adverse reactions were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a Whole: asthenia. Gastrointestinal System Disorders: abdominal pain. Metabolic and Nutritional Disorders: hypercholesterolemia. Nervous System Disorders: paraesthesia. Laboratory Abnormalities - In controlled monotherapy trials of hypertensive patients, BYSTOLIC was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count. Postmarketing Experience - The following adverse reactions have been identified from spontaneous reports of BYSTOLIC received worldwide and have not been listed elsewhere.
AMERICAN HEALTH & DRUG BENEFITS
vational database of patients suffering acute MI at 19 US hospitals from January 2003 to June 2004. The patients had interviews at baseline and at 12 months to obtain sociodemographic, clinical, and treatment data. The study included 2344 patients.
These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to BYSTOLIC. Adverse reactions common in the population have generally been omitted. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular block (both second- and third-degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud’s phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting. DRUG INTERACTIONS: CYP2D6 Inhibitors - Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) [see Clinical Pharmacology (12.5)]. Hypotensive Agents - Do not use BYSTOLIC with other β-blockers. Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity. In patients who are receiving BYSTOLIC and clonidine, discontinue BYSTOLIC for several days before the gradual tapering of clonidine. Digitalis Glycosides - Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers - BYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide. USE IN SPECIFIC POPULATIONS: Pregnancy: Teratogenic Effects, Category C - Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance. In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD). Labor and Delivery - Nebivolol caused prolonged gestation and dystocia at doses ≥5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation). No studies of nebivolol were conducted in pregnant women. Use BYSTOLIC during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers - Studies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excreted in human milk. Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended during nursing. Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility [see Nonclinical Toxicology (13.1)]. Geriatric Use - Of the 2800 patients in the U.S.sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients. Heart Failure - In a placebo-controlled trial of 2128 patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with nebivolol compared to placebo. However, if heart failure worsens consider discontinuation of BYSTOLIC. OVERDOSAGE: In clinical trials and worldwide postmarketing experience there were reports of BYSTOLIC overdose. The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension. Other important adverse reactions reported with BYSTOLIC overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse reactions associated with β-blocker overdose include bronchospasm and heart block. The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure, and vomiting. The patient recovered. Because of extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance. If overdose occurs, provide general supportive and specific symptomatic treatment. Based on expected pharmacologic actions and recommendations for other β-blockers, consider the following general measures, including stopping BYSTOLIC, when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful. Heart Block (second- or third-degree): Monitor and treat with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Congestive Heart Failure: Initiate therapy with digitalis glycosides and diuretics. In certain cases, consider the use of inotropic and vasodilating agents. Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β2-agonist and/or aminophylline. Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required. Supportive measures should continue until clinical stability is achieved. The half-life of low doses of nebivolol is 12-19 hours. Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment.
Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA Licensed from Mylan Laboratories, Inc. Under license from Janssen Pharmaceutica N.V., Beerse, Belgium Rev. 02/10 © 2010 Forest Laboratories, Inc.
General health status was measured using the Short Form-12 (SF-12), which consists of physical and mental components, with higher scores reflecting better health status. Disease-specific health was measured using the Seattle Angina Questionnaire (SAQ), which includes subscales for angina frequency and disease perception.
Patients reporting insufficient money left over at the end of the month are at increased risk of hospital readmission after MI and have worse general health, more angina, and a worse perception of their condition. The SAQ subscales range from zero to 100, with higher scores indicating fewer anginal symptoms and better condition perception. Financial stress was assessed during hospitalization by asking patients, “In general, how do your finances work out at the end of the month?” The patients chose 1 of 3 responses: • Some money left over at the end of the month—52.9% • Just enough to make ends meet— 31.4% • Not enough to make ends meet— 15.7%. After adjustments for differences in baseline comorbidities, age, and other characteristics, those who answered “not enough to make ends meet” had 70% greater angina frequency than those who answered “some money left over.” Their disease perception was also 7.7 points worse on the SAQ disease perception subscale than the group that answered “some money left over.” A 5point difference on this scale is considered clinically significant for individual patients, the researchers noted. On the SF-12, after adjusting for the same variables, patients who answered “not enough to make ends meet” scored 3.5 points worse on the physical component score and 3.0 points worse on the mental component score than those who answered “some money left over.” The adjusted mortality rate at 4 years was 13% higher, and the adjusted rate of readmissions at 1 year was 51% higher, among those who answered “not enough to make ends meet” compared with those who answered “some money left over,” although only the difference in risk of readmission reached statistical significance. ■
JUPITER: Statin Prophylaxis Cost-Effective for People with Low LDL-C and Elevated CRP By Caroline Helwick
mathematical simulation showed that statin treatment for persons with normal low-density lipoprotein cholesterol (LDL-C) and elevated levels of C-reactive protein (CRP) would be cost-effective, but could strain Medicare resources. The study was presented by Julia F. Slejko, a PhD candidate at the University of Colorado School of Pharmacy, Denver. Using data from the landmark JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial, Ms Slejko and colleagues concluded that they have “compelling evidence that more adults could benefit from statin treatment by preventing vascular adverse events than are presently included in the National Cholesterol Education Program Adult Treatment Panel [NCEP].” The JUPITER trial demonstrated that statin therapy reduced vascular events in persons with LDL-C below the current treatment thresholds
(≤130 mg/dL) with elevated CRP levels (≥2.0 mg/L). The current analysis was not funded by a pharmaceutical company. The benefit would come from considering elevated CRP as a primary risk factor for cardiovascular events, she said. If the NCEP guidelines were expanded to address CRP, an estimated 6 million to 10 million adults would become new statin users, in addition to the 6.5 million who are currently on these medications, Ms Slejko predicted. The study used a Markov decision model to simulate cardiac events (myocardial infarction and angina), stroke, and subsequent health status in the average American adult with elevated CRP but normal LDL-C levels, using either preventive statin therapy or no statins. Statin therapy costs included the cost of drug, physician visits, CRP and lipid screening, creatine kinase test, and liver panels. Drug costs were based on 80-mg generic simvastatin, a
Postdischarge Heart Failure Management Cuts Readmissions, Costs
isease management after discharge can lower the hospital readmission and mortality rates for patients with heart failure (HF) aged ≥65 years. It may also improve patients’ quality of life (QoL) and help reduce costs, reported Anitha Rajamanickam, MD, of the Cleveland Clinic, Ohio. About 50% of elderly patients with HF are readmitted within 6 months of discharge, and approximately 60% of Medicare reimbursements are for acute hospitalizations and readmissions. Comprehensive discharge planning plus postdischarge support may reduce readmission rates and improve outcomes. In a systematic review and metaanalysis of randomized clinical trials, Dr Rajamanickam and colleagues identified 34 trials meeting the study criteria. Studies were conducted in 12 countries and randomized 6657 persons (mean age, 70 years). Mean follow-up was 9 months. The readmission rates showed a significant drop for the intervention arm in these studies. Postdischarge intervention approaches included single home visits, increased clinic follow-up, home visits and/or frequent telephone contact, and extended home care. All-cause readmissions totaled 1602
among 3617 patients in the postdischarge intervention arm versus 1654 among 3398 patients in the usual care arm, for a 15% reduction in risk (95% confidence interval [CI], 0.79-0.93). There was an even greater reduction
The cost-savings in the most recent studies ranged from $74 to $1272. in readmissions for HF and cardiovascular reasons—767 of 2450 patients in the intervention arm compared with 935 of 2230 patients in the usual care arm—a 34% risk reduction (95% CI, 0.56-0.78). Overall mortality was reduced by 15% (95% CI, 0.75-0.97). The differences were not a result of increased numbers of patients being put on angiotensin-converting enzyme inhibitors, beta-blockers, or diuretics. QoL scores also improved in the intervention arm, and overall medical costs were reduced, translating into a monthly cost-savings per patient of $238. The cost-savings in the most recent studies (2002-2006) ranged from $74 to $1272. In a cost-utility analysis, frequent telephone contact was shown to be the most cost-effective intervention.—CH ■
“An estimation of the entire cost of this approach is needed to inform policymakers.”—Julia F. Slejko dose equipotent to rosuvastatin 20 mg, which was used in JUPITER. Expected costs were estimated in 2008 US dollars. Effectiveness was estimated as quality-adjusted life-years (QALYs),
using the generally accepted cutoff of $50,000 per QALY. The Markov simulation used a hypothetical 57-year-old person who would require lifetime statin therapy. The researchers concluded that in 92% of the cases, the cost of a QALY would be $40,457. “This research suggests that statin prevention in those with elevated CRP levels is cost-effective,” Ms Slejko said. “This may support the hypothesis that expanding NCEP guidelines to address CRP would also be cost-effective.” But this approach may burden the healthcare system. “If this strategy is taken, more than half of the new statin users would be Medicare beneficiaries,” she noted. “Thus, the majority of potential new statin therapy costs may be seen as an additional burden to an already strained fund. An estimation of the entire cost of this approach is needed to inform policymakers.” ■
RACE II: Strict Control of Heart Rate Not Necessary in Chronic AF Experts Suggest Changing Current Guidelines
or patients with chronic atrial fibrillation (AF), practice guidelines call for strict control of heart rate to less than 80 beats per minute at rest and 110 beats per minute during moderate exercise. But a study reported at the ACC.10 demonstrated that a more lenient cutoff—110 beats per minute at all times—was just as effective at preventing adverse cardiovascular outcomes. Compared with tight control, “Lenient rate control is more convenient, since fewer outpatient visits, fewer examinations, lower doses of rate-control drugs, and less of the combination of drugs are needed,” noted principal investigator Isabelle Van Gelder, MD, of University Medical Center Groningen, the Netherlands, during the late-breaking clinical trials session. The multicenter Rate Control Efficacy in Permanent Atrial Fibrillation (RACE II) trial included 614 patients from 33 centers with permanent AF and mean resting heart rate of more than 80 beats per minute at baseline. During a dose-adjustment phase, patients in both groups were given ≥1 negative dromotropic drugs until the heart rate target was achieved. The mean resting heart rate was 93 beats per minute in the lenient group and 76 beats per minute in the strict group (P <.001).
Nearly all patients (97.7%) in the lenient group achieved the target compared with 67% of patients in the strict control group (P <.001). The lenient group achieved its target heart rates after 75 total healthcare visits compared with 684 visits for the strict control group (P <.001), Dr Van Gelder reported. After 2 to 3 years of follow-up, the clinical composite cardiovascular end point was reached by 12.9% of the lenient group and 14.9% of the strict group, which proved the noninferiority of the lenient approach. Symptoms of AF, hospitalizations, and adverse events also occurred at similar rates for the 2 groups. These findings led Dr Van Gelder and colleagues to suggest that the current guidelines should be called into question, and perhaps they should even be changed to reflect the new findings. They proposed that lenient rate control be adopted as “the first-choice rate-control strategy in patients with permanent atrial fibrillation” in high-risk and low-risk groups. Ralph Brindis, MD, MPH, a cardiologist at Kaiser Permanente, Oakland, CA, and President-Elect of the ACC, commented that, “The concept that you, as a clinician, can actually feel comfortable having a patient at a higher resting heart rate is huge.”—CH ■
Comparative Effectiveness Research
Applying Comparative Effectiveness Research... impact general medicine journals (Hochman M, et al. JAMA. 2010;303: 951-958). Of the 33% of studies applying comparative effectiveness research (CER) to evaluate medications, only a minority compared pharmacologic and nonpharmacologic therapies, and few focused on cost or safety. “Fewer than one third of medication studies published in top journals provide comparative effectiveness findings that help doctors choose the best treatments for their patients, and studies that do focus on comparing available treatments are limited in their scope,” said Cathleen D. Biga, CEO of Cardiovascular Management of Illinois. CER in Cardiology The need for CER in cardiology is great; in fact, cardiovascular (CV) disease is ranked among the top 3 recommended CER priorities, along with healthcare delivery and health disparities. For example, a recent study showed that a high number of cardiac catheterizations are done without proper indication (Patel MR, et al. N Engl J Med. 2010;362:886-895). Among
nearly 400,000 patients undergoing catheterization, only about 38% actually had obstructive coronary artery disease; 39% had no obstruction. “A 39% rate of normal coronaries is way too high today,” said William Oetgen, MD, a member of the American College of Cardiology (ACC) Disease Management Task Force. Rita Redberg, MD, Professor of Medicine at the University of California, San Francisco School of Medicine, noted that the use of imaging stress tests and cardiac catheterizations has risen steadily since the mid-1990s. Medicare spending on imaging services more than doubled between 2000 and 2006, from 6.9% to 14.1%, “and it has been hard to show a change in outcomes as a result,” Dr Redberg said. Using CER to Improve CV Care Panelists agreed that CER findings should be used to improve patient care. George P. Rodgers, MD, a cardiologist in Austin, TX, described how his heart hospital reduced length of stay and more effectively used beds by being aware of its practices and using that data to alter the discharge
Events Post-PCI More Frequent in Patients with Public Health Insurance By Wayne Kuznar
atients younger than age 65 who have no health insurance or have government-sponsored insurance experience higher adjusted rates of major cardiovascular (CV) events after a percutaneous coronary intervention (PCI) than those with private insurance, a new analysis shows. “Provision of public health insurance may thus not have a dramatic effect on rates of major adverse cardiovascular events after PCI,” according to Michael A. Gaglia Jr, MD, and colleagues at Washington Hospital Center and the MedStar Health Research Institute, Washington, DC. Patients of lower socioeconomic status are known to have higher rates of CV morbidity and mortality, and the type of insurance (or lack thereof) is an important component of socioeconomic status.
Table Adjusted Hazard Ratios for Major CV Events at 1 Year Age <65 yrs Hazard ratioa P Uninsured 2.41 .003 Medicaid 1.59 .03 Medicare 2.18 <.001 a
Reference group: privately insured patients aged <65 years.
The effect of insurance type on long-term outcomes after a PCI (angioplasty and stenting) is not well-established, so the researchers conducted a retrospective analysis of 13,573 patients who underwent PCI at a single center, including 3433 patients with PCI for acute myocardial infarction (MI). Nearly half (49.0%) of patients had private insurance, 45.3% had Medicare, 3.6% had Medicaid, and 2.1% had no insurance. Medicaid patients were more likely to be black (66.7%), whereas uninsured patients were more likely to be white (52.5%). The main outcome assessed was major adverse CV events at 1 year— a composite of all-cause death, Qwave MI, and revascularization of the target PCI vessel. Among those younger than age 65, uninsured patients had more than twice the risk of major CV events compared with those who had private insurance; those with Medicaid had a 59% increased risk, and those with Medicare had twice the risk (Table). There were too few uninsured people aged ≥65 years to draw conclusions. ■
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process. “Patients were being discharged primarily in the late afternoon and early evening. They were leaving with a poor understanding about postdischarge care, therefore we had a high readmission rate and
Continued from page 1 the Medicare Acute Care Episode Demonstration Project, which will provide global payments for episodes of acute care to improve quality for feefor-service Medicare beneficiaries; produce savings for providers, beneficiar-
“That’s the elephant in the room….Real reform will come when it [ie, patient care] is outcomes-based.”—George P. Rodgers, MD
our cost per case was high. We were not following all the ACC guidelines,” Dr Rodgers said. “We drilled down to understand what was happening, then developed a team approach to discharging patients, in particular using a nurse practitioner to discuss postdischarge care with patients in the morning and following guidelines more closely,” Dr Rodgers said. “We were able to cut the patient stay by over half a day. This is important, because hours matter in the hospital. Our readmission rate declined, and our patients were better satisfied, because they like predictability. With objective data, we could compare this.” But Suzette Jaskie, CEO of West Michigan Heart and Priority Health, Grand Rapids, MI, noted that her concern involves percutaneous coronary intervention (PCI). “Elective PCI lacks good evidence,” she said. “But if you put a policy to this one—ouch!” “Yes, that’s the elephant in the room,” Dr Rodgers agreed. “As long as the system of payment is fee for service, procedures will continue to be the big issue. Real reform will come when it is outcomes-based.” Physician engagement is critical to healthcare reform, but as an administrator, Ms Jaskie says this is lacking. “We really need physician input and engagement around the important questions before they are answered for us.” Role of CER in Payment Reform The question is how CER, as an evidence-based process, can guide payment reform, according to Ms Jaskie. “Data show that $40 billion is spent annually on heart failure, and a sizable portion is estimated to be on unnecessary readmissions,” she said. “Readmission at 30 days is a focus for CMS [Centers for Medicare & Medicaid Services] and payers alike. How can data be used to focus payment reform that maximizes patient outcomes at a lower cost than current practice?” A number of processes are being studied in attempts to do so. One is
ies, and Medicare; improve price and quality transparency for better decision-making; and increase provider collaboration. “The new parts are the inclusion of decision makers and the conscious effort to fold patients into CER,” Dr Redberg noted. The idea of using CER to make coverage decisions is not universally accepted, Ms Jaskie said. CER will help all parties to make betterinformed decisions, compare difficult treatment choices, and avoid reimbursements for therapies with little or no benefit. But all patients are individuals and “one size does not fit all,” she added. “It is hard to make blanket statements of ineffectiveness, as the drug performs differently in different subsets and at different times,” Dr Redberg pointed out. Therefore, therapies that may be effective for a given patient may not be reimbursed. There is active debate about linking CER data to coverage decisions. “Professional societies don’t want this,” according to Dr Redberg. The ACC supports CER, as stated in its 2009 Advocacy Position Statement: Principles for comparative effectiveness research (Drozda JP, et al. J Am Coll Cardiol. 2009;54:1744-1746), added James Palazzo, a consultant from Grapevine, TX. “They see it as a train that is leaving the station,” he said. But within their statement is the position that CER should not be used to determine physician reimbursement. Dr Oetgen offered, “The idea that CER should have nothing to do with payment is terminally naïve. It’s all about cost-savings today.” Ms Jaskie concurred. “I agree 100% that it’s naïve that what we learn by CER will not be applied to payment policy. It has to be,” she said. Using CER toward payment reform may be necessary, but it will not be easy, the participants agreed. In a feefor-service system that rewards volume, it is “hard to achieve reform and it is definitely messy,” Dr Redberg maintained. ■
Comparative Effectiveness Research
Ticagrelor Confers Superior Survival in CABG Surgery Compared with Clopidogrel Lack of Bleeding Risk Enhances Outcomes By Wayne Kuznar
n a head-to-head comparison between the 2 drugs in patients with acute coronary syndromes (ACS) who underwent coronary artery bypass graft (CABG) surgery, the investigational antiplatelet agent ticagrelor was superior to clopidogrel in preventing deaths, said lead investigator Claus Held, MD, PhD, Associate Professor of Cardiology, Uppsala Clinical Research Center, Sweden. Ticagrelor has a rapid offset of action that would permit patients to stop the drug and go to surgery relatively early, without the risk of bleeding. “Functional recovery of circulating platelets occurs within 48 hours” of stopping the drug, Dr Held said. In contrast, clopidogrel’s offset is 5 to 7 days. Dr Held analyzed outcomes in a subset of patients enrolled in a study of 18,264 patients with ACS who were
randomized to ticagrelor or to clopidogrel after the index event. All patients also received aspirin. According to the previously reported results of the larger study, patients assigned to ticagrelor had a 16% reduction in the primary composite end point of cardiovascular death, stroke, or myocardial infarction compared with those assigned to clopidogrel. Dr Held’s analysis focused on outcomes in the 1261 patients who underwent CABG. Although clopidogrel was supposed to be stopped 5 days before surgery, about one half of patients randomized to the drug were still taking it within 5 days before surgery, he said. Ticagrelor was recommended to be stopped 24 to 72 hours before surgery. The study drugs were to be restarted as soon as possible after sur-
“There was no significant increase in bleeding [with ticagrelor] despite the reduction in mortality.” —Claus Held, MD, PhD gery and before hospital discharge. At 12 months, total mortality was halved among the patients assigned
to ticagrelor compared with those receiving clopidogrel (4.6% vs 9.2%, respectively). “There was no significant increase in bleeding [with ticagrelor] despite the reduction in mortality,” said Dr Held. In addition, fewer ticagrelor patients reached the primary composite end point (10.5% vs 12.6%, respectively). In the larger trial, ticagrelor was associated with a 25% increase in the rate of major bleeding not related to CABG. The reversibility of ticagrelor may have played a role in the superior outcomes with this drug, he indicated. As evidence, the reduction in mortality with ticagrelor “was greater when the drug was stopped closer to the time of surgery.” There was also speculation of an unknown pleiotropic effect of ticagrelor that could explain its superiority over clopidogrel. “We are trying to understand the mechanism and we don’t yet have the answers,” said Dr Held. ■
New Comparative Data: Still No Answer on Safety, Efficacy of Drug-Eluting versus Bare Metal Stents for Acute MI Cost-Benefit Analysis Could Settle These Questions
ong-term follow-up from 2 studies has reenergized the debate over the preferential use of drug-eluting stents (DES) over bare metal stents (BMS) in patients with myocardial infarction (MI); the investigators call for more research on the relative costs and benefits on the 2 stents in patients with MI. The 3-year results of a Danish study suggest an increase in cardiovascular (CV) mortality with the use of DES compared with BMS, despite lower rates of major adverse cardiac events in the DES group, much like the results of the study at 8 months, said Peter Clemmensen, MD, President of the Danish Heart Foundation. Dr Clemmensen and colleagues randomized 626 patients to receive DES or BMS within 12 hours of STsegment elevation MI. After 3 years, major adverse CV events (cardiac death, any cause of death, another MI, stroke, or revascularization of the target lesion or the target vessel) occurred more often in patients with BMS, although this difference was driven by more repeat revascularization procedures rather than more deaths, recurrent MIs, or strokes. In fact, CV death occurred in only 1.9%
“The results present a conundrum: as a patient, would you rather have a risk of cardiac death or in case you survive, have a lesser chance of going back to the hospital to have a new PCI?” —Peter Clemmensen, MD of the BMS group compared with 6.1% of the DES group, and there was a strong trend toward fewer deaths from any cause in patients with BMS. Dr Clemmensen said, “The results present a conundrum: as a patient,
would you rather have a risk of cardiac death or in case you survive, have a lesser chance of going back to the hospital to have a new PCI [percutaneous coronary intervention] procedure?” Stent thrombosis could not account for the excess CV mortality in the DES group, because stent thrombosis rates were not significantly different between the 2 groups. The 1.6% CV mortality rate in the BMS arm was lower than that observed in previous trials of BMS in this setting, he added, which “would disfavor the DES arm.” A second comparison between DES and BMS in acute MI followed patients for 5 years and yielded no difference in safety or efficacy between the 2 groups, as well as no significant difference in the rate of late stent thrombosis, said lead investigator Maarten Vink, MD, of the Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, the Netherlands. Given the higher cost of DES, no apparent clinical advantage, and a possible risk of very late stent thrombosis, “there’s no reason to implant older DES” in patients with acute MI, said Dr Vink. He noted these results may not apply to later generations of
DES, which poses a problem for comparative effectiveness studies, because older generations of DES are being replaced by newer ones before the long-term results with past generations of DES are even known. Some 619 patients with acute MI were randomized to a paclitaxeleluting stent (a first-generation DES) or BMS. The primary composite end point of cardiac death, recurrent MI, and target lesion revascularization was achieved by 18.3% in the group assigned to paclitaxel-eluting stents and by 22.0% in the group assigned to BMS, a nonsignificant difference. The rate of “definite” stent thrombosis was twice as high in the group receiving DES but this difference was not significant. However, the difference in the rates of definite stent thrombosis between the 2 groups widened over time, explained Dr Vink, so DES may very well be associated with an increased risk of very late stent thrombosis. “Devices are being accepted with too little data,” said Dr Clemmensen. “We need to design larger trials earlier in the lifespan of a device to get a definitive answer to the efficacy… long-term.”—WK ■
Comparative Effectiveness Research
Catheter Therapy for Mitral Valve Repair Safer than Surgery Effective Option for Frail Elderly Patients By Wayne Kuznar
n a study comparing the 2 methods for valve repair/replacement in patients with significant mitral regurgitation, delivery of a clip through a catheter to repair a leaky mitral valve is safer than open-chest surgery and represents a new option for patients who are not candidates for or wish to avoid surgery, said lead investigator Ted Feldman, MD, Director of the Cardiac Catheterization Laboratory at North Shore University Health System, Evanston, IL. “For the right patients, this adds a new choice in the armamentarium for this disease,” said Dr Feldman. “The elderly and the frail will be very wellsuited for this therapy.” The mitral valve clip was not quite as effective as surgery in reducing the severity of mitral regurgitation, but major complications were much less frequent in the group that received the
mitral clip compared with surgery. The study included 279 persons who had moderate-to-severe (grade 3+) or severe (grade 4+) mitral regurgitation, who met the criteria for mitral valve surgery. Participants were randomized in a 2:1 ratio to the mitral clip or surgeries. At 30 days, major complications occurred in: • 9.6% of patients treated with the clip (none of those listed below) • 57% of patients treated with surgery, including 2 deaths, 2 major strokes, and 4 emergency cardiovascular surgeries. “The important finding is the fact that the actual safety difference between the 2 approaches is striking. The mitral clip procedure is one of the safest procedures that we have ever done in interventional cardiology,” declared Dr Feldman. “A critical point
is that surgery still remains an option for a patient after clip therapy.” At 1-year follow-up, the mitral clip was deemed successful in 72.4% of
“The actual safety difference between the 2 approaches is striking. The mitral clip procedure is one of the safest procedures that we have ever done in interventional cardiology.”—Ted Feldman, MD patients compared with a success rate of 87.8% in the patients who had surgery. Success was defined as no death and freedom from mitral valve surgery or reoperation, as well as a reduction in the severity of mitral regurgitation to a grade of 2+ or less (grade 2 is considered moderate mitral regurgitation).
“Clearly, this is a very exciting technology, but the trial set the bar for success way too low,” said J. Scott Millikan, MD, a surgeon at the Billings Clinic in Montana. He noted that only half of the patients who successfully received the clip left the catheter laboratory with less than 2+ mitral regurgitation. A total of 11 patients who were randomized to surgery elected to forgo it, “despite our admonitions that they needed mechanical therapy for their valve,” said Dr Feldman. “I have many patients like that, and they are certainly better suited by having 2+ mitral regurgitation than not having any therapy.” In Europe, the mitral clip costs about $27,000, in addition to the procedural and hospitalization costs, but the total costs would probably be much less than valve surgery, which also involves a longer hospital stay. ■
Less-Invasive Treatment Post-MI May Explain 50% Excess Mortality in Women than in Men W omen suffering myocardial infarction (MI) are being shortchanged compared with men when it comes to in-hospital treatment—primary angioplasty and stenting—and this difference in treatment strategies may account for the significantly worse in-hospital and 30-day post-MI survival rates in women compared with men, researchers reported at ACC.10. Women admitted to the hospital for MI underwent far fewer cardiac catheterizations than men, reported François Schiele, MD, Chief of Cardiology at University Hospital of Besançon, France. The implication is that treating women more aggressively may improve their post-MI outcomes, including survival. “When there are no clear contraindications, women should be treated with all recommended strategies, including invasive strategies,” Dr Schiele said. The researchers analyzed data from a regional registry of patients treated for MI between January 2006 and December 2007. Of the 3510 patients in the registry, 32% (1119) were women. Women were 9 years older than men on average, had more comorbidities (ie, diabetes, hypertension, dyslipidemia, history of MI, smoking history, previous angioplasty) and received fewer MI treatments. Their in-hospital mortality was twice as high as that of
men (9.7% vs 5.0%), and their mortality over the following month was also almost twice as high (12.4% vs 7.0%). Using a statistical method known as propensity matching, the researchers established 649 pairs of men and women who were closely matched according to their baseline clinical characteristics. A second propensity analysis matched 584 pairs of men and women according to baseline characteristics as well as treatment strategies.
“When there are no clear contraindications, women should be treated with all recommended strategies, including invasive strategies.”—François Schiele, MD In the first 649 pairs, the men were 57% more likely to undergo coronary angiography than the women. Among the patients who had more serious MI, characterized by an elevation in the ST segment of their electrocardiograms, men were far more likely to receive therapy to reperfuse the artery, whether by thrombolytic therapy (72% more often) or by angioplasty (24% more often). In addition, men had a 48% lower in-hospital mortality rate and a 30%
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lower mortality rate at 30 days compared with the matched women. In the second pair analysis, which matched treatment strategies in addition to baseline characteristics, the mortality differences disappeared between the genders. That is, when the
difference in treatment was removed, the difference in outcomes disappeared as well. This finding suggests that “a higher use of invasive procedures and reperfusion strategy could reduce the difference in mortality,” said Dr Schiele.—WK ■
CABANA: Ablation versus Drug Therapy for Complex Atrial Fibrillation
or complex, symptomatic atrial fibrillation (AF), catheter ablation appears better than drug therapy, according to initial results released at ACC.10 of the CABANA pilot trial, which is currently enrolling patients. Patients undergoing radiofrequency catheter ablation had a 58% reduced risk of symptomatic recurrence at 12 months compared with patients taking rate and rhythm control medication (65% vs 41%, P = .033), reported Douglas L. Packer, MD, of the Mayo Clinic, Rochester, MN. However, the ablation effect was not particularly durable, because recurrence rates tended to catch up over time, he added. The majority of patients had persistent or long-standing persistent AF and class 3 or 4 severity, which signified a “more problematic” population than have been included in other trials, and one that is difficult to treat effectively, said Dr Packer. Patients (n = 60) were randomized
to drug therapy (n = 31) and to catheter ablation (n = 29). The first AF events (excluding the 3-month postprocedural healing) occurred earlier in the drug therapy group, with 52% of patients experiencing events by month 6 compared with 24% of patients in the ablation arm. Freedom from symptoms at month 12 was 51% more likely with ablation. However, recurrence of any AF, flutter, or tachycardia became more likely with ablation over time, whereas recurrence with drug therapy remained more stable. Therefore, late recurrences with ablation may reduce its longterm effectiveness, Dr Packer said. “Given this patient population with more complicated atrial fibrillation, this pilot study establishes the feasibility and importance of conducting a pivotal trial for establishing long-term outcome, mortality, quality of life, and cost of therapy for atrial fibrillation,” he noted.
Angioedema Risk 50% Higher with ACE Inhibitors than with ARBs But Risk Still Higher than in Some Antihypertensives By Wayne Kuznar
he risk of angioedema with angiotensin receptor blockers (ARBs) is less than half of that with angiotensinconverting enzyme (ACE) inhibitors. However, these 2 drug classes confer a significantly greater risk of angioedema than placebo and some of the other antihypertensive drug classes, according to a study by researchers at St. Luke’s-Roosevelt Hospital Center in New York City. Angioedema is a rare but potentially life-threatening side effect of ACE inhibitors, possibly related to potentiation of bradykinin levels with these agents. ARBs also increase bradykinin levels by stimulation of the angiotensin II receptor, but the rate at which they cause angioedema has not been well studied. In a new meta-analysis, investigators
reviewed 18 clinical trials that involved ACE inhibitors—totaling follow-up of 488,111 person-years—and 9 trials on ARBs—totaling 220,490 person-years. The goal was to look for rates of angioedema associated with ACE inhibitors and with ARB compared with placebo-taking controls or antihypertensive drugs from other classes. Results of the meta-analysis showed the following rates of angioedema per 100,000 person-years with different classes: • 0.03% with calcium channel blockers • 0.05% with diuretics • 0.09% with placebo • 0.14% with ARBs • 0.23% with beta-blockers • 0.29% with ACE inhibitors. The risks of angioedema with ACE inhibitors and ARBs were 1.6 and 3.3
times higher, respectively, for patients with heart failure compared with those with hypertension and other cardiovascular diseases.
“There are 30 million patients who take ACE inhibitors per year, which means that there will be somewhere around 70,000 to 80,000 patients who might get angioedema in a year.”—Harikrishna J. Makani, MD “There are 30 million patients who take ACE inhibitors per year, which means that there will be somewhere around 70,000 to 80,000 patients who
INVEST: Rethinking Aggressive Blood Pressure Control in Diabetic Patients A ggressive blood pressure (BP) control for diabetic patients with coronary artery disease (CAD) or who are at high risk for cardiovascular disease (CVD) should be reconsidered based on new evidence released at ACC.10, showing that it offers no advantage in terms of outcomes compared with standard control in this patient population. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends a goal BP of <130/80 mm Hg in patients with diabetes. The American Diabetes Association and the National Institutes of Health mirror this recommendation, but evidence to support these recommendations had been lacking, particularly for diabetic patients with CAD. A retrospective analysis of data from a subset of patients in INVEST (International Verapamil SR-Trandolapril Study), which compared BP treatment strategies, showed an increased risk of mortality in diabetic patients with CVD who achieved a systolic BP (SBP) <115 mm Hg compared with SBP between 130 mm Hg and 140 mm Hg, said Rhonda M. Cooper-DeHoff, PharmD, Associate Professor of Pharmacy and Medicine at the University of Florida, Gainesville. Of 22,576 patients with hypertension and CAD who were enrolled in INVEST, Dr Cooper-DeHoff focused on the 6400 patients with diabetes.
INVEST was designed to compare 2 multidrug strategies and their effect on cardiovascular (CV) outcomes, with target BP <130/85 mm Hg. In this new analysis, patients were categorized according to their on-treatment BP level. Patients with SBP ≥140 mm Hg (34%) were categorized as “not controlled.” Those who achieved SBP <130 mm Hg were classified as “tight control,” and those with SBP between 130 mm Hg and 140 mm Hg were classified as “usual control.” Patients in the not controlled group had a nearly 50% greater risk of the combined end point of death, myocardial infarction (MI), or stroke compared with the usual care group (Table). There was no significant difference between the tight versus usual control groups for these outcomes.
might get angioedema in a year,” said Harikrishna J. Makani, MD, St. Luke’sRoosevelt Hospital and Columbia University College of Physicians and Surgeons, New York City, and lead investigator of the meta-analysis. In a direct head-to-head comparison of ACE inhibitors with ARBs, the risk of angioedema with ACE inhibitors therapy was 2.2-fold higher than with ARBs. Dr Makani noted that although ARBs are better tolerated than ACE inhibitors and are associated with less angioedema, “it’s the overall effect you have to look at as well,” for each patient. In randomized clinical trials of patients with heart failure in which the 2 classes were compared, ACE inhibitors had a slightly better effect on mortality, he said. ■
SEE ALSO ACCORD Lipid trial on page 19.
“Less than 140 [mm Hg] is the message we need to be getting out there; less than 130 [mm Hg] probably isn’t necessary to achieve benefit and may be harmful in some populations.”—Rhonda M. Cooper-DeHoff, PharmD
However, the risk of all-cause mortality increased by 15% in the tight control versus the usual care group. This increase in mortality from any cause started at about 3 years, and the difference in mortality risk between the 2 groups persisted with extended follow-up, which reached 11 years for some patients (Table). Analysis showed that the excess risk of dying started when SBP dropped
<115 mm Hg; it was even greater when SBP was ≤110 mm Hg. “Less than 140 [mm Hg] is the message we need to be getting out there; less than 130 [mm Hg] probably isn’t necessary to achieve benefit and may be harmful in some populations,” said Dr Cooper-DeHoff. “We wonder whether it is time to rethink lower blood pressure goals in patients with diabetes and coronary artery disease.”
Table INVEST Outcomes Rates Follow-up (N = 6400) Tight control, Outcome N (%) Primary outcome Nonfatal MI Nonfatal stroke Total MI Total stroke All-cause mortality
Usual control, Not controlled, N (%) N (%)
Extended follow-up (N = 4370) All-cause mortality
INVEST indicates International Verapamil SR-Trandolapril Study; MI, myocardial infarction.
ACCORD Reinforces INVEST’s Findings A second study that reinforced this finding was the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, in which 4733 high-risk diabetic patients were enrolled. Patients were assigned to intensive BP control (target SBP <120 mm Hg) or standard control (target SBP <140 mm Hg). At 1 year, average SBP levels were 119 mm Hg in the intensive control group and 134 mm Hg in the standard control group. The lower BP in the intensive control group was Continued on page 16
Hypertension High Calcium Channel Blockers Discontinuation Rate Caused by Pedal Edema Addition of an ACE Inhibitor or ARB Helps By Wayne Kuznar
ver the long-term, more than one fourth of hypertensive patients discontinue calcium channel blocker therapy because of pedal edema, reported researchers from St. Luke’sRoosevelt Hospital Center in New York City. Adding an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to a calcium channel blocker reduces the withdrawal rate from calcium channel blocker monotherapy, the same investigators found in a separate study. They performed a meta-analysis of 111 randomized controlled studies that included 79,631 patients with hypertension who were treated with calcium channel blocker monotherapy or no therapy/placebo (control group). Of patients who received calcium channel blockers, 17.7% had pedal edema compared with 5.7% of patients
in the control or placebo groups. The patient withdrawal rate because of edema was higher in patients receiving calcium channel blockers compared with those in the control/placebo group (4.2% vs 0.2%, respectively). “Both the incidence of edema and patient withdrawal rate due to edema increased with the duration of therapy with calcium channel blockers,” said Harikrishna J. Makani, MD, St. Luke’sRoosevelt Hospital and Columbia University College of Physicians and Surgeons, New York City, and lead investigator of this meta-analysis. The incidence of edema with highdose calcium channel blockers (>50% the usual maximal dose) was 2.9 times higher than with low-dose calcium channel blockers. The incidence of pedal edema progressively increased with the duration of calcium channel
blocker therapy up to 6 months. Long-term follow-up showed that more than 25% of patients with pedal edema discontinued calcium channel blocker therapy because of this side effect.
In another meta-analysis conducted by the same investigators, the combination of an ACE inhibitor or ARB with calcium channel blockers was shown to reduce the incidence
and withdrawal rates of pedal edema, Dr Makani reported. That analysis was done on 17 randomized controlled trials that included 12,611 patients. The mean duration of the trials was 9.2 weeks. The incidence of pedal edema with the combination of an ACE inhibitor or ARB with a calcium channel blocker was 8.3%, compared with 11.92% with calcium channel monotherapy. Likewise, patient withdrawal because of edema decreased 60% with the combination of an ACE inhibitor or ARB with a calcium channel blocker compared with calcium channel blocker monotherapy. The analysis also showed that ACE inhibitors were more effective in reducing pedal edema associated with a calcium channel blocker compared with ARBs. ■
kalemia, and hypotension were all more common with intensive control. Despite the small decrement in renal function with tight control, there were no differences between the tight control and the standard control groups in development of end-stage renal disease or progression to dialysis. “Most of us have been teaching for many years that the lower the blood pressure, the better the outcomes;
therefore, seek to get the blood pressure lower,” said Elijah Saunders, MD, Head of the Section of Hypertension, Division of Cardiology in the Department of Medicine, University of Maryland. “The data we have suggest that we still cannot recommend bringing blood pressure down to <120 mm Hg as a way of reducing risk. I suspect that we have to examine that over a period of time.”—WK ■
“The incidence of edema and patient withdrawal rate due to edema increased with the duration of therapy with calcium channel blockers.” —Harikrishna J. Makani, MD
INVEST: Rethinking Aggressive... Continued from page 15 nearly 15-mm Hg difference in SBP,” Dr Cushman said. Consistent with other BP treatment trials, the risk of stroke was reduced by 41% with intensive treatment, he said, but serious adverse events were more likely to occur with intensive BP control than with standard control (3.3% vs 1.3%, respectively). An elevation in serum creatinine levels and the incidence of syncope, bradycardia, hyper-
“We were surprised there was not an overall cardiovascular benefit, given the large size of the study and the nearly 15-mm Hg difference in SBP.” —William C. Cushman, MD achieved by prescribing a mean of 3.4 drugs compared with 2.1 in the standard care group. At a mean follow-up of 4.7 years, the annual rate of CV mortality, MI, or stroke was 1.9% in the intensive control group versus 2.1% in the standard control group, a nonsignificant difference. The end point of death was also not significantly different between the 2 groups, said lead investigator William C. Cushman, MD, Chief of the Preventive Medicine Section, Veterans Affairs Medical Center, Memphis, TN. “We were surprised there was not an overall cardiovascular benefit, given the large size of the study and the
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Genotyping Improves Warfarin Therapy, Reduces Costs Point-of-Care Test Will Cost $50 When Introduced in 2011 By Caroline Helwick
enetic testing to guide the initiation of warfarin dosing may reduce hospitalizations by nearly 30%, resulting in cost-savings, results of a prospective community-based trial conducted by Medco suggest. Patients genotyped for the warfarin metabolism gene CYP2C0 and the vitamin K blood-clotting activator gene VKORC1 had 27% fewer hospitalizations for bleeding and thromboembolism compared with historical controls (P = .039), reported Robert S. Epstein, MD, MS, Chief Medical Officer and President, Medco Research Institute, Medco Health Solutions, during a late-breaking clinical trials session at ACC.10. The cost of genetic testing—approximately $250 to $400 (differs by laboratory)—is justified by the savings. “If we reduce just 2 hospitalizations per 100 patients tested, that more than compensates for the cost of genotyping,” Dr Epstein said. Thomas Moyer, PhD, of the Mayo Clinic in Rochester, MN, who presented data during a session on genomics, commented on this study, saying, “The genetic test costs 10 times less than a head CT [computed tomography] scan that is ordered because a patient has a stroke with warfarin, and 1000 times less than hospitalization due to a major bleed.” He said that a point-ofcare test will become available in 2011 and will cost just $50. The MM-WES (Medco-Mayo Warfarin Genotyping Effectiveness Study) enrolled 896 patients who were initiated on long-term outpatient warfarin therapy and who were genotyped from blood samples or buccal swabs. Their physicians received a printout of the genotyping results for both genes, as well as a template recommendation for warfarin dose and monitoring frequency. Warfarin sensitivity varied greatly
according to genotype (Table), which dictated medication adjustments. For patients with below-normal warfarin sensitivity, median dose increase was 6.65 mg; those with moderate-tovery-high sensitivity had a mean dose-dependent decrease of 3.65 mg to 17.33 mg.
“With this test, we identified 33% of patients who may require a modest or significant reduction in warfarin dose.” —Thomas Moyer, PhD “With this test, we identified 33% of patients who may require a modest or significant reduction in warfarin dose,” Dr Moyer said. When patients were found to have very sensitive genotypes, Medco called the physician to explain the greatly increased risks associated with standard dosing and recommended more frequent monitoring. Physicians responded positively to the program and to the intervention. “The vast majority had not known of warfarin genotyping,” Dr Moyer said. “With this test, we can give the physician more confidence in treating these patients. In some cases, they may treat more aggressively than they might otherwise.”
Genotyping Greatly Improved Outcomes Compared with matched historical controls, genotyping resulted in a 27% reduction in hospitalization for bleeding or thromboembolism (P <.001) and a 28% reduction in all-cause hospitalization (P = .039). In addition, the sooner patients were genotyped after starting warfarin, the better were the outcomes, said Dr Epstein. At the genomics session, Dr Moyer presented follow-up data and elaborated on how the program worked. He said that 160 days after treatment, allcause hospitalizations were significantly reduced by 31%—from 20.5% to 14.0% (P <.001); hospitalizations associated with bleeding or thromboembolism were reduced by 40%—from 6.2% to 3.2% (P = .005). Propensity score adjustments were done to control for differences between the groups with respect to indications for therapy, concomitant drug use, medical conditions, and any relevant history. The Hawthorne Effect? The narrow therapeutic range of warfarin makes it difficult to strike the right balance between the risk of bleeding and the risk of thromboembolic events. The wide variability in patients’ sensitivity to the drug further complicates dosing. Efforts to
Table Warfarin Sensitivity, by Genotype Genotype
Warfarin sensitivity, %
Less sensitive (2C9*1*1 VK GG)
Typical (2C9*1*1 VK GA)
Mild sensitivity (2C9*1*2 VK GG)
More sensitivity (2C9*1*3 VK GA) (2C9*2*3 VK GG) (2C9*1*1 VK AA)
Very sensitive (2C9*2*3 VK GA)
Extremely sensitive (2C9*2*3 VK AA)
“If we reduce just 2 hospitalizations per 100 patients tested, that more than compensates for the cost of genotyping.” —Robert S. Epstein, MD, MS improve safety have been researched for some time. According to Dr Epstein, clinicians can use genetic testing to predict the best warfarin dose early-on, which will result in a more stable dose, and ultimately, a lower risk for negative outcomes. But study discussant Mandeep R. Mehra, MBBS, of the University of Maryland, Baltimore, said that the study design was not adequate to show that genotyping results in better management and greater safety. He suggested that it may be more likely that the differences in hospitalization stemmed from the greater attention paid to the experimental group, a phenomenon known as the “Hawthorne effect.” Dr Epstein responded that if the results are a reflection of better patient management, then that in itself is a positive result. “Warfarin has been used for 50 years,” he noted, “and we have been talking about better attention the whole time.” ■ SEE ALSO “Novel Anticoagulant Safe and Well-Tolerated,” page 21.
TRITON-TIMI 38 Substudy: Genetic Variant Affects Response to Clopidogrel
common genetic variant in the ABCB1 gene rendered patients less responsive to dual antiplatelet therapy with clopidogrel but not with prasugrel (plus aspirin), in a retrospective genetic substudy of the TRITON-TIMI 38 (Trial to Assess Im provement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction). TRITON-TIMI 38 was a phase 3 head-to-head study comparing the
effects of prasugrel versus clopidogrel in patients with acute coronary syndromes who underwent percutaneous coronary intervention with stenting. The study enrolled 13,608 patients from 30 countries who were treated for up to 15 months. The ABCB1 gene contains the genetic code for P-glycoprotein, which plays an important role in the absorption of certain medications, including antiplatelet drugs. Evidence suggests that the C3435T genetic variant in the
“Multiple genetic variations may impact a patient’s response to antiplatelet medications, and these effects appear to differ from medication to medication.” —Jessica Mega, MD, MPH ABCB1 gene is associated with altered disposition of several drugs.
In this substudy, investigators analyzed clinical outcomes of 2943 patients tested for the C3435T variant in the ABCB1 gene. Of these patients, 27% had 2 C3435T variants. Among the clopidogrel-treated patients, those who had these 2 variants had a 66% increased risk for the primary composite end point of cardiovascular death, myocardial infarction, or stroke compared with those without the variant (12.9% vs 8.2%, respectively; P = .033), reported Jessica Mega, Continued on page 18
Genomic Analysis Coming Soon to a Laboratory Near You By Caroline Helwick “
ecause of the ‘genomics gold rush,’ more discoveries about the root causes of disease have been made in the past 3 months than in the history of man,” said Eric J. Topol, MD, Director of the Scripps Translational Science Institute, Professor of Translational Genomics, and the Gary and Mary West Chair of Innovative Medicine at the Scripps Research Institute, La Jolla, CA. Dr Topol made this bold statement during his ACC.10 lecture, “Moving Toward Personalized Medicine,” in which he envisioned a future that puts genetics and pharmacogenetics at the forefront as a clinical decisionmaking tool. In 2010 alone, researchers have come to understand the genetics underlying atrial fibrillation, type 2 diabetes, anxiety disorder, pancreatic cancer, dementia, chronic obstructive pulmonary disease, celiac disease, and other conditions, he said. “Whole genome sequencing is where the field is moving now,” Dr Topol said. “Until now, all we could detect were single nucleotide polymorphisms [SNPs] at the 5% threshold or greater. Now we are getting down to lower thresholds.” This is an important factor in iden-
tifying persons at greatly increased risk for disease. Whereas common SNPs carry about a 25% excess risk, rare variants may increase the risks for certain diseases 20- to 50-fold. He described, for example, a highly penetrant form of morbid obesity in which deletions on chromosome 16p11.2 raise the risk 43-fold. This information is not just for laboratory researchers anymore. “Consumers are gaining access to this information,” he said. “It’s a changing time.” And whereas decoding the human genome once involved analyzing 3 billion base pairs—and took 10 years the first time it was done, in 2003—it is accomplished in just 1 week today, he
tool, which showed he has normal alleles for the CYP2C19 enzyme, and can therefore expect to have a typical response to clopidogrel therapy, but
“Because of the ‘genomics gold rush,’ more discoveries about the root causes of disease have been made in the past 3 months than in the history of man.”—Eric J. Topol, MD
said. The ease of such decoding is clear by the emergence of tests targeting the consumer. Dr Topol disclosed that he has had a genetic scan from deCODEme, a genetic health scan
he has a 29% risk for atrial fibrillation—a 20% increased risk over the average person. Dr Topol imagined a future in which a patient’s individual genomic profile
CARE: Genotyping Can Identify Which Patients Will Respond to Statins A
genotyping analysis performed on the CARE (Cholesterol and Recurrent Events) trial population identified a genetic subset of patients who derived the most benefit from pravastatin. “After adjusting for age, sex, and ethnicity, we found that pravastatin reduced events in carriers of the 719Arg allele of KIF6, but not in noncarriers,” said coinvestigator Olga A. Iakoubova, MD, PhD, of Celera, a genomics analysis company in Alameda, CA. Based on their results, Dr Iakoubova reasoned that to prevent 1 cardiovascular event, statins need to be given to just 10 allele carriers but to 125 noncarriers of the allele. Approximately 60% of individuals carry the variation, which renders them more likely to have higher low-density lipoprotein cholesterol levels but also makes them more responsive to statins. “With statin therapy, these persons can reduce their risk to a level that is even lower than noncarriers,” she said. The CARE trial was a double-blind
“We found that pravastatin reduced events in carriers of the 719Arg allele of KIF6, but not in noncarriers.” —Olga A. Iakoubova, MD, PhD
study that enrolled 4159 patients with myocardial infarction (MI), randomly assigned to receive 40 mg/day pravastatin or placebo. A similar genetic analysis also showed an effect only in KIF6 719Arg carriers, but that
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analysis included only white patients. The present study was more inclusive that adjusted for population structure based on 3109 patients for whom DNA was available. Results showed that carriers of KIF6 719Arg received significant benefit from pravastatin therapy compared with placebo, with a 37% reduction in MI and fatal coronary events when adjusting for age, sex, and self-reported ethnicity. No benefit from pravastatin over placebo was observed in noncarriers. The cumulative incidence of primary end point events among carriers of the allele was higher in the placebo versus the pravastatin group (P = .009), with an absolute risk reduction of 5% with 5 years of pravastatin therapy. In the noncarriers, however, no difference was found in the cumulative incidence of events between the 2 groups. Dr Iakoubova suggests that noncarriers should perhaps receive additional treatment to lower their lipid levels.—CH ■
may be loaded onto his or her personal “smart phone,” and these data may be accessed during a physician visit to guide treatment choices. “When the cardiologist prescribes a statin, for example, the patient and physician can check for a genetic risk for myopathy, for example,” he envisions. But physicians need a lot of preparation for this. A survey of >10,000 physicians conducted by Medco and the American Medical Association showed that only 25% of physicians had received education on the use of genetic testing to guide treatment decisions, and only 10% felt that they had the necessary training and knowledge to put pharmacogenetic testing to good use. ■
TRITON-TIMI 38... Continued from page 17 MD, MPH, of Brigham and Women’s Hospital, Boston. In contrast, response to prasugrel was not dependent on the absence of the variant. Prasugrel-treated patients with 2 C3435T variants did not have a significantly increased risk for the primary composite end point compared with those without the variant (11% vs 9.7%, respectively; P = .64). The investigators concluded that persons with 2 C3435T variants have less platelet inhibition and are at a significantly increased risk for recurrent ischemic events when taking clopidogrel. “These data are important because they suggest that multiple genetic variations may impact a patient’s response to antiplatelet medications, and these effects appear to differ from medication to medication,” she said. “Understanding the full scope of these genetic variations may help determine which drug to prescribe as part of the dual antiplatelet therapy a patient receives after an angioplasty with a stent.”—CH ■ SEE ALSO article on page 19.
Diabetes and CVD ACCORD Lipid: Fenofibrate plus Statin No Better than Statin Alone in Diabetics But Some Patients Gain Benefits, with a Curious Gender Difference SEE ALSO INVEST trial on page 15.
By Wayne Kuznar
he addition of fenofibrate to a statin did not reduce the risk of cardiovascular (CV) events compared with a statin alone in most patients with type 2 diabetes who are at high risk for CV disease according to results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial presented at ACC.10. However, a minority of diabetic patients with elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) levels appears to have reduced CV risk with the addition of fenofibrate, said Henry N. Ginsberg, MD, lead investigator of the trial, and Director, Irving Institute for Clinical and Translational Research, Columbia University, NY. Many cardiologists are already using fenofibrate in the dyslipidemic subgroup of patients in whom a benefit was found, and as such, this trial probably will not change practice, commented Paul Thompson, MD, Chief of Cardiology and Director of the Preventive Cardiology Program, Hartford Hospital, CT. The ACCORD Lipid trial, sponsored by the National Heart, Lung, and Blood Institute, enrolled 5518 patients with type 2 diabetes and hemoglobin A1c ≥7.5% who were being treated with simvastatin. Patients were randomized to the addition of fenofibrate or placebo. Of the patients in this trial, 37% had a previous CV event. In the fenofibrate plus statin group:
• LDL-C (low-density lipoprotein cholesterol) decreased from a median of 100 mg/dL to 81 mg/dL • HDL-C increased from 38 mg/dL to 41.2 mg/dL • Triglycerides decreased from 189 mg/dL to 147 mg/dL. In the placebo group: • LDL-C decreased from 101 mg/dL to 80 mg/dL • HDL-C and triglycerides did not change much. After a mean follow-up of 4.7 years, the primary outcome—the annual rate of major fatal/nonfatal CV events—was 2.2 in the fenofibrate recipients compared with 2.4 in the placebo group (Table), a nonsignificant difference. In a subgroup analysis, men appeared to benefit from fenofibrate therapy, whereas women appeared to be harmed by it. The study drug was discontinued because of a decrease in estimated glomerular filtration rate in 2.4% of those taking fenofibrate and in 1.1% of patients taking placebo. An especially dyslipidemic subgroup—with a triglyceride level in the
“Many patients don’t have the degree of diabetic dyslipidemia that requires another medication.” —Henry N. Ginsberg, MD highest third (≥203 mg/dL) and an HDL-C in the lowest third (≤34 mg/dL)—had a 31% reduction in CV events with fenofibrate versus placebo, noted Dr Ginsberg. Other studies have also suggested CV benefit with a fibrate drug in patients with this type of lipid profile (ie, high triglycerides, low HDL-C). This finding is consistent with current
Table ACCORD Lipid Study Primary outcome Major fatal/nonfatal CV event
Fenofibrate Events, N Rate, %/yr 291
Placebo Events, N Rate, %/yr 310
ACCORD indicates Action to Control Cardiovascular Risk in Diabetes; CV, cardiovascular.
guidelines by the Adult Treatment Panel III of the National Cholesterol Education Program, which recommends a treatment in addition to a statin for patients with hypertriglyceridemia and low HDL-C levels. “Many patients don’t have the degree of diabetic dyslipidemia that requires another medication,” said Dr Ginsberg, noting that he does use it in patients with significant hypertriglyceridemia. With a median triglyceride level of only 162 mg/dL in this patient population, “it’s not surprising that no benefit was found in the overall group,” said Dr Thompson. “I tend to think of fenofibrate as a triglyceride drug.” He added that the duration of the trial may also have been too short to show a significant benefit with fenofibrate in the entire study group, because triglycerides are a weaker risk factor for CV events than LDL-C. ■ FDA Requests More Information on Combo Pill AstraZeneca and Abbott an nounced on March 30, 2010, that the US Food and Drug Administration (FDA) requested additional information for the new drug application for the rosuvastatin/fenofibric acid delayed-release capsules combination. The companies indicated they will continue discussions with the FDA to determine the next steps and will respond to the agency’s request for additional information.
NAVIGATOR: Lifestyle Modification Still Best Strategy to Prevent Diabetes
n patients with impaired glucose tolerance (IGT) and cardiovascular disease (CVD) or risk factors for CVD, neither valsartan nor nateglinide reduced the incidence of cardiovascular (CV) events over a 5-year period, but valsartan did reduce the risk of progression to diabetes, according to investigators of the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial. These data reinforce the role of lifestyle changes in patients with IGT to prevent progression to diabetes and reduce their risk for CV events. NAVIGATOR included 9306 patients with IGT, defined as a fasting plasma glucose concentration of 95 mg/dL to 125 mg/dL, who had either known CVD or CV risk factors. Patients were randomized to (1) valsartan or placebo, or (2) to nateglinide or placebo. All patients also participated in a lifestyle modification program to help
them lose ≥5% pounds through diet and exercise. The 3 coprimary end points were (1) incidence of new-onset diabetes; (2) combined CV end point of myocardial infarction (MI), stroke, or hospitalization for heart failure (HF); and (3) 5year progression of CVD. Neither drug intervention reduced the incidence of MI, stroke, or hospitalization for HF compared with placebo. Valsartan was associated with a 14% relative reduction in incident diabetes. Previous trials of angiotensinconverting enzyme (ACE) inhibitors had slightly greater reductions in diabetes with these agents, noted Robert M. Califf, MD, MACC, coinvestigator of NAVIGATOR and Vice-Chancellor for Clinical Research at Duke University, Durham, NC. “In our view, it puts to rest an argument that has gone on for a while in the cardiovascular community about
renin-angiotensin system blockers— ACE inhibitors and angiotensin receptor blockers. A number of studies that did not have this as the primary end point found that there was a reduction in diabetes, but you couldn’t really prove it because it wasn’t a primary end point,” he said.
“22% of these people had diabetes and didn’t know it, even though they were under medical care, so this is a battle that we are all losing.” —Robert M. Califf, MD, MACC “Nateglinide was safe in this context [impaired IGT] but did not prevent the disease itself,” said NAVIGATOR coinvestigator Rury R. Holman, MD, Professor of Diabetic Medicine University of Oxford, UK. He said that
nateglinide had been proposed to reduce CVD risk in patients with IGT, because “glucose levels after meals have been uniquely associated with the risk of cardiovascular disease.” NAVIGATOR is a testament to lifestyle interventions as a means to prevent diabetes. Both groups lost weight through the lifestyle program. The effectiveness of the study drugs may have been blunted, because patients in the control group who were returned to their personal physicians with a diagnosis of IGT had intensification of other therapies to lower blood pressure and improve their lipid profiles, which may have lowered their overall CV risk. Among the 43,502 subjects who were screened for the study, “22% of these people had diabetes and didn’t know it, even though they were under medical care, so this is a battle that we are all losing,” said Dr Califf.—WK ■
In a Shift, Women Referred More Often for Cardiac Catheterization after Noninvasive Testing By Wayne Kuznar
n an apparent dramatic shift in practice patterns, women are twice as likely as men to be referred for cardiac catheterization to diagnose obstructive coronary artery disease (CAD), according to an examination of data from a large registry presented at ACC.10. Catheterization has historically been performed much more frequently in men, but the new data imply that widespread public awareness campaigns about women and cardiovascular disease (CVD) have been successful at educating physicians and altering their behavior, said lead investigator Marcelo Di Carli, MD, Director of the Noninvasive Cardiovascular Imaging Program at Brigham and Women’s Hospital, Boston.
ateness for referral to cardiac catheterization in patients after noninvasive testing, it is unclear whether the observed variation in referral to cath-
eterization reflects undertreatment, appropriate use, or overtreatment,” said Dr Di Carli. Numerous previous studies have
found undertreatment of stable CVD in women compared with men, he said, and “it seems that the pendulum has swung in the opposite direction.” ■
“Without a definitive standard of appropriateness for referral to cardiac catheterization in patients after noninvasive testing, it is unclear whether the observed variation in referral to catheterization reflects undertreatment, appropriate use, or overtreatment.” —Marcelo Di Carli, MD The registry included 1703 patients (891 women and 812 men) with an intermediate-to-high likelihood of CAD who underwent various cardiac imaging tests (ie, SPECT, positron emission tomography, and coronary computed tomography angiography). The researchers assessed the 90-day referral to cardiac catheterization in these patients. They found that 13% of women versus 6% of men were referred to cardiac catheterization. After adjustment for age, diabetes, noninvasive imaging studies, and chest pain, female sex remained a significant predictor of referral to cardiac catheterization. Whether the observed difference in this study is a result of excessive referral to cardiac catheterization in women or underutilization in men requires further investigation. “Without a definitive standard of appropriSEE ALSO “Less-Intensive Treatment Post-MI in Women…” on page 14.
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Regenerative Medicine for Cardiologists: Advances and Challenges By Wayne Kuznar
he field of regenerative medicine is longstanding and continues to evolve, but clinical advances have been few thus far, said Anthony Atala, MD, Professor and Chair, Department of Urology, Wake Forest University, and Director of the Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, during the Simon Dack Lecture at ACC.10. The new class of amniotic stem cells offers the potential to form many cell types and may be the next advance, with specific implications for cardiologists. The 3 primary challenges to clinical advances are: 1. An inability to expand cells outside of the body in large quantities. “That’s actually what got us started in this field about 20 years ago,” said Dr Atala. “Twenty years ago, most human cells from your organs would not be grown outside the body in large quantities, so we started looking at the growth factor biology.” Understanding growth factor biology has enabled the growth of cells taken from a tiny piece of tissue to expand enough to cover a football field in 60 days.
Currently, different tissue types can be grown, but several cell types— including nerve, liver, and pancreas—still cannot be grown outside of the body. 2. Inadequate biomaterials. The scaffolds being used to shape tissues and organs must replicate the mechanical and structural properties of the tissue being replaced. 3. Vascularity. Cells cannot be grown outside of the body in volumes >3 mm3—the maximum diffusion distance for vascularity. “This presents us with a dilemma: we have enough cells to cover a football field, yet we could only implant cells that would have the size of a pencil eraser,” said Dr Atala. Nature solves the problem of vascularity through branching. Scientists have now come up with biomaterials that have a branching pattern, which allows cells to form tissue layers to promote vascularity. Dr Atala discussed current strategies to grow blood vessels, flat structures, tubular structures, and hollow organs, with the latter being the most complex. Experience with tissue-engineered
Dr Atala discussed current strategies to grow blood vessels, flat structures, tubular structures, and hollow organs. vaginas shows approximation of normal biomechanical function and innervation by 6 months. There has been a similar experience with the human bladder. The first patient to undergo bladder regeneration was 12 years ago. Heart valves have also been engineered, and these valves are exercised in bioreactors before being implanted
(in animal models) to ensure that they are fully endothelialized to prevent platelet adhesion. His laboratory has also successfully grown a uterus, “by far the most complex hollow organ.” With 10 times the number of cells per centimeter as hollow organs, solid organs are the most complex organs to grow. Using a modified desktop inkjet printer, a heart can be printed “one layer at a time,” he said. “We are able to see that 4 to 6 hours later, the whole heart starts to contract.” Embryonic stem cells grow rapidly but are prone to tumor formation and rejection. Adult bone marrow stem cells have no potential for tumors or rejection but will not grow outside of the body. Stem cells found in amniotic fluid have several advantages. They grow rapidly, are not rejected, do not form tumors, and can go into all 3 germ layers like human embryonic stem cells do. Amnion stem cells can form 3dimensional aggregates of cells known as embryoid bodies; it is believed that cells at this stage of development can be directed to become virtually any cell in the human body. ■
Low Vitamin D Prevalent in MI Patients, Linked to Poor Outcomes Supplementation Cost-Effective Way to Improve CV Health By Caroline Helwick
he majority of patients with heart disease have vitamin D deficiency, and when their levels are normalized, cardiovascular (CV) outcomes improve, show new data of 2 poster presentations at ACC.10. Testing for vitamin D levels is inexpensive, and supplementation is a very cost-effective way to improve outcomes. John H. Lee, MD, Cardiology Fellow at Ochsner Clinic Foundation, New Orleans, LA, and colleagues investigated vitamin D deficiency in 239 patients who had acute myocardial infarction (MI). They classified 25-hydroxyvitamin D (25[OH]D) levels as: • Normal, ≥30 ng/mL • Deficient, ≤20 ng/mL • Insufficient, between <30 ng/mL and >20 ng/mL. A total of 75% of patients had 25(OH)D deficiency, 21% had insufficiency, and only 4% had normal vitamin D levels. “We think this is the first study to describe the vitamin D status in post-MI patients from a diverse population,” Dr Lee said. “We found an extraordinarily high prevalence of vitamin D deficiency or insufficiency (96%) in patients admitted for an MI,
which is consistent with an abundance of data associating cardiovascular disease and many of its risk factors with vitamin D deficiency.”
“We found an extraordinarily high prevalence of vitamin D deficiency…in patients admitted for an MI, which is consistent with an abundance of data associating cardiovascular disease…with vitamin D deficiency.” —John H. Lee, MD Although no differences were found in relation to age or sex, a significantly greater proportion of deficient patients were non-white and had lower social support, no insurance, diabetes, and lower levels of physical activity. Higher parathyroid hormone levels, higher body mass index, and current smoking were also more common among those with 25(OH) deficiency.
The findings made sense to Joseph B. Muhlestein, MD, Cardiologist at Intermountain Medical Center, Murray, UT. “I have been testing vitamin D in my heart disease patients, and I have found that about 85% are deficient,” he said. Dr Muhlestein and colleagues identified 9491 patients with a low baseline vitamin D level (≤30 ng/mL) and at least 1 follow-up measurement. The last measured level was used to determine if patients whose levels were normalized (>30 ng/mL) had less risk of death, coronary artery disease (CAD), acute MI, heart failure (HF), and renal failure. The mean baseline vitamin D level was 19.3 ng/mL. Among patients who were normalized, the average vitamin D level was 33.1 ng/mL compared with 21.9 ng/mL for those who were not normalized. Patients whose levels were normal on follow-up had less risk of death, CAD, HF, and renal failure than patients who remained deficient. Patients who remained deficient had a 26% increase in composite CV outcomes, including: • 33% increase in acute MI • 32% increase in renal failure
• 30% increase in deaths • 20% increase in HF • 17% increase in CAD • 3% increase in stroke. The optimal dose of vitamin D supplementation may vary. Some patients require high doses, and patients undergo baseline testing, followed by treatment, and then retesting to see if they have normalized. “We propose that you have to go up to 43 ng/mL to get the most benefit,” Dr Muhlestein said. ■
Novel Investigational Anticoagulant Safe and Well-Tolerated By Caroline Helwick
he investigational anticoagulant betrixaban could simplify the prevention of strokes in high-risk patients with atrial fibrillation (AF), according to results of a phase 2 clinical trial presented at ACC.10. Betrixaban had a similar or lower risk for serious bleeding compared with warfarin and was easier to administer, said Michael D. Ezekowitz, MD, PhD, Vice President of the Lankenau Institute for Medical Research, Wynnewood, PA, and Professor of Medicine, Jefferson Medical College, Philadelphia.
would be administered as an injection, to reverse the anticoagulation activity of betrixaban. “Betrixaban is in an early stage of development, but these results provide helpful indicators regarding the path
“Betrixaban appears to be safe and well-tolerated in a real-life, diverse atrial fibrillation population.” —Michael D. Ezekowitz, MD, PhD Betrixaban directly inhibits factor Xa, a key enzyme in the blood-clotting cascade. Dose adjustments for renal impairment are not necessary, because this drug is not excreted through the kidneys. “The most important finding is that betrixaban appears to be safe and welltolerated in a real-life, diverse atrial fibrillation population,” Dr Ezekowitz said. The study was unusual in its enrollment of a wide variety of patients with AF, regardless of kidney function, age, weight, or need for other medications. The EXPLORE Xa trial included 508 patients from 35 centers in the United States, Canada, and Germany. All patients had AF and at least 1 additional risk factor for stroke. Patients were randomly assigned to 1 of 3 doses of betrixaban (40 mg, 60 mg, or 80 mg) or to warfarin therapy, with the dose adjusted as necessary. “Compared to well-treated, experienced warfarin patients, there was a dose-dependent effect on the primary end point of major and clinically relevant nonmajor bleeding,” he reported. After a follow-up of 3 to 12 months, there was no difference in the rate of stroke or death between any of the betrixaban arms and warfarin. However, betrixaban 40 mg daily was associated with less major bleeding and clinically relevant nonmajor bleeding compared with warfarin (1 patient vs 4 patients). At higher doses, the bleeding rates were similar among the arms. Stroke range was within the range seen with warfarin. A unique aspect of the betrixaban program is that the drug is being developed along with an antidote that
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forward for further development of this drug,” Dr Ezekowitz said. He was asked to compare it to dabigatran, the factor Xa inhibitor now in late stages of development. Dr Ezekowitz responded that because no direct com-
WARNING: AVOID USE IN PREGNANCY When used in pregnancy, drugs that act directly on the reninangiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS tablets should be discontinued as soon as possible. See Warnings and Precautions.
BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Hypertension MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. Cardiovascular Risk Reduction MICARDIS is indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors. High risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ damage. MICARDIS can be used in addition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy). Studies of telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider re-trying the ACE inhibitor after the cough resolves. Use of telmisartan with an ACE inhibitor is not recommended.
WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue MICARDIS tablets as soon as possible [see Boxed Warning]. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Inform mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester that most reports of fetal toxicity have been associated with second and third trimester exposure. Nonetheless, when patients become pregnant or are considering pregnancy, have the patient discontinue the use of MICARDIS tablets as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, MICARDIS should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Hypotension In patients with an activated renin-angiotensin system, such as volumeand/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of ther-
parison has been done on the relative efficacy of these, he could not comment on this, adding that dabigatran had “raised the bar” for anticoagulants, and it appears that betrixaban has cleared that higher threshold. ■
apy with MICARDIS. Either correct this condition prior to administration of MICARDIS, or start treatment under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Hyperkalemia Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassiumcontaining salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk. Impaired Hepatic Function As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients. Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results have been reported with MICARDIS. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of MICARDIS in patients with unilateral or bilateral renal artery stenosis but anticipate an effect similar to that seen with ACE inhibitors. Dual Blockade of the Renin-Angiotensin-Aldosterone System As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function. The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of MICARDIS and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of MICARDIS and ramipril is not recommended.
ADVERSE REACTIONS The following adverse reaction is described elsewhere in labeling: Renal dysfunction upon use with ramipril. Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Hypertension MICARDIS has been evaluated for safety in more than 3700 patients, including 1900 treated for over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of MICARDIS (20-160 mg) monotherapy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated with placebo. Adverse events occurring at an incidence of ≥1% in patients treated with MICARDIS and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1. Table 1 Adverse Events Occurring at an Incidence of ≥ 1% in Patients Treated with MICARDIS and at a Greater Rate Than in Patients Treated with Placebo Te lmis a rt a n ( n= 1455 ) %
P l a ce bo ( n= 380 ) %
Upper respiratory tract infection
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In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with Micardis® (telmisartan) tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in 6 placebocontrolled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets. Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia. Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Cardiovascular Risk Reduction Because common adverse reactions were well characterized in studies of telmisartan in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of telmisartan for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations for adverse events were 8.4% on telmisartan and 7.6% on placebo. The only serious adverse events at least 1% more common on telmisartan than placebo were intermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%). Postmarketing Experience The following adverse reactions have been identified during postapproval use of MICARDIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction, and tendon pain (including tendonitis, tenosynovitis). Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS.
initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range. Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including MICARDIS. Therefore, monitor serum lithium levels during concomitant use. Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steadystate Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Concomitant use of MICARDIS and ramipril is not recommended. Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.
USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects, Pregnancy Categories C (first trimester) and D (second and third trimesters). See Warnings and Precautions. Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients receiving MICARDIS in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and 130 (4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Of the total number of patients receiving MICARDIS in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Insufficiency Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency.
OVERDOSAGE Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.
© Copyright 2009, Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Rev: November 2009
DRUG INTERACTIONS Digoxin: When MICARDIS was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Therefore, monitor digoxin levels when
THET E DONLY ARB TO REDUCE I N D I CA CV RISK
In high-risk∗ patients who are unable to take an ACE-I,
REDUCE THE RISK OF MI, STROKE, OR DEATH FROM CV CAUSES ARB: Angiotensin receptor blocker. CV: Cardiovascular. ACE-I: Angiotensin-converting enzyme inhibitor. MI: Myocardial infarction.
Supported by ONTARGET and TRANSCEND, two studies in a large-scale clinical program with entry criteria similar to those used in the HOPE trial with ramipril— MICARDIS® (telmisartan) 80 mg tablets reduce MI, stroke, or death from CV causes in a broad range of high-risk patients with or without hypertension.1-3 ∗
High risk is evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin dependent or non-insulin dependent) with evidence of end-organ damage.
Important Safety Information and Full Indication WARNING: AVOID USE IN PREGNANCY When used in pregnancy, drugs that act directly on the reninangiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS® (telmisartan) tablets should be discontinued as soon as possible (See Warnings and Precautions ).
• MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. • MICARDIS is indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors. • High risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin dependent or non-insulin dependent) with evidence of end-organ damage. MICARDIS can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, lipid-lowering therapy, etc). • Studies of telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider retrying the ACE inhibitor after the cough resolves. • Use of telmisartan with an ACE inhibitor is not recommended. • Volume depletion and/or salt depletion should be corrected in patients before initiation of therapy or start treatment under close medical supervision with a reduced dose, otherwise symptomatic hypotension may occur.
• In patients with impaired hepatic function, initiate telmisartan at low doses and titrate slowly. • Monitor carefully in patients with impaired renal function, especially in patients whose renal function may depend on the activity of the reninangiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction); treatment of these patients with ACE inhibitors and ARBs has been associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure and/or death. In patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen may occur. • Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE inhibitor to an angiotensin II receptor antagonist) should be used with caution and should include close monitoring of renal function. Concomitant use of telmisartan with ramipril is not recommended. References: 1. Micardis PI. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2009. 2. Teo K, Yusuf S, Sleight P, et al; and the ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in highrisk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004;148:52-61. 3. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G; and the HOPE Study Investigators. Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.
Please see Brief Summary of Prescribing Information on following pages.
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