Heart Failure

SAN DIEGO – The 5-year results of the PARTNER 1 trial in presented at the annual meeting of the American College of Cardiology were reassuring for clinicians treating patients with severe aortic stenosis at high risk for surgery, said to Dr. Jeffrey J. Popma of Beth Israel DeaconessMedical Center, Boston, in a video interview. The data showed comparable mortality between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR), as well as long-term durability of the SAPIEN transcatheter valve, he said.

With these similar outcome results, Dr. Popma asks, can the less-invasive TAVR procedure be considered the preferred treatment over SAVR in these very-sick patients?

chackett@frontlinemedcom.com

SAN DIEGO – The 5-year results of the PARTNER 1 trial in presented at the annual meeting of the American College of Cardiology were reassuring for clinicians treating patients with severe aortic stenosis at high risk for surgery, said to Dr. Jeffrey J. Popma of Beth Israel DeaconessMedical Center, Boston, in a video interview. The data showed comparable mortality between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR), as well as long-term durability of the SAPIEN transcatheter valve, he said.

With these similar outcome results, Dr. Popma asks, can the less-invasive TAVR procedure be considered the preferred treatment over SAVR in these very-sick patients?

chackett@frontlinemedcom.com

SAN DIEGO – The 5-year results of the PARTNER 1 trial in presented at the annual meeting of the American College of Cardiology were reassuring for clinicians treating patients with severe aortic stenosis at high risk for surgery, said to Dr. Jeffrey J. Popma of Beth Israel DeaconessMedical Center, Boston, in a video interview. The data showed comparable mortality between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR), as well as long-term durability of the SAPIEN transcatheter valve, he said.

With these similar outcome results, Dr. Popma asks, can the less-invasive TAVR procedure be considered the preferred treatment over SAVR in these very-sick patients?

chackett@frontlinemedcom.com

SAN DIEGO – Five years out, transcatheter aortic valve replacement beat standard therapy in patients with severe, inoperable aortic stenosis, and measured up to surgery in high-risk patients.

The final data from the PARTNER 1 data showed TAVR as an alternative to surgery for some high-risk surgical patients, Dr. Michael Mack reported at the annual scientific sessions of the American College of Cardiology. High-risk surgical patients had similar all-cause mortality, cardiovascular mortality, stroke, and hospital readmission rates, regardless of whether they underwent TAVR or surgical valve replacement, Dr. Mack of Baylor Scott & White Health in Plano, Texas, and his associates wrote in an article published online simultaneously with the presentation (Lancet 2015 Mar. 15 [doi: 10.1016/ S0140-6736(15)60308-7]). “Functional outcomes were also similar and preservation of valve hemodynamics was equivalent in both groups,” they wrote.

The trial also showed “a sustained benefit of TAVR” for inoperable aortic stenosis, “as measured by all-cause mortality, cardiovascular mortality, repeat hospital admission, and functional status. Valves were durable, with no increase in transvalvular gradient, attrition of valve area, or worsening of aortic regurgitation,” Dr. Samir Kapadia at the Cleveland Clinic in Ohio and his associates reported in an related article that was not presented at the ACC meeting but was published at the same time as Dr. Mack’s presentation (Lancet 2015 Mar. 15 [doi: 10.1016/ S0140-6736(15)60290-2]). Based on the findings, “TAVR should be strongly considered for patients who are not surgical candidates for aortic valve replacement,” the researchers added. “Appropriate selection of patients will help to maximize the benefit of TAVR and reduce mortality from coexisting severe comorbidities.”

The Placement of Aortic Transcatheter Valves (PARTNER 1) trial compared TAVR, standard nonsurgical treatment, and surgery in patients with severe, symptomatic aortic stenosis. The inoperable cohort included 358 patients who averaged 83 years of age. The high-risk cohort enrolled 699 patients whose overall average Society of Thoracic Surgeons (STS) Predicted Risk of Mortality Score was more than 11%. Inoperable patients were randomized to TAVR or standard treatment (usually including balloon aortic valvuloplasty), while high-risk patients were randomized to TAVR or surgical valve replacement.

Five years after treatment, almost 72% of TAVR patients in the inoperable cohort had died, compared with 94% of patients who received standard treatment (hazard ratio, 0.50; 95% confidence interval, 0.39-0.65; P < .0001), Dr. Kapadia and his associates reported. Notably, 86% (or 42 of 49) of surviving TAVR patients had New York Heart Association class 1 or 2 symptoms, compared with only 60% of patients who received standard treatment. Echocardiography did not reveal valve deterioration, the investigators said.

Patients in the high-risk group also faced substantial mortality – only about a third were alive 5 years after TAVR or surgery, Dr. Mack reported. Also, 14% of TAVR patients developed moderate to severe valvular regurgitation, compared with only 1% of the surgery group; P < .0001), and this complication was tied to lower survival, they wrote. “The clinical outcomes and valve performance in this trial might not reflect that of subsequent generations of balloon-expandable transcatheter valves, present operator expertise and experience, and more rigorous patient selection for TAVR,” he cautioned. “The patients selected for treatment in this trial, which started in 2007, are also representative of clinical practice at that time; clinicians have since refined patient selection, at least partly on the basis of early outcomes from this trial.”

Edwards Lifesciences funded the study. Several authors reported receiving travel reimbursements from Edwards Lifesciences and financial or consulting relationships with Abbott Vascular, Edwards Lifesciences, Medtronic, Thubrikar Aortic Valve, St Jude Medical, Philips Healthcare, Sorin Medical, DirectFlow, Boston Scientific, Cardiosolutions, ValvXchange, and Posthorax.

SAN DIEGO – Five years out, transcatheter aortic valve replacement beat standard therapy in patients with severe, inoperable aortic stenosis, and measured up to surgery in high-risk patients.

The final data from the PARTNER 1 data showed TAVR as an alternative to surgery for some high-risk surgical patients, Dr. Michael Mack reported at the annual scientific sessions of the American College of Cardiology. High-risk surgical patients had similar all-cause mortality, cardiovascular mortality, stroke, and hospital readmission rates, regardless of whether they underwent TAVR or surgical valve replacement, Dr. Mack of Baylor Scott & White Health in Plano, Texas, and his associates wrote in an article published online simultaneously with the presentation (Lancet 2015 Mar. 15 [doi: 10.1016/ S0140-6736(15)60308-7]). “Functional outcomes were also similar and preservation of valve hemodynamics was equivalent in both groups,” they wrote.

The trial also showed “a sustained benefit of TAVR” for inoperable aortic stenosis, “as measured by all-cause mortality, cardiovascular mortality, repeat hospital admission, and functional status. Valves were durable, with no increase in transvalvular gradient, attrition of valve area, or worsening of aortic regurgitation,” Dr. Samir Kapadia at the Cleveland Clinic in Ohio and his associates reported in an related article that was not presented at the ACC meeting but was published at the same time as Dr. Mack’s presentation (Lancet 2015 Mar. 15 [doi: 10.1016/ S0140-6736(15)60290-2]). Based on the findings, “TAVR should be strongly considered for patients who are not surgical candidates for aortic valve replacement,” the researchers added. “Appropriate selection of patients will help to maximize the benefit of TAVR and reduce mortality from coexisting severe comorbidities.”

The Placement of Aortic Transcatheter Valves (PARTNER 1) trial compared TAVR, standard nonsurgical treatment, and surgery in patients with severe, symptomatic aortic stenosis. The inoperable cohort included 358 patients who averaged 83 years of age. The high-risk cohort enrolled 699 patients whose overall average Society of Thoracic Surgeons (STS) Predicted Risk of Mortality Score was more than 11%. Inoperable patients were randomized to TAVR or standard treatment (usually including balloon aortic valvuloplasty), while high-risk patients were randomized to TAVR or surgical valve replacement.

Five years after treatment, almost 72% of TAVR patients in the inoperable cohort had died, compared with 94% of patients who received standard treatment (hazard ratio, 0.50; 95% confidence interval, 0.39-0.65; P < .0001), Dr. Kapadia and his associates reported. Notably, 86% (or 42 of 49) of surviving TAVR patients had New York Heart Association class 1 or 2 symptoms, compared with only 60% of patients who received standard treatment. Echocardiography did not reveal valve deterioration, the investigators said.

Patients in the high-risk group also faced substantial mortality – only about a third were alive 5 years after TAVR or surgery, Dr. Mack reported. Also, 14% of TAVR patients developed moderate to severe valvular regurgitation, compared with only 1% of the surgery group; P < .0001), and this complication was tied to lower survival, they wrote. “The clinical outcomes and valve performance in this trial might not reflect that of subsequent generations of balloon-expandable transcatheter valves, present operator expertise and experience, and more rigorous patient selection for TAVR,” he cautioned. “The patients selected for treatment in this trial, which started in 2007, are also representative of clinical practice at that time; clinicians have since refined patient selection, at least partly on the basis of early outcomes from this trial.”

Edwards Lifesciences funded the study. Several authors reported receiving travel reimbursements from Edwards Lifesciences and financial or consulting relationships with Abbott Vascular, Edwards Lifesciences, Medtronic, Thubrikar Aortic Valve, St Jude Medical, Philips Healthcare, Sorin Medical, DirectFlow, Boston Scientific, Cardiosolutions, ValvXchange, and Posthorax.

SAN DIEGO – Five years out, transcatheter aortic valve replacement beat standard therapy in patients with severe, inoperable aortic stenosis, and measured up to surgery in high-risk patients.

The final data from the PARTNER 1 data showed TAVR as an alternative to surgery for some high-risk surgical patients, Dr. Michael Mack reported at the annual scientific sessions of the American College of Cardiology. High-risk surgical patients had similar all-cause mortality, cardiovascular mortality, stroke, and hospital readmission rates, regardless of whether they underwent TAVR or surgical valve replacement, Dr. Mack of Baylor Scott & White Health in Plano, Texas, and his associates wrote in an article published online simultaneously with the presentation (Lancet 2015 Mar. 15 [doi: 10.1016/ S0140-6736(15)60308-7]). “Functional outcomes were also similar and preservation of valve hemodynamics was equivalent in both groups,” they wrote.

The trial also showed “a sustained benefit of TAVR” for inoperable aortic stenosis, “as measured by all-cause mortality, cardiovascular mortality, repeat hospital admission, and functional status. Valves were durable, with no increase in transvalvular gradient, attrition of valve area, or worsening of aortic regurgitation,” Dr. Samir Kapadia at the Cleveland Clinic in Ohio and his associates reported in an related article that was not presented at the ACC meeting but was published at the same time as Dr. Mack’s presentation (Lancet 2015 Mar. 15 [doi: 10.1016/ S0140-6736(15)60290-2]). Based on the findings, “TAVR should be strongly considered for patients who are not surgical candidates for aortic valve replacement,” the researchers added. “Appropriate selection of patients will help to maximize the benefit of TAVR and reduce mortality from coexisting severe comorbidities.”

The Placement of Aortic Transcatheter Valves (PARTNER 1) trial compared TAVR, standard nonsurgical treatment, and surgery in patients with severe, symptomatic aortic stenosis. The inoperable cohort included 358 patients who averaged 83 years of age. The high-risk cohort enrolled 699 patients whose overall average Society of Thoracic Surgeons (STS) Predicted Risk of Mortality Score was more than 11%. Inoperable patients were randomized to TAVR or standard treatment (usually including balloon aortic valvuloplasty), while high-risk patients were randomized to TAVR or surgical valve replacement.

Five years after treatment, almost 72% of TAVR patients in the inoperable cohort had died, compared with 94% of patients who received standard treatment (hazard ratio, 0.50; 95% confidence interval, 0.39-0.65; P < .0001), Dr. Kapadia and his associates reported. Notably, 86% (or 42 of 49) of surviving TAVR patients had New York Heart Association class 1 or 2 symptoms, compared with only 60% of patients who received standard treatment. Echocardiography did not reveal valve deterioration, the investigators said.

Patients in the high-risk group also faced substantial mortality – only about a third were alive 5 years after TAVR or surgery, Dr. Mack reported. Also, 14% of TAVR patients developed moderate to severe valvular regurgitation, compared with only 1% of the surgery group; P < .0001), and this complication was tied to lower survival, they wrote. “The clinical outcomes and valve performance in this trial might not reflect that of subsequent generations of balloon-expandable transcatheter valves, present operator expertise and experience, and more rigorous patient selection for TAVR,” he cautioned. “The patients selected for treatment in this trial, which started in 2007, are also representative of clinical practice at that time; clinicians have since refined patient selection, at least partly on the basis of early outcomes from this trial.”

Edwards Lifesciences funded the study. Several authors reported receiving travel reimbursements from Edwards Lifesciences and financial or consulting relationships with Abbott Vascular, Edwards Lifesciences, Medtronic, Thubrikar Aortic Valve, St Jude Medical, Philips Healthcare, Sorin Medical, DirectFlow, Boston Scientific, Cardiosolutions, ValvXchange, and Posthorax.

SNOWMASS, COLO. – Under intense fiscal pressure to curb early hospital readmissions for heart failure, cardiologists and hospital administrators are taking a hard look at the traditional role of the emergency department as the point of triage for patients with decompensated heart failure.

“Alternatives to the emergency department for ambulatory triage and intervention are essential,” Dr. Akshay Desai said at the Annual Cardiovascular Conference at Snowmass.

“Traditionally, when our patients become decompensated, we send them from our office or clinic to the ED. And 80%-90% of those who present to the ED with the diagnosis of heart failure are admitted to the hospital. So this means that the ED is a pretty ineffective triage point for heart failure patients. Most ED staff are concerned about ambulatory follow-up and feel it’s safer to follow patients in the hospital. The message here is we need a more robust ambulatory framework to manage patients with milder decompensation so they don’t all need to come into the hospital,” said Dr. Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston.

Hospital admission is of questionable value for a large fraction of decompensating heart failure patients. After all, not that much happens to them in the hospital that couldn’t take place in a less costly setting.

“For the most part, our patients in the hospital for decompensated heart failure get IV diuretics, with an average weight loss of about 4 kg. Surveillance is typically once- or twice-daily laboratory tests and a bedside clinical visit by a physician at 7:30 in the morning. Few patients get much else. There’s little diagnostic testing, few other therapies that require intensive monitoring, and most patients feel a little better by their first day in the hospital,” he said.

This suggests the need for what he called “an evolved model of heart failure care” in which the ED is replaced as the point of service by some form of ambulatory center that can serve as a buffer limiting the number of patients who need to come into the hospital.

“It could be a home-based strategy of IV diuretic administration, a clinic-based strategy of outpatient diuretic administration, or an observation unit based in the ED. All of these are now being tested in various models across the country as alternatives to help manage the readmission problem, and also to make life better for our patients, who’d prefer not to be in the hospital if they could be managed in other ways,” Dr. Desai continued.

Reducing 30-day readmission rates after a hospitalization for heart failure is seen by health policy makers as an opportunity to simultaneously improve care and reduce costs. But studies show only about half of readmissions in patients with heart failure are cardiovascular related, just half of those cardiovascular readmissions are heart failure related, and only about 30% of heart failure readmissions are truly preventable. However, wide variation exists across the country in risk-adjusted 30-day readmission rates, suggesting there is an opportunity for improvement in outlier hospitals.

Numerous factors have been linked to high heart failure readmission rates, including patient sociodemographic characteristics, comorbid conditions, and serum markers of heart failure severity. One underappreciated factor, in Dr. Desai’s view, is that readmission rates are significantly higher in hospitals that are financially and clinically resource poor, as shown in a Harvard School of Public Health analysis of Medicare claims data for more than 900,000 heart failure discharges. These resource-poor hospitals provide care for underserved populations, and they are experiencing a disproportionate burden of the financial penalties imposed for early readmission.

“As we seek to improve care for patients with heart failure, we should ensure that penalties for poor performance do not worsen disparities in quality of care,” according to the Harvard investigators (Circ. Cardiovasc. Qual. Outcomes 2011;4:53-9).

Dr. Desai reported serving as a consultant to 5AM Ventures, AtCor Medical, Novartis, and St. Jude Medical.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Under intense fiscal pressure to curb early hospital readmissions for heart failure, cardiologists and hospital administrators are taking a hard look at the traditional role of the emergency department as the point of triage for patients with decompensated heart failure.

“Alternatives to the emergency department for ambulatory triage and intervention are essential,” Dr. Akshay Desai said at the Annual Cardiovascular Conference at Snowmass.

“Traditionally, when our patients become decompensated, we send them from our office or clinic to the ED. And 80%-90% of those who present to the ED with the diagnosis of heart failure are admitted to the hospital. So this means that the ED is a pretty ineffective triage point for heart failure patients. Most ED staff are concerned about ambulatory follow-up and feel it’s safer to follow patients in the hospital. The message here is we need a more robust ambulatory framework to manage patients with milder decompensation so they don’t all need to come into the hospital,” said Dr. Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston.

Hospital admission is of questionable value for a large fraction of decompensating heart failure patients. After all, not that much happens to them in the hospital that couldn’t take place in a less costly setting.

“For the most part, our patients in the hospital for decompensated heart failure get IV diuretics, with an average weight loss of about 4 kg. Surveillance is typically once- or twice-daily laboratory tests and a bedside clinical visit by a physician at 7:30 in the morning. Few patients get much else. There’s little diagnostic testing, few other therapies that require intensive monitoring, and most patients feel a little better by their first day in the hospital,” he said.

This suggests the need for what he called “an evolved model of heart failure care” in which the ED is replaced as the point of service by some form of ambulatory center that can serve as a buffer limiting the number of patients who need to come into the hospital.

“It could be a home-based strategy of IV diuretic administration, a clinic-based strategy of outpatient diuretic administration, or an observation unit based in the ED. All of these are now being tested in various models across the country as alternatives to help manage the readmission problem, and also to make life better for our patients, who’d prefer not to be in the hospital if they could be managed in other ways,” Dr. Desai continued.

Reducing 30-day readmission rates after a hospitalization for heart failure is seen by health policy makers as an opportunity to simultaneously improve care and reduce costs. But studies show only about half of readmissions in patients with heart failure are cardiovascular related, just half of those cardiovascular readmissions are heart failure related, and only about 30% of heart failure readmissions are truly preventable. However, wide variation exists across the country in risk-adjusted 30-day readmission rates, suggesting there is an opportunity for improvement in outlier hospitals.

Numerous factors have been linked to high heart failure readmission rates, including patient sociodemographic characteristics, comorbid conditions, and serum markers of heart failure severity. One underappreciated factor, in Dr. Desai’s view, is that readmission rates are significantly higher in hospitals that are financially and clinically resource poor, as shown in a Harvard School of Public Health analysis of Medicare claims data for more than 900,000 heart failure discharges. These resource-poor hospitals provide care for underserved populations, and they are experiencing a disproportionate burden of the financial penalties imposed for early readmission.

“As we seek to improve care for patients with heart failure, we should ensure that penalties for poor performance do not worsen disparities in quality of care,” according to the Harvard investigators (Circ. Cardiovasc. Qual. Outcomes 2011;4:53-9).

Dr. Desai reported serving as a consultant to 5AM Ventures, AtCor Medical, Novartis, and St. Jude Medical.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Under intense fiscal pressure to curb early hospital readmissions for heart failure, cardiologists and hospital administrators are taking a hard look at the traditional role of the emergency department as the point of triage for patients with decompensated heart failure.

“Alternatives to the emergency department for ambulatory triage and intervention are essential,” Dr. Akshay Desai said at the Annual Cardiovascular Conference at Snowmass.

“Traditionally, when our patients become decompensated, we send them from our office or clinic to the ED. And 80%-90% of those who present to the ED with the diagnosis of heart failure are admitted to the hospital. So this means that the ED is a pretty ineffective triage point for heart failure patients. Most ED staff are concerned about ambulatory follow-up and feel it’s safer to follow patients in the hospital. The message here is we need a more robust ambulatory framework to manage patients with milder decompensation so they don’t all need to come into the hospital,” said Dr. Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston.

Hospital admission is of questionable value for a large fraction of decompensating heart failure patients. After all, not that much happens to them in the hospital that couldn’t take place in a less costly setting.

“For the most part, our patients in the hospital for decompensated heart failure get IV diuretics, with an average weight loss of about 4 kg. Surveillance is typically once- or twice-daily laboratory tests and a bedside clinical visit by a physician at 7:30 in the morning. Few patients get much else. There’s little diagnostic testing, few other therapies that require intensive monitoring, and most patients feel a little better by their first day in the hospital,” he said.

This suggests the need for what he called “an evolved model of heart failure care” in which the ED is replaced as the point of service by some form of ambulatory center that can serve as a buffer limiting the number of patients who need to come into the hospital.

“It could be a home-based strategy of IV diuretic administration, a clinic-based strategy of outpatient diuretic administration, or an observation unit based in the ED. All of these are now being tested in various models across the country as alternatives to help manage the readmission problem, and also to make life better for our patients, who’d prefer not to be in the hospital if they could be managed in other ways,” Dr. Desai continued.

Reducing 30-day readmission rates after a hospitalization for heart failure is seen by health policy makers as an opportunity to simultaneously improve care and reduce costs. But studies show only about half of readmissions in patients with heart failure are cardiovascular related, just half of those cardiovascular readmissions are heart failure related, and only about 30% of heart failure readmissions are truly preventable. However, wide variation exists across the country in risk-adjusted 30-day readmission rates, suggesting there is an opportunity for improvement in outlier hospitals.

Numerous factors have been linked to high heart failure readmission rates, including patient sociodemographic characteristics, comorbid conditions, and serum markers of heart failure severity. One underappreciated factor, in Dr. Desai’s view, is that readmission rates are significantly higher in hospitals that are financially and clinically resource poor, as shown in a Harvard School of Public Health analysis of Medicare claims data for more than 900,000 heart failure discharges. These resource-poor hospitals provide care for underserved populations, and they are experiencing a disproportionate burden of the financial penalties imposed for early readmission.

“As we seek to improve care for patients with heart failure, we should ensure that penalties for poor performance do not worsen disparities in quality of care,” according to the Harvard investigators (Circ. Cardiovasc. Qual. Outcomes 2011;4:53-9).

Dr. Desai reported serving as a consultant to 5AM Ventures, AtCor Medical, Novartis, and St. Jude Medical.

bjancin@frontlinemedcom.com

After noticing that paroxetine, a selective serotonin reuptake inhibitor normally used to treat depression, stopped the progression of heart failure in mice, researchers have concluded that the drug could be reclassified for use in humans, investigators wrote in Science Translational Medicine.

Courtesy American Heart Association

According to researchers from Temple University School of Medicine, genetically modified mice with heart failure (HF) were given paroxetine for 4 weeks. The drug blocked GRK2 (a protein normally elevated in people with heart failure), improved the left ventricle’s capacity to pump blood, and protected the heart muscle from scar formation and fibrosis within the first 2 weeks of treatment.

The researchers concluded, “These data present compelling evidence of a causal role for GRK2 in the maladaptive progression of cardiac remodeling and dysfunction leading to HF, especially after ischemic injury. Therefore, the development of small-molecule inhibitors of GRK2 appears warranted for pharmacologic treatment of HF.”

Read more in Science Translational Medicine.

After noticing that paroxetine, a selective serotonin reuptake inhibitor normally used to treat depression, stopped the progression of heart failure in mice, researchers have concluded that the drug could be reclassified for use in humans, investigators wrote in Science Translational Medicine.

Courtesy American Heart Association

According to researchers from Temple University School of Medicine, genetically modified mice with heart failure (HF) were given paroxetine for 4 weeks. The drug blocked GRK2 (a protein normally elevated in people with heart failure), improved the left ventricle’s capacity to pump blood, and protected the heart muscle from scar formation and fibrosis within the first 2 weeks of treatment.

The researchers concluded, “These data present compelling evidence of a causal role for GRK2 in the maladaptive progression of cardiac remodeling and dysfunction leading to HF, especially after ischemic injury. Therefore, the development of small-molecule inhibitors of GRK2 appears warranted for pharmacologic treatment of HF.”

Read more in Science Translational Medicine.

After noticing that paroxetine, a selective serotonin reuptake inhibitor normally used to treat depression, stopped the progression of heart failure in mice, researchers have concluded that the drug could be reclassified for use in humans, investigators wrote in Science Translational Medicine.

Courtesy American Heart Association

According to researchers from Temple University School of Medicine, genetically modified mice with heart failure (HF) were given paroxetine for 4 weeks. The drug blocked GRK2 (a protein normally elevated in people with heart failure), improved the left ventricle’s capacity to pump blood, and protected the heart muscle from scar formation and fibrosis within the first 2 weeks of treatment.

The researchers concluded, “These data present compelling evidence of a causal role for GRK2 in the maladaptive progression of cardiac remodeling and dysfunction leading to HF, especially after ischemic injury. Therefore, the development of small-molecule inhibitors of GRK2 appears warranted for pharmacologic treatment of HF.”

Read more in Science Translational Medicine.

Genetic testing is now part of routine practice in at least some U.S. centers for managing a short list of cardiovascular disease scenarios.

Although it remains well shy of ubiquitous for cardiovascular practice, for at least four important settings genetic testing has begun to play a key role: diagnosis of inherited cardiac conditions such as cardiomyopathies and channelopathies, diagnosis of homozygous and heterozygous familial hypercholesterolemia, treatment of stented coronary-disease patients with clopidogrel, and use when starting patients on warfarin.

©ktsimage/Thinkstock.com

Cardiomyopathies and channelopathies

Genetic testing of patients with any of the several inherited diseases that fall into these categories, including hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome, and Brugada, received official recommendation from the Heart Rhythm Society and European Heart Rhythm Society in 2011 (Europace 2011;813:1077-109), and genetic testing for patients with hypertrophic cardiomyopathy and their first-degree relatives received a class I level B rating in guidelines for this specific cardiomyopathy released last year from the European Society of Cardiology (Eur. Heart J. 2014;35:2733-79).

Those endorsements put these cardiac diseases on the firmest ground for categorization as routine practice, a status that grew firmer still when researchers announced in January 2015 new evidence that better clarified the genetic underpinnings of dilated cardiomyopathy, the most common inherited cardiac condition.

“Genetic testing clearly contributes to risk assessment” of cardiomyopathies and channelopathies, Dr. Ray E. Hershberger said during a talk last November at the American Heart Association scientific sessions in Chicago. “Finding a plausible genetic cause for a condition lays the foundation for more durable intervention,” said Dr. Hershberger, professor and director of human genetics at Ohio State University in Columbus.

“Genetic testing for dilated cardiomyopathy is becoming increasingly important in clinical practice. Genetic testing is available, affordable, and efficient,” Dr. Luisa Mestroni, director of the Adult Medical Genetics Program of the University of Colorado, Denver, said during a separate talk at the AHA meeting. She cited three commercially available genetic tests for dilated cardiomyopathy that use next-generation sequencing and screen dozens of implicated genes. The genetic findings are available within about 10 weeks and cost in the range of several thousand dollars. Similar panels also exist for the other cardiomyopathies and channelopathies. Perhaps the most significant limitation on genetic testing for these patients is that it be done within the context of genetic counseling, said both Dr. Mestroni and Dr. Hershberger.

Genetic testing for dilated cardiomyopathy has been hindered by the disorder’s genetic heterogeneity, but understanding of the genetic picture grew much clearer in January with publication of genetic findings from 5,267 people representing the full spectrum of cardiac status, including fully-assessed healthy controls; 3,603 unselected community dwellers taken from the Framingham and Jackson Heart Studies; 374 unselected, ambulatory patients with dilated cardiomyopathy; and 155 patients with severe, end-stage dilated cardiomyopathy. The large, multicenter team of mostly British and U.S. researchers validated the findings in 163 additional patients with familial dilated cardiomyopathy (Sci. Transl. Med. 2015;7:[doi: 10.1126/scitranslmed.3010134].

The findings showed that mutations that produce truncated forms of titin, the body’s largest protein and a critical part of cardiac muscle, appear in about 2% of the general population, about 13% of ambulatory patients with dilated cardiomyopathy, and about 20% of patients with end-stage DCM. In addition, the truncations that occur in people who lack clinical disease tended to affect minor titin isoforms and produce mild functional changes, while the titin truncation mutations in people with severe disease were in the most commonly used isoforms and at sites that severely impaired function.

Until now, in the United Kingdom, “it would not have been standard of care to do gene testing [for patients with suspected dilated cardiomyopathy] unless there was a clear family history or some phenotypic indicator, but going forward we believe the yield from titin truncations [as well as from other, less common known mutations] is sufficient to include genetic testing in a patient’s work-up,” Dr. James S. Ware, a coauthor of the new report and a cardiologist at Imperial College, London, said during a press conference in January.

“The American College of Cardiology and American Heart Association guidelines for managing cardiomyopathy say that it is critical to perform longitudinal clinical follow-up on all first-degree relatives of patients with cardiomyopathy. The cost for longitudinal clinical screening is huge and also poses inconvenience for the family members screened. Genetic testing can now identify which family members really need clinical follow-up and which ones don’t need it,” said Dr. Cristine E. Seidman, a coauthor of the new titin-genetics report, professor of genetics and medicine at Harvard Medical School, and director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital, Boston.

Familial hypercholesterolemia

Routine screening for familial hypercholesterolemia (FH) is not as widely endorsed, but it does have backers, and evidence shows that the approach is cost effective. In part, that’s because both heterozygous and homozygous FH are substantially more common than had been believed until recently. Recent study results documented prevalence rates roughly threefold more common than previously calculated.

For example, a study published last year of more than 104,000 residents of the Netherlands documented a homozygous FH prevalence of 1 in 300,000 (Eur. Heart J. 2014 [doi.org/10.1093/eurheartj/ehu058]). Results from a 2012 study of more than 69,000 Danish residents demonstrated a prevalence of 1 in 137 for people with heterozygous FH (J. Clin. Endocrinol. Metab. 2012;97:3956-64).

“Genetic testing improves the care of individual patients with FH because with genetic testing you can catch patients with FH presymptomatically and you can then treat them and change their long-term prognosis,” Dr. Anne Tybjaerg-Hansen, professor of clinical biochemistry and chief physician at Copenhagen University Hospital, said in a talk at the AHA meeting last November. She cited a report last year from Australia on a model demonstrating the cost effectiveness of testing first-degree relatives of index patients diagnosed with FH, an approach known as cascade screening (J. Clin. Lipidology 2014;8:390-400).

Last year, a consensus panel of the European Atherosclerosis Society recommended that genetic testing “should be considered” for both the diagnostic work-up of index cases with suspected FH and for cascade screening of first-degree relatives of confirmed cases (Eur. Heart J. 2014;35:2146-57). The European panel noted that genetic testing was potentially useful not only to confirm a clinical diagnosis but also to better distinguish patients with heterozygous and homozygous FH. The panel’s report last year endorsed the updated understanding that heterozygous FH occurs in roughly 1 in every 200 people, while homozygous FH has a prevalence of 1 case in every 160,000-300,000 people.

Despite these relatively high prevalence rates, FH is woefully underdiagnosed. A 2013 report from the European Atherosclerosis Society cited recent data documenting that less than 1% of U.S. residents with FH are currently identified (Eur. Heart J. 2013;34:3478-90). The same report noted that less than half of all FH patients have been identified in every country worldwide with reported statistics – aside from the Netherlands, which topped the world with an estimated identification rate of 71% of patients with either form of FH.

Clopidogrel responsiveness

It’s now been several years since researchers determined that roughly 30% of people fail to adequately metabolize the antiplatelet drug clopidogrel into its active form, a finding that in 2010 led the Food and Drug Administration to mandate a boxed warning on clopidogrel’s labeling. The cytochrome P450 (CYP) 2C19 gene codes for the enzyme that activates clopidogrel, and the warning states that people in this significant minority carry alleles of the CYP2C19 gene that make them poor clopidogrel metabolizers and hence clinicians should consider using “alternative treatment strategies.” Usually this means treatment with prasugrel (Effient) or ticagrelor (Brilinta), two thienopyridines that match clopidogrel’s efficacy but do not require metabolic conversion and so are effective even in poor-metabolizing patients.

But years after this well documented and well publicized problem with blind clopidogrel dosing first became apparent, many clinicians remain uncertain how to deal with the issue and how to use genetic testing to clarify the risk faced by individual patients (Circulation 2012;122:445-8).

“The evidence for CYP2C19 is really strong, but because prospective, randomized clinical trials of genotype-directed antiplatelet testing have not been performed, there is a lot of resistance to adoption of genotype-directed treatment,” Dr. Alan R. Shuldiner said in a talk at the November AHA meeting. An editorial published in late 2011 called the boxed warning on clopidogrel “irrational exuberance” (JAMA 2011;306:2727-8). Dr. Shuldiner and others contend that overall evidence today supports a need to screen the CYP2C19 gene before starting clopidogrel, although he conceded that the optimal clinical algorithm for using testing has not yet been devised and that paying for screening remains problematic.

Despite these limitations, Dr. Shuldiner and several colleagues from around the United States issued recommendations in 2013 for the implementation of CYP2C19 genetic testing in patients (Clin. Pharmacol. Ther. 2013;94:317-23) on behalf of the Clinical Pharmacogenetics Implementation Consortium. And in February 2013, clinicians at the University of Maryland in Baltimore began to implement those recommendations as one of eight U.S. sites participating in the PGRN Translational Pharmacogenetics Program.

“It took us 18 months to figure out how to implement pharmacogenetics in the cath lab,” said Dr. Shuldiner, former director of the program for personalized and genomic medicine at the University of Maryland, and now vice president of translation genomics at Regeneron in Tarrytown, N.Y.

From February 2013 through August 2014, the University of Maryland program screened on a routine basis 557 patients undergoing percutaneous coronary intervention (PCI) – with a 5-hour turnaround time on the results – enrolled 446 into the program, found 67 patients with an “actionable” genotype, and actually prescribed an alternative therapy because of the genotype in 37 patients. Patients usually did not receive the genomic-guided treatment because of a contraindication, Dr. Shuldiner said. He concluded that the Maryland experience shows routine screening is doable, and with its strong evidence base warrants use in all catheterization labs.

PCI patients at the University of Florida in Gainesville also now routinely undergo genomic assessment,said during a separate session at the AHA meeting. “Physicians recently began starting their acute coronary syndrome (ACS) patients on ticagrelor, and then when they get the genotype if the patient has an allele associated with good metabolism and can’t afford ticagrelor and needs to change to clopidogrel we know it will be okay. That’s the way we deal with the delay” in getting the genomic results. “At least you know that the patient is protected [with ticagrelor] during the really hot period,” said Dr. Cavallari, director of the center for pharmacogenomics of the University of Florida.

“For ACS patients if you treat with prasugrel or ticagrelor then you’ve pretty much overcome the roadblock, but for patients on clopidogrel I think it is very reasonable to use genetic testing or platelet-reactivity testing, especially for patients with a stented left main coronary,” Dr. Jessica L. Mega said during a panel discussion with Dr. Cavallari at the meeting. “We have pretty good data to suggest that at least in the peri-PCI patients who are homozygous for the *2 allele [the worst clopidogrel metabolizers] should not be on a standard clopidogrel dosage.”

Dr. Mega agreed with other genetic-testing proponents who see a double standard surrounding these tests. “I think there is a little genetic exceptionalism going on, and people feel differently about using genomics compared with other biomarkers. We have good data, and we just need to act on it,” said Dr. Mega, a cardiologist at Brigham and Women’s Hospital in Boston. “If you had an ACS event and received a stent in your left anterior descending coronary and were known to have a *2 allele or had high on-treatment platelet activity would you want to go home on 75 mg a day of clopidogrel?” Dr. Mega asked during a talk at the meeting.

Warfarin dosing

Evidence has implicated polymorphisms in two genes, CYP2C9 and VKORC1, as playing key roles in warfarin metabolism and suggested that determination of a patient’s allele profile for these two genes could assist in more quickly finding the best warfarin dose for a patients requiring oral antithrombotic therapy to reach their target International Normalized Ratio (INR).

In late 2013, researchers reported results from two major prospective trials designed to test the efficacy of genetic analysis of these two genes. The results were split. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial with 455 patients in the United Kingdom and Sweden showed that genotype-based dosing at the start of warfarin therapy increased the time in the therapeutic range, the primary outcome, by 7 percentage points and reduced the incidence of excessive anticoagulation, the time required to reach a therapeutic INR, the time required to reach a stable dose, and the number of adjustments in the dose of warfarin (N. Engl. J. Med. 2013;369:2294-303). But results from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial, which included 1,015 patients at 18 U.S. centers, showed that after 4 weeks genotyping-based warfarin dosing produced no significant between-group difference in the mean percentage of time in the therapeutic range (N. Engl. J. Med. 2013;369:2283-93).These inconsistent results, and especially the COAG study’s inability to show a benefit from genetic analysis in improving warfarin-dose selection, “called into question the clinical utility” of genetic testing, Dr. Cavallari wrote in a comment she coauthored last July (Clin. Pharmacol. Ther. 2014;96:22-4).

But recent data from Dr. Cavallari’s research group suggests that the value of genetic testing in patients starting warfarin may have been masked by the high proportion of African Americans in the COAG study, 27% of enrolled patients, and the finding that these patients did poorly because the alleles they carry most frequently were not covered by the genetic-test panel used in the study.

Before she moved to Gainesville, Dr. Cavallari worked at the University of Illinois in Chicago and she and her associates there began in August 2012 to routinely genotype patients prior to the start of warfarin treatment, using the information to guide initial dosing levels. The analyses they performed included several alleles commonly seen in African Americans – roughly two-thirds of the 389 patients they screened under this program were African American.

Expanding the testing panel had a major impact on efficacy. Results reported by her group at the AHA meeting last November showed that immediately following the start of warfarin treatment the percentage of INR levels that fell out of the therapeutic range was 42%, a statistically significant improvement over the 65% rate seen in 308 historic controls drawn from the year immediately preceding the start of routine genotyping (Circulation 2014;130A:16119). The results showed that the average number of days for patients to reach their first INR measurement in the therapeutic range fell from 11 days prior to genotyping to 4 days, and the average number of days needed on treatment with low-molecular-weight heparin, a bridging strategy until a therapeutic INR is achieved, fell from 10 days among the historic controls to an average of 2 days. The between-group differences for all three of these metrics reached statistical significance in analyses that adjusted for multiple variables, and that used propensity scoring, Dr. Cavallari said.But although genotyping prior to starting warfarin “is available and reasonable to use, until Medicare starts paying for it, doing this will be hard to implement,” Dr. Cavallari conceded during a November talk. Although warfarin-oriented genetic testing may be performed routinely at the University of Illinois, a lot of clinicians elsewhere are holding back, in part because of reimbursement issues and in part because “they want to see proof of better patient outcomes,” said Pharm.D., a cardiovascular pharmacology researcher at the University of Connecticut in Storrs. Like many who look at the evidence for routine genetic testing in cardiovcascular medicine, they “want to see differences in hard clinical outcomes before incorporating it into their practices,” Dr. Baker said.

Dr. Hershberger, Dr. Mestroni, Dr. Ware, Dr. Seidman, Dr. Tybjaerg-Hansen, and Dr. Cavallari had no disclosures. Dr. Shuldiner is an employee of Regeneron. Dr. Mega has been a consultant to Janssen, Boehinger Ingelheim, American Genomics, Bayer, and Portola, and has received research grants from eight companies. Dr. Baker received a research grant from Gilead.

mzoler@frontlinemedcom.com 


On Twitter @mitchelzoler

Genetic testing is now part of routine practice in at least some U.S. centers for managing a short list of cardiovascular disease scenarios.

Although it remains well shy of ubiquitous for cardiovascular practice, for at least four important settings genetic testing has begun to play a key role: diagnosis of inherited cardiac conditions such as cardiomyopathies and channelopathies, diagnosis of homozygous and heterozygous familial hypercholesterolemia, treatment of stented coronary-disease patients with clopidogrel, and use when starting patients on warfarin.

©ktsimage/Thinkstock.com

Cardiomyopathies and channelopathies

Genetic testing of patients with any of the several inherited diseases that fall into these categories, including hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome, and Brugada, received official recommendation from the Heart Rhythm Society and European Heart Rhythm Society in 2011 (Europace 2011;813:1077-109), and genetic testing for patients with hypertrophic cardiomyopathy and their first-degree relatives received a class I level B rating in guidelines for this specific cardiomyopathy released last year from the European Society of Cardiology (Eur. Heart J. 2014;35:2733-79).

Those endorsements put these cardiac diseases on the firmest ground for categorization as routine practice, a status that grew firmer still when researchers announced in January 2015 new evidence that better clarified the genetic underpinnings of dilated cardiomyopathy, the most common inherited cardiac condition.

“Genetic testing clearly contributes to risk assessment” of cardiomyopathies and channelopathies, Dr. Ray E. Hershberger said during a talk last November at the American Heart Association scientific sessions in Chicago. “Finding a plausible genetic cause for a condition lays the foundation for more durable intervention,” said Dr. Hershberger, professor and director of human genetics at Ohio State University in Columbus.

“Genetic testing for dilated cardiomyopathy is becoming increasingly important in clinical practice. Genetic testing is available, affordable, and efficient,” Dr. Luisa Mestroni, director of the Adult Medical Genetics Program of the University of Colorado, Denver, said during a separate talk at the AHA meeting. She cited three commercially available genetic tests for dilated cardiomyopathy that use next-generation sequencing and screen dozens of implicated genes. The genetic findings are available within about 10 weeks and cost in the range of several thousand dollars. Similar panels also exist for the other cardiomyopathies and channelopathies. Perhaps the most significant limitation on genetic testing for these patients is that it be done within the context of genetic counseling, said both Dr. Mestroni and Dr. Hershberger.

Genetic testing for dilated cardiomyopathy has been hindered by the disorder’s genetic heterogeneity, but understanding of the genetic picture grew much clearer in January with publication of genetic findings from 5,267 people representing the full spectrum of cardiac status, including fully-assessed healthy controls; 3,603 unselected community dwellers taken from the Framingham and Jackson Heart Studies; 374 unselected, ambulatory patients with dilated cardiomyopathy; and 155 patients with severe, end-stage dilated cardiomyopathy. The large, multicenter team of mostly British and U.S. researchers validated the findings in 163 additional patients with familial dilated cardiomyopathy (Sci. Transl. Med. 2015;7:[doi: 10.1126/scitranslmed.3010134].

The findings showed that mutations that produce truncated forms of titin, the body’s largest protein and a critical part of cardiac muscle, appear in about 2% of the general population, about 13% of ambulatory patients with dilated cardiomyopathy, and about 20% of patients with end-stage DCM. In addition, the truncations that occur in people who lack clinical disease tended to affect minor titin isoforms and produce mild functional changes, while the titin truncation mutations in people with severe disease were in the most commonly used isoforms and at sites that severely impaired function.

Until now, in the United Kingdom, “it would not have been standard of care to do gene testing [for patients with suspected dilated cardiomyopathy] unless there was a clear family history or some phenotypic indicator, but going forward we believe the yield from titin truncations [as well as from other, less common known mutations] is sufficient to include genetic testing in a patient’s work-up,” Dr. James S. Ware, a coauthor of the new report and a cardiologist at Imperial College, London, said during a press conference in January.

“The American College of Cardiology and American Heart Association guidelines for managing cardiomyopathy say that it is critical to perform longitudinal clinical follow-up on all first-degree relatives of patients with cardiomyopathy. The cost for longitudinal clinical screening is huge and also poses inconvenience for the family members screened. Genetic testing can now identify which family members really need clinical follow-up and which ones don’t need it,” said Dr. Cristine E. Seidman, a coauthor of the new titin-genetics report, professor of genetics and medicine at Harvard Medical School, and director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital, Boston.

Familial hypercholesterolemia

Routine screening for familial hypercholesterolemia (FH) is not as widely endorsed, but it does have backers, and evidence shows that the approach is cost effective. In part, that’s because both heterozygous and homozygous FH are substantially more common than had been believed until recently. Recent study results documented prevalence rates roughly threefold more common than previously calculated.

For example, a study published last year of more than 104,000 residents of the Netherlands documented a homozygous FH prevalence of 1 in 300,000 (Eur. Heart J. 2014 [doi.org/10.1093/eurheartj/ehu058]). Results from a 2012 study of more than 69,000 Danish residents demonstrated a prevalence of 1 in 137 for people with heterozygous FH (J. Clin. Endocrinol. Metab. 2012;97:3956-64).

“Genetic testing improves the care of individual patients with FH because with genetic testing you can catch patients with FH presymptomatically and you can then treat them and change their long-term prognosis,” Dr. Anne Tybjaerg-Hansen, professor of clinical biochemistry and chief physician at Copenhagen University Hospital, said in a talk at the AHA meeting last November. She cited a report last year from Australia on a model demonstrating the cost effectiveness of testing first-degree relatives of index patients diagnosed with FH, an approach known as cascade screening (J. Clin. Lipidology 2014;8:390-400).

Last year, a consensus panel of the European Atherosclerosis Society recommended that genetic testing “should be considered” for both the diagnostic work-up of index cases with suspected FH and for cascade screening of first-degree relatives of confirmed cases (Eur. Heart J. 2014;35:2146-57). The European panel noted that genetic testing was potentially useful not only to confirm a clinical diagnosis but also to better distinguish patients with heterozygous and homozygous FH. The panel’s report last year endorsed the updated understanding that heterozygous FH occurs in roughly 1 in every 200 people, while homozygous FH has a prevalence of 1 case in every 160,000-300,000 people.

Despite these relatively high prevalence rates, FH is woefully underdiagnosed. A 2013 report from the European Atherosclerosis Society cited recent data documenting that less than 1% of U.S. residents with FH are currently identified (Eur. Heart J. 2013;34:3478-90). The same report noted that less than half of all FH patients have been identified in every country worldwide with reported statistics – aside from the Netherlands, which topped the world with an estimated identification rate of 71% of patients with either form of FH.

Clopidogrel responsiveness

It’s now been several years since researchers determined that roughly 30% of people fail to adequately metabolize the antiplatelet drug clopidogrel into its active form, a finding that in 2010 led the Food and Drug Administration to mandate a boxed warning on clopidogrel’s labeling. The cytochrome P450 (CYP) 2C19 gene codes for the enzyme that activates clopidogrel, and the warning states that people in this significant minority carry alleles of the CYP2C19 gene that make them poor clopidogrel metabolizers and hence clinicians should consider using “alternative treatment strategies.” Usually this means treatment with prasugrel (Effient) or ticagrelor (Brilinta), two thienopyridines that match clopidogrel’s efficacy but do not require metabolic conversion and so are effective even in poor-metabolizing patients.

But years after this well documented and well publicized problem with blind clopidogrel dosing first became apparent, many clinicians remain uncertain how to deal with the issue and how to use genetic testing to clarify the risk faced by individual patients (Circulation 2012;122:445-8).

“The evidence for CYP2C19 is really strong, but because prospective, randomized clinical trials of genotype-directed antiplatelet testing have not been performed, there is a lot of resistance to adoption of genotype-directed treatment,” Dr. Alan R. Shuldiner said in a talk at the November AHA meeting. An editorial published in late 2011 called the boxed warning on clopidogrel “irrational exuberance” (JAMA 2011;306:2727-8). Dr. Shuldiner and others contend that overall evidence today supports a need to screen the CYP2C19 gene before starting clopidogrel, although he conceded that the optimal clinical algorithm for using testing has not yet been devised and that paying for screening remains problematic.

Despite these limitations, Dr. Shuldiner and several colleagues from around the United States issued recommendations in 2013 for the implementation of CYP2C19 genetic testing in patients (Clin. Pharmacol. Ther. 2013;94:317-23) on behalf of the Clinical Pharmacogenetics Implementation Consortium. And in February 2013, clinicians at the University of Maryland in Baltimore began to implement those recommendations as one of eight U.S. sites participating in the PGRN Translational Pharmacogenetics Program.

“It took us 18 months to figure out how to implement pharmacogenetics in the cath lab,” said Dr. Shuldiner, former director of the program for personalized and genomic medicine at the University of Maryland, and now vice president of translation genomics at Regeneron in Tarrytown, N.Y.

From February 2013 through August 2014, the University of Maryland program screened on a routine basis 557 patients undergoing percutaneous coronary intervention (PCI) – with a 5-hour turnaround time on the results – enrolled 446 into the program, found 67 patients with an “actionable” genotype, and actually prescribed an alternative therapy because of the genotype in 37 patients. Patients usually did not receive the genomic-guided treatment because of a contraindication, Dr. Shuldiner said. He concluded that the Maryland experience shows routine screening is doable, and with its strong evidence base warrants use in all catheterization labs.

PCI patients at the University of Florida in Gainesville also now routinely undergo genomic assessment,said during a separate session at the AHA meeting. “Physicians recently began starting their acute coronary syndrome (ACS) patients on ticagrelor, and then when they get the genotype if the patient has an allele associated with good metabolism and can’t afford ticagrelor and needs to change to clopidogrel we know it will be okay. That’s the way we deal with the delay” in getting the genomic results. “At least you know that the patient is protected [with ticagrelor] during the really hot period,” said Dr. Cavallari, director of the center for pharmacogenomics of the University of Florida.

“For ACS patients if you treat with prasugrel or ticagrelor then you’ve pretty much overcome the roadblock, but for patients on clopidogrel I think it is very reasonable to use genetic testing or platelet-reactivity testing, especially for patients with a stented left main coronary,” Dr. Jessica L. Mega said during a panel discussion with Dr. Cavallari at the meeting. “We have pretty good data to suggest that at least in the peri-PCI patients who are homozygous for the *2 allele [the worst clopidogrel metabolizers] should not be on a standard clopidogrel dosage.”

Dr. Mega agreed with other genetic-testing proponents who see a double standard surrounding these tests. “I think there is a little genetic exceptionalism going on, and people feel differently about using genomics compared with other biomarkers. We have good data, and we just need to act on it,” said Dr. Mega, a cardiologist at Brigham and Women’s Hospital in Boston. “If you had an ACS event and received a stent in your left anterior descending coronary and were known to have a *2 allele or had high on-treatment platelet activity would you want to go home on 75 mg a day of clopidogrel?” Dr. Mega asked during a talk at the meeting.

Warfarin dosing

Evidence has implicated polymorphisms in two genes, CYP2C9 and VKORC1, as playing key roles in warfarin metabolism and suggested that determination of a patient’s allele profile for these two genes could assist in more quickly finding the best warfarin dose for a patients requiring oral antithrombotic therapy to reach their target International Normalized Ratio (INR).

In late 2013, researchers reported results from two major prospective trials designed to test the efficacy of genetic analysis of these two genes. The results were split. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial with 455 patients in the United Kingdom and Sweden showed that genotype-based dosing at the start of warfarin therapy increased the time in the therapeutic range, the primary outcome, by 7 percentage points and reduced the incidence of excessive anticoagulation, the time required to reach a therapeutic INR, the time required to reach a stable dose, and the number of adjustments in the dose of warfarin (N. Engl. J. Med. 2013;369:2294-303). But results from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial, which included 1,015 patients at 18 U.S. centers, showed that after 4 weeks genotyping-based warfarin dosing produced no significant between-group difference in the mean percentage of time in the therapeutic range (N. Engl. J. Med. 2013;369:2283-93).These inconsistent results, and especially the COAG study’s inability to show a benefit from genetic analysis in improving warfarin-dose selection, “called into question the clinical utility” of genetic testing, Dr. Cavallari wrote in a comment she coauthored last July (Clin. Pharmacol. Ther. 2014;96:22-4).

But recent data from Dr. Cavallari’s research group suggests that the value of genetic testing in patients starting warfarin may have been masked by the high proportion of African Americans in the COAG study, 27% of enrolled patients, and the finding that these patients did poorly because the alleles they carry most frequently were not covered by the genetic-test panel used in the study.

Before she moved to Gainesville, Dr. Cavallari worked at the University of Illinois in Chicago and she and her associates there began in August 2012 to routinely genotype patients prior to the start of warfarin treatment, using the information to guide initial dosing levels. The analyses they performed included several alleles commonly seen in African Americans – roughly two-thirds of the 389 patients they screened under this program were African American.

Expanding the testing panel had a major impact on efficacy. Results reported by her group at the AHA meeting last November showed that immediately following the start of warfarin treatment the percentage of INR levels that fell out of the therapeutic range was 42%, a statistically significant improvement over the 65% rate seen in 308 historic controls drawn from the year immediately preceding the start of routine genotyping (Circulation 2014;130A:16119). The results showed that the average number of days for patients to reach their first INR measurement in the therapeutic range fell from 11 days prior to genotyping to 4 days, and the average number of days needed on treatment with low-molecular-weight heparin, a bridging strategy until a therapeutic INR is achieved, fell from 10 days among the historic controls to an average of 2 days. The between-group differences for all three of these metrics reached statistical significance in analyses that adjusted for multiple variables, and that used propensity scoring, Dr. Cavallari said.But although genotyping prior to starting warfarin “is available and reasonable to use, until Medicare starts paying for it, doing this will be hard to implement,” Dr. Cavallari conceded during a November talk. Although warfarin-oriented genetic testing may be performed routinely at the University of Illinois, a lot of clinicians elsewhere are holding back, in part because of reimbursement issues and in part because “they want to see proof of better patient outcomes,” said Pharm.D., a cardiovascular pharmacology researcher at the University of Connecticut in Storrs. Like many who look at the evidence for routine genetic testing in cardiovcascular medicine, they “want to see differences in hard clinical outcomes before incorporating it into their practices,” Dr. Baker said.

Dr. Hershberger, Dr. Mestroni, Dr. Ware, Dr. Seidman, Dr. Tybjaerg-Hansen, and Dr. Cavallari had no disclosures. Dr. Shuldiner is an employee of Regeneron. Dr. Mega has been a consultant to Janssen, Boehinger Ingelheim, American Genomics, Bayer, and Portola, and has received research grants from eight companies. Dr. Baker received a research grant from Gilead.

mzoler@frontlinemedcom.com 


On Twitter @mitchelzoler

Genetic testing is now part of routine practice in at least some U.S. centers for managing a short list of cardiovascular disease scenarios.

Although it remains well shy of ubiquitous for cardiovascular practice, for at least four important settings genetic testing has begun to play a key role: diagnosis of inherited cardiac conditions such as cardiomyopathies and channelopathies, diagnosis of homozygous and heterozygous familial hypercholesterolemia, treatment of stented coronary-disease patients with clopidogrel, and use when starting patients on warfarin.

©ktsimage/Thinkstock.com

Cardiomyopathies and channelopathies

Genetic testing of patients with any of the several inherited diseases that fall into these categories, including hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome, and Brugada, received official recommendation from the Heart Rhythm Society and European Heart Rhythm Society in 2011 (Europace 2011;813:1077-109), and genetic testing for patients with hypertrophic cardiomyopathy and their first-degree relatives received a class I level B rating in guidelines for this specific cardiomyopathy released last year from the European Society of Cardiology (Eur. Heart J. 2014;35:2733-79).

Those endorsements put these cardiac diseases on the firmest ground for categorization as routine practice, a status that grew firmer still when researchers announced in January 2015 new evidence that better clarified the genetic underpinnings of dilated cardiomyopathy, the most common inherited cardiac condition.

“Genetic testing clearly contributes to risk assessment” of cardiomyopathies and channelopathies, Dr. Ray E. Hershberger said during a talk last November at the American Heart Association scientific sessions in Chicago. “Finding a plausible genetic cause for a condition lays the foundation for more durable intervention,” said Dr. Hershberger, professor and director of human genetics at Ohio State University in Columbus.

“Genetic testing for dilated cardiomyopathy is becoming increasingly important in clinical practice. Genetic testing is available, affordable, and efficient,” Dr. Luisa Mestroni, director of the Adult Medical Genetics Program of the University of Colorado, Denver, said during a separate talk at the AHA meeting. She cited three commercially available genetic tests for dilated cardiomyopathy that use next-generation sequencing and screen dozens of implicated genes. The genetic findings are available within about 10 weeks and cost in the range of several thousand dollars. Similar panels also exist for the other cardiomyopathies and channelopathies. Perhaps the most significant limitation on genetic testing for these patients is that it be done within the context of genetic counseling, said both Dr. Mestroni and Dr. Hershberger.

Genetic testing for dilated cardiomyopathy has been hindered by the disorder’s genetic heterogeneity, but understanding of the genetic picture grew much clearer in January with publication of genetic findings from 5,267 people representing the full spectrum of cardiac status, including fully-assessed healthy controls; 3,603 unselected community dwellers taken from the Framingham and Jackson Heart Studies; 374 unselected, ambulatory patients with dilated cardiomyopathy; and 155 patients with severe, end-stage dilated cardiomyopathy. The large, multicenter team of mostly British and U.S. researchers validated the findings in 163 additional patients with familial dilated cardiomyopathy (Sci. Transl. Med. 2015;7:[doi: 10.1126/scitranslmed.3010134].

The findings showed that mutations that produce truncated forms of titin, the body’s largest protein and a critical part of cardiac muscle, appear in about 2% of the general population, about 13% of ambulatory patients with dilated cardiomyopathy, and about 20% of patients with end-stage DCM. In addition, the truncations that occur in people who lack clinical disease tended to affect minor titin isoforms and produce mild functional changes, while the titin truncation mutations in people with severe disease were in the most commonly used isoforms and at sites that severely impaired function.

Until now, in the United Kingdom, “it would not have been standard of care to do gene testing [for patients with suspected dilated cardiomyopathy] unless there was a clear family history or some phenotypic indicator, but going forward we believe the yield from titin truncations [as well as from other, less common known mutations] is sufficient to include genetic testing in a patient’s work-up,” Dr. James S. Ware, a coauthor of the new report and a cardiologist at Imperial College, London, said during a press conference in January.

“The American College of Cardiology and American Heart Association guidelines for managing cardiomyopathy say that it is critical to perform longitudinal clinical follow-up on all first-degree relatives of patients with cardiomyopathy. The cost for longitudinal clinical screening is huge and also poses inconvenience for the family members screened. Genetic testing can now identify which family members really need clinical follow-up and which ones don’t need it,” said Dr. Cristine E. Seidman, a coauthor of the new titin-genetics report, professor of genetics and medicine at Harvard Medical School, and director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital, Boston.

Familial hypercholesterolemia

Routine screening for familial hypercholesterolemia (FH) is not as widely endorsed, but it does have backers, and evidence shows that the approach is cost effective. In part, that’s because both heterozygous and homozygous FH are substantially more common than had been believed until recently. Recent study results documented prevalence rates roughly threefold more common than previously calculated.

For example, a study published last year of more than 104,000 residents of the Netherlands documented a homozygous FH prevalence of 1 in 300,000 (Eur. Heart J. 2014 [doi.org/10.1093/eurheartj/ehu058]). Results from a 2012 study of more than 69,000 Danish residents demonstrated a prevalence of 1 in 137 for people with heterozygous FH (J. Clin. Endocrinol. Metab. 2012;97:3956-64).

“Genetic testing improves the care of individual patients with FH because with genetic testing you can catch patients with FH presymptomatically and you can then treat them and change their long-term prognosis,” Dr. Anne Tybjaerg-Hansen, professor of clinical biochemistry and chief physician at Copenhagen University Hospital, said in a talk at the AHA meeting last November. She cited a report last year from Australia on a model demonstrating the cost effectiveness of testing first-degree relatives of index patients diagnosed with FH, an approach known as cascade screening (J. Clin. Lipidology 2014;8:390-400).

Last year, a consensus panel of the European Atherosclerosis Society recommended that genetic testing “should be considered” for both the diagnostic work-up of index cases with suspected FH and for cascade screening of first-degree relatives of confirmed cases (Eur. Heart J. 2014;35:2146-57). The European panel noted that genetic testing was potentially useful not only to confirm a clinical diagnosis but also to better distinguish patients with heterozygous and homozygous FH. The panel’s report last year endorsed the updated understanding that heterozygous FH occurs in roughly 1 in every 200 people, while homozygous FH has a prevalence of 1 case in every 160,000-300,000 people.

Despite these relatively high prevalence rates, FH is woefully underdiagnosed. A 2013 report from the European Atherosclerosis Society cited recent data documenting that less than 1% of U.S. residents with FH are currently identified (Eur. Heart J. 2013;34:3478-90). The same report noted that less than half of all FH patients have been identified in every country worldwide with reported statistics – aside from the Netherlands, which topped the world with an estimated identification rate of 71% of patients with either form of FH.

Clopidogrel responsiveness

It’s now been several years since researchers determined that roughly 30% of people fail to adequately metabolize the antiplatelet drug clopidogrel into its active form, a finding that in 2010 led the Food and Drug Administration to mandate a boxed warning on clopidogrel’s labeling. The cytochrome P450 (CYP) 2C19 gene codes for the enzyme that activates clopidogrel, and the warning states that people in this significant minority carry alleles of the CYP2C19 gene that make them poor clopidogrel metabolizers and hence clinicians should consider using “alternative treatment strategies.” Usually this means treatment with prasugrel (Effient) or ticagrelor (Brilinta), two thienopyridines that match clopidogrel’s efficacy but do not require metabolic conversion and so are effective even in poor-metabolizing patients.

But years after this well documented and well publicized problem with blind clopidogrel dosing first became apparent, many clinicians remain uncertain how to deal with the issue and how to use genetic testing to clarify the risk faced by individual patients (Circulation 2012;122:445-8).

“The evidence for CYP2C19 is really strong, but because prospective, randomized clinical trials of genotype-directed antiplatelet testing have not been performed, there is a lot of resistance to adoption of genotype-directed treatment,” Dr. Alan R. Shuldiner said in a talk at the November AHA meeting. An editorial published in late 2011 called the boxed warning on clopidogrel “irrational exuberance” (JAMA 2011;306:2727-8). Dr. Shuldiner and others contend that overall evidence today supports a need to screen the CYP2C19 gene before starting clopidogrel, although he conceded that the optimal clinical algorithm for using testing has not yet been devised and that paying for screening remains problematic.

Despite these limitations, Dr. Shuldiner and several colleagues from around the United States issued recommendations in 2013 for the implementation of CYP2C19 genetic testing in patients (Clin. Pharmacol. Ther. 2013;94:317-23) on behalf of the Clinical Pharmacogenetics Implementation Consortium. And in February 2013, clinicians at the University of Maryland in Baltimore began to implement those recommendations as one of eight U.S. sites participating in the PGRN Translational Pharmacogenetics Program.

“It took us 18 months to figure out how to implement pharmacogenetics in the cath lab,” said Dr. Shuldiner, former director of the program for personalized and genomic medicine at the University of Maryland, and now vice president of translation genomics at Regeneron in Tarrytown, N.Y.

From February 2013 through August 2014, the University of Maryland program screened on a routine basis 557 patients undergoing percutaneous coronary intervention (PCI) – with a 5-hour turnaround time on the results – enrolled 446 into the program, found 67 patients with an “actionable” genotype, and actually prescribed an alternative therapy because of the genotype in 37 patients. Patients usually did not receive the genomic-guided treatment because of a contraindication, Dr. Shuldiner said. He concluded that the Maryland experience shows routine screening is doable, and with its strong evidence base warrants use in all catheterization labs.

PCI patients at the University of Florida in Gainesville also now routinely undergo genomic assessment,said during a separate session at the AHA meeting. “Physicians recently began starting their acute coronary syndrome (ACS) patients on ticagrelor, and then when they get the genotype if the patient has an allele associated with good metabolism and can’t afford ticagrelor and needs to change to clopidogrel we know it will be okay. That’s the way we deal with the delay” in getting the genomic results. “At least you know that the patient is protected [with ticagrelor] during the really hot period,” said Dr. Cavallari, director of the center for pharmacogenomics of the University of Florida.

“For ACS patients if you treat with prasugrel or ticagrelor then you’ve pretty much overcome the roadblock, but for patients on clopidogrel I think it is very reasonable to use genetic testing or platelet-reactivity testing, especially for patients with a stented left main coronary,” Dr. Jessica L. Mega said during a panel discussion with Dr. Cavallari at the meeting. “We have pretty good data to suggest that at least in the peri-PCI patients who are homozygous for the *2 allele [the worst clopidogrel metabolizers] should not be on a standard clopidogrel dosage.”

Dr. Mega agreed with other genetic-testing proponents who see a double standard surrounding these tests. “I think there is a little genetic exceptionalism going on, and people feel differently about using genomics compared with other biomarkers. We have good data, and we just need to act on it,” said Dr. Mega, a cardiologist at Brigham and Women’s Hospital in Boston. “If you had an ACS event and received a stent in your left anterior descending coronary and were known to have a *2 allele or had high on-treatment platelet activity would you want to go home on 75 mg a day of clopidogrel?” Dr. Mega asked during a talk at the meeting.

Warfarin dosing

Evidence has implicated polymorphisms in two genes, CYP2C9 and VKORC1, as playing key roles in warfarin metabolism and suggested that determination of a patient’s allele profile for these two genes could assist in more quickly finding the best warfarin dose for a patients requiring oral antithrombotic therapy to reach their target International Normalized Ratio (INR).

In late 2013, researchers reported results from two major prospective trials designed to test the efficacy of genetic analysis of these two genes. The results were split. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial with 455 patients in the United Kingdom and Sweden showed that genotype-based dosing at the start of warfarin therapy increased the time in the therapeutic range, the primary outcome, by 7 percentage points and reduced the incidence of excessive anticoagulation, the time required to reach a therapeutic INR, the time required to reach a stable dose, and the number of adjustments in the dose of warfarin (N. Engl. J. Med. 2013;369:2294-303). But results from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial, which included 1,015 patients at 18 U.S. centers, showed that after 4 weeks genotyping-based warfarin dosing produced no significant between-group difference in the mean percentage of time in the therapeutic range (N. Engl. J. Med. 2013;369:2283-93).These inconsistent results, and especially the COAG study’s inability to show a benefit from genetic analysis in improving warfarin-dose selection, “called into question the clinical utility” of genetic testing, Dr. Cavallari wrote in a comment she coauthored last July (Clin. Pharmacol. Ther. 2014;96:22-4).

But recent data from Dr. Cavallari’s research group suggests that the value of genetic testing in patients starting warfarin may have been masked by the high proportion of African Americans in the COAG study, 27% of enrolled patients, and the finding that these patients did poorly because the alleles they carry most frequently were not covered by the genetic-test panel used in the study.

Before she moved to Gainesville, Dr. Cavallari worked at the University of Illinois in Chicago and she and her associates there began in August 2012 to routinely genotype patients prior to the start of warfarin treatment, using the information to guide initial dosing levels. The analyses they performed included several alleles commonly seen in African Americans – roughly two-thirds of the 389 patients they screened under this program were African American.

Expanding the testing panel had a major impact on efficacy. Results reported by her group at the AHA meeting last November showed that immediately following the start of warfarin treatment the percentage of INR levels that fell out of the therapeutic range was 42%, a statistically significant improvement over the 65% rate seen in 308 historic controls drawn from the year immediately preceding the start of routine genotyping (Circulation 2014;130A:16119). The results showed that the average number of days for patients to reach their first INR measurement in the therapeutic range fell from 11 days prior to genotyping to 4 days, and the average number of days needed on treatment with low-molecular-weight heparin, a bridging strategy until a therapeutic INR is achieved, fell from 10 days among the historic controls to an average of 2 days. The between-group differences for all three of these metrics reached statistical significance in analyses that adjusted for multiple variables, and that used propensity scoring, Dr. Cavallari said.But although genotyping prior to starting warfarin “is available and reasonable to use, until Medicare starts paying for it, doing this will be hard to implement,” Dr. Cavallari conceded during a November talk. Although warfarin-oriented genetic testing may be performed routinely at the University of Illinois, a lot of clinicians elsewhere are holding back, in part because of reimbursement issues and in part because “they want to see proof of better patient outcomes,” said Pharm.D., a cardiovascular pharmacology researcher at the University of Connecticut in Storrs. Like many who look at the evidence for routine genetic testing in cardiovcascular medicine, they “want to see differences in hard clinical outcomes before incorporating it into their practices,” Dr. Baker said.

Dr. Hershberger, Dr. Mestroni, Dr. Ware, Dr. Seidman, Dr. Tybjaerg-Hansen, and Dr. Cavallari had no disclosures. Dr. Shuldiner is an employee of Regeneron. Dr. Mega has been a consultant to Janssen, Boehinger Ingelheim, American Genomics, Bayer, and Portola, and has received research grants from eight companies. Dr. Baker received a research grant from Gilead.

mzoler@frontlinemedcom.com 


On Twitter @mitchelzoler

Heart failure patients who reported difficulty performing everyday tasks were more likely to be hospitalized and to die early, reported Dr. Shannon M. Dunlay and associates from the Mayo Clinic.

American Heart Association

In a cohort study of 1,128 Minnesota adults aged 20 years or older, nearly 60% reported having difficulty with at least one daily activity such as eating, dressing, using the toilet, housekeeping, climbing stairs, bathing, walking, using transportation, and managing medications. Patients with severe or worsening difficulty at follow-up were at significantly increased risk for readmission (hazard ratio, 1.51) and death (HR, 2.10), the investigators reported.

These results “provide new insight into the burden of functional disability in patients with” heart failure, Dr. Dunlay and her associates wrote.

Read the full article at Circulation Heart Failure (2015 Feb. 25 [doi:10.1161/CIRCHEARTFAILURE.114.001542]).

Heart failure patients who reported difficulty performing everyday tasks were more likely to be hospitalized and to die early, reported Dr. Shannon M. Dunlay and associates from the Mayo Clinic.

American Heart Association

In a cohort study of 1,128 Minnesota adults aged 20 years or older, nearly 60% reported having difficulty with at least one daily activity such as eating, dressing, using the toilet, housekeeping, climbing stairs, bathing, walking, using transportation, and managing medications. Patients with severe or worsening difficulty at follow-up were at significantly increased risk for readmission (hazard ratio, 1.51) and death (HR, 2.10), the investigators reported.

These results “provide new insight into the burden of functional disability in patients with” heart failure, Dr. Dunlay and her associates wrote.

Read the full article at Circulation Heart Failure (2015 Feb. 25 [doi:10.1161/CIRCHEARTFAILURE.114.001542]).

Heart failure patients who reported difficulty performing everyday tasks were more likely to be hospitalized and to die early, reported Dr. Shannon M. Dunlay and associates from the Mayo Clinic.

American Heart Association

In a cohort study of 1,128 Minnesota adults aged 20 years or older, nearly 60% reported having difficulty with at least one daily activity such as eating, dressing, using the toilet, housekeeping, climbing stairs, bathing, walking, using transportation, and managing medications. Patients with severe or worsening difficulty at follow-up were at significantly increased risk for readmission (hazard ratio, 1.51) and death (HR, 2.10), the investigators reported.

These results “provide new insight into the burden of functional disability in patients with” heart failure, Dr. Dunlay and her associates wrote.

Read the full article at Circulation Heart Failure (2015 Feb. 25 [doi:10.1161/CIRCHEARTFAILURE.114.001542]).

SNOWMASS, COLO. – The 12-lead Holter monitor is an invaluable and underutilized tool for turning cardiac resynchronization therapy nonresponders into responders, according to Dr. N.A. Mark Estes III.

“The Achilles heel of CRT right now is the failure to respond that occurs in one-quarter to one-third of patients who receive the device. And I think it’s less and less due to a problem of poor patient selection or technical failure, but instead due to common mistakes made in patients who’ve been properly selected and in whom a CRT device has been placed appropriately. I think there’s a lot of room for improvement here,” said Dr. Estes, director of the cardiac arrhythmia center and professor of medicine at Tufts University in Boston.

One common mistake is to accept at face value the CRT device counter when it shows a high percentage of ventricular pacing that’s supposed to be indicative of adequate biventricular pacing in patients. That’s not reliable in patients with coexisting heart failure and atrial fibrillation. In fact, the device pacing counter can markedly overestimate the degree of effective biventricular pacing in patients with permanent atrial fibrillation undergoing CRT. That’s because it may incorrectly count fusion and pseudofusion beats as paced events, even though ventricular capture and atrioventricular resynchronization fail to occur during such beats. The 12-lead Holter monitor will tell the real story regarding ventricular rate control and the percentage of fully paced beats, Dr. Estes said at the Annual Cardiovascular Conference at Snowmass.

“In patients with atrial fibrillation, you can’t just do an EKG, and you can’t just do an interrogation of the device and see that they have 90% or 95% biventricular pacing, which is the sweet spot you need to be North of to make sure they’re having benefit. You really need to do the 24-hour Holter monitor,” the cardiologist emphasized.

“It happens all the time,” he continued. “It happens in my own institution, where we have people come in with heart failure who are being evaluated for an LVAD [left ventricular assist device] because when their CRT device is interrogated, it shows 95% pacing. Everyone’s getting ready to put in the LVAD, and we put them on a Holter monitor and guess what? They’re 60% paced. And sometimes you can have dramatic – really dramatic – improvements by just slowing the ventricular response.”

Increasingly, however, he and his fellow electrophysiologists are alternatively turning to atrioventricular junction ablation in suitable candidates for the catheter-based procedure in order to improve their clinical response to CRT.

Dr. Estes cited a study by Columbia University cardiologists as being highly influential in shaping the new understanding of how to use 12-lead Holter monitoring to identify patients with atrial fibrillation who aren’t responding to CRT. They studied 19 patients with permanent atrial fibrillation who were on CRT, all of whom were on beta-blockers, amiodarone, and digoxin for rate control. Although device interrogation showed all 19 patients had in excess of 90% biventricular pacing 12 months after CRT implantation, only 9 patients were actually clinical responders to CRT as defined by at least a 1-grade improvement in New York Heart Association functional class.

Upon wearing an ambulatory 12-lead Holter monitor for 24 hours, only the nine patients with clinical improvement in response to CRT actually had effective pacing; 94% of their heart beats over the course of 24 hours were fully paced, with a mere 2% fusion beats and less than 4% pseudofusion beats. The other 10 patients had an average of only 60% fully paced beats, along with 16% fusion and 24% pseudofusion beats.

The CRT clinical responders also showed evidence of reverse remodeling, with significantly greater improvements in left ventricular ejection fraction, end-systolic dimension, end-diastolic diameter, and end-systolic and end-diastolic volume, compared with nonresponders.

The lesson, according to the investigators, is that the percentage of biventricular pacing, as obtained from CRT device interrogation, is an unreliable indicator of effective pacing in patients with permanent atrial fibrillation. The goal of CRT programming in this population is to try to achieve 100% biventricular capture on the 12-lead Holter monitor (J. Am. Coll. Cardiol. 2009;53:1050-5).

A series of landmark randomized trials has established that in suitable candidates for CRT with NYHA class I through ambulatory class IV heart failure with reduced ejection fraction, the device therapy provides on average about a 17% reduction in all-cause mortality and a 29% decrease in hospitalizations for heart failure above and beyond the benefits obtained through guideline-directed medical therapy. However, the improvements seen in patients with NYHA class I symptoms are less impressive than in those with NYHA class II-IV disease. And it’s possible that the randomized controlled trials overestimate the true benefit from CRT.

“This is a group of extremely experienced investigators who know the literature well. They’re typically quite savvy with patient selection, and they’re vested in getting the right patients into these trials. Unfortunately, there’s not a registry of all eligible patients, so we can’t tell exactly how those patients were selected. It would have been helpful,” Dr. Estes said.

It’s clear from the randomized trials that the ideal patient for CRT is a woman under age 65 with nonischemic cardiomyopathy with a left bundle branch block, normal sinus rhythm, and a QRS duration of 150 milliseconds or more. That’s who’s most likely to obtain clinical benefit from the therapy. The flip side of that is that an older male patient with ischemia, atrial fibrillation, a QRS of 120-150 milliseconds, and non–left bundle branch block is less likely to respond.

“We’ve figured this out. I think we’ve gotten pretty good at giving patients an honest estimate of their probability of responding independent of our ability to get a lead into a good spot in the coronary sinus,” Dr. Estes said. “More than 95% of patients can be adequately resynchronized currently with the tools we have, so it’s not the barrier that it once represented. We have many different techniques available.”

Despite intensive efforts by investigators using sophisticated nuclear studies, echocardiography, and MRI, however, nothing to date has been able to predict who’s going to respond to CRT as well as a simple electrical parameter: the QRS duration.

“It remains really the gold standard. It’s an electrical marker for what is a mechanical event,” Dr. Estes said.

He reported serving as a consultant to Medtronic, St. Jude Medical, and Boston Scientific and receiving research support from Boston Scientific and St. Jude Medical.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The 12-lead Holter monitor is an invaluable and underutilized tool for turning cardiac resynchronization therapy nonresponders into responders, according to Dr. N.A. Mark Estes III.

“The Achilles heel of CRT right now is the failure to respond that occurs in one-quarter to one-third of patients who receive the device. And I think it’s less and less due to a problem of poor patient selection or technical failure, but instead due to common mistakes made in patients who’ve been properly selected and in whom a CRT device has been placed appropriately. I think there’s a lot of room for improvement here,” said Dr. Estes, director of the cardiac arrhythmia center and professor of medicine at Tufts University in Boston.

One common mistake is to accept at face value the CRT device counter when it shows a high percentage of ventricular pacing that’s supposed to be indicative of adequate biventricular pacing in patients. That’s not reliable in patients with coexisting heart failure and atrial fibrillation. In fact, the device pacing counter can markedly overestimate the degree of effective biventricular pacing in patients with permanent atrial fibrillation undergoing CRT. That’s because it may incorrectly count fusion and pseudofusion beats as paced events, even though ventricular capture and atrioventricular resynchronization fail to occur during such beats. The 12-lead Holter monitor will tell the real story regarding ventricular rate control and the percentage of fully paced beats, Dr. Estes said at the Annual Cardiovascular Conference at Snowmass.

“In patients with atrial fibrillation, you can’t just do an EKG, and you can’t just do an interrogation of the device and see that they have 90% or 95% biventricular pacing, which is the sweet spot you need to be North of to make sure they’re having benefit. You really need to do the 24-hour Holter monitor,” the cardiologist emphasized.

“It happens all the time,” he continued. “It happens in my own institution, where we have people come in with heart failure who are being evaluated for an LVAD [left ventricular assist device] because when their CRT device is interrogated, it shows 95% pacing. Everyone’s getting ready to put in the LVAD, and we put them on a Holter monitor and guess what? They’re 60% paced. And sometimes you can have dramatic – really dramatic – improvements by just slowing the ventricular response.”

Increasingly, however, he and his fellow electrophysiologists are alternatively turning to atrioventricular junction ablation in suitable candidates for the catheter-based procedure in order to improve their clinical response to CRT.

Dr. Estes cited a study by Columbia University cardiologists as being highly influential in shaping the new understanding of how to use 12-lead Holter monitoring to identify patients with atrial fibrillation who aren’t responding to CRT. They studied 19 patients with permanent atrial fibrillation who were on CRT, all of whom were on beta-blockers, amiodarone, and digoxin for rate control. Although device interrogation showed all 19 patients had in excess of 90% biventricular pacing 12 months after CRT implantation, only 9 patients were actually clinical responders to CRT as defined by at least a 1-grade improvement in New York Heart Association functional class.

Upon wearing an ambulatory 12-lead Holter monitor for 24 hours, only the nine patients with clinical improvement in response to CRT actually had effective pacing; 94% of their heart beats over the course of 24 hours were fully paced, with a mere 2% fusion beats and less than 4% pseudofusion beats. The other 10 patients had an average of only 60% fully paced beats, along with 16% fusion and 24% pseudofusion beats.

The CRT clinical responders also showed evidence of reverse remodeling, with significantly greater improvements in left ventricular ejection fraction, end-systolic dimension, end-diastolic diameter, and end-systolic and end-diastolic volume, compared with nonresponders.

The lesson, according to the investigators, is that the percentage of biventricular pacing, as obtained from CRT device interrogation, is an unreliable indicator of effective pacing in patients with permanent atrial fibrillation. The goal of CRT programming in this population is to try to achieve 100% biventricular capture on the 12-lead Holter monitor (J. Am. Coll. Cardiol. 2009;53:1050-5).

A series of landmark randomized trials has established that in suitable candidates for CRT with NYHA class I through ambulatory class IV heart failure with reduced ejection fraction, the device therapy provides on average about a 17% reduction in all-cause mortality and a 29% decrease in hospitalizations for heart failure above and beyond the benefits obtained through guideline-directed medical therapy. However, the improvements seen in patients with NYHA class I symptoms are less impressive than in those with NYHA class II-IV disease. And it’s possible that the randomized controlled trials overestimate the true benefit from CRT.

“This is a group of extremely experienced investigators who know the literature well. They’re typically quite savvy with patient selection, and they’re vested in getting the right patients into these trials. Unfortunately, there’s not a registry of all eligible patients, so we can’t tell exactly how those patients were selected. It would have been helpful,” Dr. Estes said.

It’s clear from the randomized trials that the ideal patient for CRT is a woman under age 65 with nonischemic cardiomyopathy with a left bundle branch block, normal sinus rhythm, and a QRS duration of 150 milliseconds or more. That’s who’s most likely to obtain clinical benefit from the therapy. The flip side of that is that an older male patient with ischemia, atrial fibrillation, a QRS of 120-150 milliseconds, and non–left bundle branch block is less likely to respond.

“We’ve figured this out. I think we’ve gotten pretty good at giving patients an honest estimate of their probability of responding independent of our ability to get a lead into a good spot in the coronary sinus,” Dr. Estes said. “More than 95% of patients can be adequately resynchronized currently with the tools we have, so it’s not the barrier that it once represented. We have many different techniques available.”

Despite intensive efforts by investigators using sophisticated nuclear studies, echocardiography, and MRI, however, nothing to date has been able to predict who’s going to respond to CRT as well as a simple electrical parameter: the QRS duration.

“It remains really the gold standard. It’s an electrical marker for what is a mechanical event,” Dr. Estes said.

He reported serving as a consultant to Medtronic, St. Jude Medical, and Boston Scientific and receiving research support from Boston Scientific and St. Jude Medical.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The 12-lead Holter monitor is an invaluable and underutilized tool for turning cardiac resynchronization therapy nonresponders into responders, according to Dr. N.A. Mark Estes III.

“The Achilles heel of CRT right now is the failure to respond that occurs in one-quarter to one-third of patients who receive the device. And I think it’s less and less due to a problem of poor patient selection or technical failure, but instead due to common mistakes made in patients who’ve been properly selected and in whom a CRT device has been placed appropriately. I think there’s a lot of room for improvement here,” said Dr. Estes, director of the cardiac arrhythmia center and professor of medicine at Tufts University in Boston.

One common mistake is to accept at face value the CRT device counter when it shows a high percentage of ventricular pacing that’s supposed to be indicative of adequate biventricular pacing in patients. That’s not reliable in patients with coexisting heart failure and atrial fibrillation. In fact, the device pacing counter can markedly overestimate the degree of effective biventricular pacing in patients with permanent atrial fibrillation undergoing CRT. That’s because it may incorrectly count fusion and pseudofusion beats as paced events, even though ventricular capture and atrioventricular resynchronization fail to occur during such beats. The 12-lead Holter monitor will tell the real story regarding ventricular rate control and the percentage of fully paced beats, Dr. Estes said at the Annual Cardiovascular Conference at Snowmass.

“In patients with atrial fibrillation, you can’t just do an EKG, and you can’t just do an interrogation of the device and see that they have 90% or 95% biventricular pacing, which is the sweet spot you need to be North of to make sure they’re having benefit. You really need to do the 24-hour Holter monitor,” the cardiologist emphasized.

“It happens all the time,” he continued. “It happens in my own institution, where we have people come in with heart failure who are being evaluated for an LVAD [left ventricular assist device] because when their CRT device is interrogated, it shows 95% pacing. Everyone’s getting ready to put in the LVAD, and we put them on a Holter monitor and guess what? They’re 60% paced. And sometimes you can have dramatic – really dramatic – improvements by just slowing the ventricular response.”

Increasingly, however, he and his fellow electrophysiologists are alternatively turning to atrioventricular junction ablation in suitable candidates for the catheter-based procedure in order to improve their clinical response to CRT.

Dr. Estes cited a study by Columbia University cardiologists as being highly influential in shaping the new understanding of how to use 12-lead Holter monitoring to identify patients with atrial fibrillation who aren’t responding to CRT. They studied 19 patients with permanent atrial fibrillation who were on CRT, all of whom were on beta-blockers, amiodarone, and digoxin for rate control. Although device interrogation showed all 19 patients had in excess of 90% biventricular pacing 12 months after CRT implantation, only 9 patients were actually clinical responders to CRT as defined by at least a 1-grade improvement in New York Heart Association functional class.

Upon wearing an ambulatory 12-lead Holter monitor for 24 hours, only the nine patients with clinical improvement in response to CRT actually had effective pacing; 94% of their heart beats over the course of 24 hours were fully paced, with a mere 2% fusion beats and less than 4% pseudofusion beats. The other 10 patients had an average of only 60% fully paced beats, along with 16% fusion and 24% pseudofusion beats.

The CRT clinical responders also showed evidence of reverse remodeling, with significantly greater improvements in left ventricular ejection fraction, end-systolic dimension, end-diastolic diameter, and end-systolic and end-diastolic volume, compared with nonresponders.

The lesson, according to the investigators, is that the percentage of biventricular pacing, as obtained from CRT device interrogation, is an unreliable indicator of effective pacing in patients with permanent atrial fibrillation. The goal of CRT programming in this population is to try to achieve 100% biventricular capture on the 12-lead Holter monitor (J. Am. Coll. Cardiol. 2009;53:1050-5).

A series of landmark randomized trials has established that in suitable candidates for CRT with NYHA class I through ambulatory class IV heart failure with reduced ejection fraction, the device therapy provides on average about a 17% reduction in all-cause mortality and a 29% decrease in hospitalizations for heart failure above and beyond the benefits obtained through guideline-directed medical therapy. However, the improvements seen in patients with NYHA class I symptoms are less impressive than in those with NYHA class II-IV disease. And it’s possible that the randomized controlled trials overestimate the true benefit from CRT.

“This is a group of extremely experienced investigators who know the literature well. They’re typically quite savvy with patient selection, and they’re vested in getting the right patients into these trials. Unfortunately, there’s not a registry of all eligible patients, so we can’t tell exactly how those patients were selected. It would have been helpful,” Dr. Estes said.

It’s clear from the randomized trials that the ideal patient for CRT is a woman under age 65 with nonischemic cardiomyopathy with a left bundle branch block, normal sinus rhythm, and a QRS duration of 150 milliseconds or more. That’s who’s most likely to obtain clinical benefit from the therapy. The flip side of that is that an older male patient with ischemia, atrial fibrillation, a QRS of 120-150 milliseconds, and non–left bundle branch block is less likely to respond.

“We’ve figured this out. I think we’ve gotten pretty good at giving patients an honest estimate of their probability of responding independent of our ability to get a lead into a good spot in the coronary sinus,” Dr. Estes said. “More than 95% of patients can be adequately resynchronized currently with the tools we have, so it’s not the barrier that it once represented. We have many different techniques available.”

Despite intensive efforts by investigators using sophisticated nuclear studies, echocardiography, and MRI, however, nothing to date has been able to predict who’s going to respond to CRT as well as a simple electrical parameter: the QRS duration.

“It remains really the gold standard. It’s an electrical marker for what is a mechanical event,” Dr. Estes said.

He reported serving as a consultant to Medtronic, St. Jude Medical, and Boston Scientific and receiving research support from Boston Scientific and St. Jude Medical.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Differentiating constrictive pericarditis from restrictive cardiomyopathy in patients with right heart failure with a normal ejection fraction is “one of the most difficult diagnostic challenges in cardiology today,” but reliable results can be achieved using a careful step-by-step approach, Dr. Rick A. Nishimura said at the Annual Cardiovascular Conference at Snowmass.

Under current terminology for heart failure, cardiologists speak of HFrEF, or heart failure with reduced ejection fraction, and HFpEF, or heart failure with preserved ejection fraction. But there is a third group of patients who are often mistakenly thought to have HFpEF: those with severe right heart failure and a normal ejection fraction, classically caused by constrictive pericarditis or restrictive cardiomyopathy.

Unlike patients with HFpEF, these people are not hypertensive and they don’t have pulmonary congestion. Instead, they present predominantly with ascites, peripheral edema, fatigue, and marked elevation in jugular venous pressure, noted Dr. Nishimura, professor of medicine at the Mayo Clinic in Rochester, Minn.

Before elaborating on his own tried-and-true, step-by-step approach, he highlighted several diagnostic procedures he considers less than reliable. One is advanced imaging with CT or MRI looking for the pericardial thickening that is widely viewed as an anatomic hallmark of constrictive pericarditis.

“Remember, 22% of patients with proven constrictive pericarditis actually have a normal pericardium on CT or MRI, because it’s their fibrotic epicardium that’s causing the constrictive pericarditis. And roughly 70% of patients are going to have some thickened pericardium after radiation therapy or coronary artery bypass graft surgery without having constrictive pericarditis. So CT and MRI are helpful, but they’re not going to be diagnostic,” according to the cardiologist.

Similarly, while it’s often been said that constrictive pericarditis can be diagnosed based upon a classic trio of hemodynamic findings obtained through heart catheterization – namely, early rapid filling with a left ventricular end-diastolic pressure equal to the right ventricular end-diastolic pressure, a right ventricular end-diastolic pressure greater than one-third of the right ventricular systolic pressure, and a pulmonary artery pressure below 50 mm Hg – these criteria didn’t reliably separate the last 100 patients who came to the catheterization lab at the Mayo Clinic with either constrictive pericarditis or restrictive cardiomyopathy, he continued.

Dr. Nishimura’s approach to the work-up of patients with unexplained right heart failure and a normal ejection begins with the history and physical examination. The history in a patient with constrictive pericarditis is classically one of radiation therapy years earlier for a malignancy, or prior CABG surgery. And the physical exam has to reveal the presence of high neck veins.

“If you don’t see high neck veins due to elevated jugular venous pressure with rapid x and y descents, the patient doesn’t have constrictive pericarditis, no matter what the echocardiogram shows,” Dr. Nishimura asserted.

If those findings are present, however, then on 2-D echocardiography he’s looking for three things that point to constrictive pericarditis: a brisk septal shudder due to rapid filling in early diastole with every heart beat; an early diastolic posterior motion of the intraventricular septum, known as the septal bounce, that occurs as a consequence of the less compliant ventricular walls; and dilation of the inferior vena cava indicative of increased right atrial pressure.

When all three findings are present on 2-D echo, he turns to Doppler echo for hemodynamic information. If Doppler shows a reduction in transmitral driving pressure from the lungs to the heart during inspiration, as the intrathoracic pressure drops but the left ventricular pressure does not, the work-up is done. That patient has constrictive pericarditis and needs to be referred to surgery for pericardiectomy, which will bring rapid improvement.

In roughly one-quarter of patients with constrictive pericarditis, however, that full constellation of 2-D and Doppler echocardiographic findings isn’t present. It then becomes necessary to move on to cardiac catheterization. The first two things to look for in the cath lab are elevated end-equalization of diastolic pressures and low cardiac output.

“If they’re in the cath lab and they’ve got normal filling pressures and a normal cardiac output, they do not have clinically significant constrictive pericarditis, no matter what the echo shows. So those two things are necessary to see, but of course they’re not diagnostic. So we go further,” Dr. Nishimura said.

A patient with constrictive pericarditis will have enhanced ventricular interaction arising from the restraint imposed by a rigid, diseased pericardium. That’s crucial. This increased ventricular interaction is manifest as an increase in the size of the right ventricle during inspiration while the area of the left ventricle is getting smaller.

In contrast, during inspiration and expiration in a patient with restrictive cardiomyopathy, as the right ventricle gets smaller, so does the left ventricle.

“The ratio of the right ventricle to left ventricle area under the curve during inspiration versus expiration gives a very nice distinction between constrictive pericarditis and restrictive cardiomyopathy. Enhanced ventricular interaction is the most sensitive and specific finding for constrictive pericarditis,” according to Dr. Nishimura.

He added that, in addition to constrictive pericarditis and restrictive cardiomyopathy, there is a third and underappreciated cause of right heart failure with a normal ejection fraction: severe tricuspid regurgitation. This abnormality may not be readily apparent upon echocardiography in a patient with a pacemaker lead or automatic implantable cardioverter-defibrillator lead, which can cause acoustic shadowing that results in underestimation of the severity of tricuspid regurgitation. The clue here is the observation of hepatic vein systolic flow reversal, which can only be caused by severe tricuspid regurgitation.

“Think tricuspid regurgitation in patients who have a pacemaker lead or AICD, and also in older women with longstanding atrial fibrillation who dilate their tricuspid annulus and develop more and more tricuspid regurgitation. Take those patients to the cath lab and do a right ventriculogram, which will show tricuspid regurgitation,” Dr. Nishimura advised.

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Differentiating constrictive pericarditis from restrictive cardiomyopathy in patients with right heart failure with a normal ejection fraction is “one of the most difficult diagnostic challenges in cardiology today,” but reliable results can be achieved using a careful step-by-step approach, Dr. Rick A. Nishimura said at the Annual Cardiovascular Conference at Snowmass.

Under current terminology for heart failure, cardiologists speak of HFrEF, or heart failure with reduced ejection fraction, and HFpEF, or heart failure with preserved ejection fraction. But there is a third group of patients who are often mistakenly thought to have HFpEF: those with severe right heart failure and a normal ejection fraction, classically caused by constrictive pericarditis or restrictive cardiomyopathy.

Unlike patients with HFpEF, these people are not hypertensive and they don’t have pulmonary congestion. Instead, they present predominantly with ascites, peripheral edema, fatigue, and marked elevation in jugular venous pressure, noted Dr. Nishimura, professor of medicine at the Mayo Clinic in Rochester, Minn.

Before elaborating on his own tried-and-true, step-by-step approach, he highlighted several diagnostic procedures he considers less than reliable. One is advanced imaging with CT or MRI looking for the pericardial thickening that is widely viewed as an anatomic hallmark of constrictive pericarditis.

“Remember, 22% of patients with proven constrictive pericarditis actually have a normal pericardium on CT or MRI, because it’s their fibrotic epicardium that’s causing the constrictive pericarditis. And roughly 70% of patients are going to have some thickened pericardium after radiation therapy or coronary artery bypass graft surgery without having constrictive pericarditis. So CT and MRI are helpful, but they’re not going to be diagnostic,” according to the cardiologist.

Similarly, while it’s often been said that constrictive pericarditis can be diagnosed based upon a classic trio of hemodynamic findings obtained through heart catheterization – namely, early rapid filling with a left ventricular end-diastolic pressure equal to the right ventricular end-diastolic pressure, a right ventricular end-diastolic pressure greater than one-third of the right ventricular systolic pressure, and a pulmonary artery pressure below 50 mm Hg – these criteria didn’t reliably separate the last 100 patients who came to the catheterization lab at the Mayo Clinic with either constrictive pericarditis or restrictive cardiomyopathy, he continued.

Dr. Nishimura’s approach to the work-up of patients with unexplained right heart failure and a normal ejection begins with the history and physical examination. The history in a patient with constrictive pericarditis is classically one of radiation therapy years earlier for a malignancy, or prior CABG surgery. And the physical exam has to reveal the presence of high neck veins.

“If you don’t see high neck veins due to elevated jugular venous pressure with rapid x and y descents, the patient doesn’t have constrictive pericarditis, no matter what the echocardiogram shows,” Dr. Nishimura asserted.

If those findings are present, however, then on 2-D echocardiography he’s looking for three things that point to constrictive pericarditis: a brisk septal shudder due to rapid filling in early diastole with every heart beat; an early diastolic posterior motion of the intraventricular septum, known as the septal bounce, that occurs as a consequence of the less compliant ventricular walls; and dilation of the inferior vena cava indicative of increased right atrial pressure.

When all three findings are present on 2-D echo, he turns to Doppler echo for hemodynamic information. If Doppler shows a reduction in transmitral driving pressure from the lungs to the heart during inspiration, as the intrathoracic pressure drops but the left ventricular pressure does not, the work-up is done. That patient has constrictive pericarditis and needs to be referred to surgery for pericardiectomy, which will bring rapid improvement.

In roughly one-quarter of patients with constrictive pericarditis, however, that full constellation of 2-D and Doppler echocardiographic findings isn’t present. It then becomes necessary to move on to cardiac catheterization. The first two things to look for in the cath lab are elevated end-equalization of diastolic pressures and low cardiac output.

“If they’re in the cath lab and they’ve got normal filling pressures and a normal cardiac output, they do not have clinically significant constrictive pericarditis, no matter what the echo shows. So those two things are necessary to see, but of course they’re not diagnostic. So we go further,” Dr. Nishimura said.

A patient with constrictive pericarditis will have enhanced ventricular interaction arising from the restraint imposed by a rigid, diseased pericardium. That’s crucial. This increased ventricular interaction is manifest as an increase in the size of the right ventricle during inspiration while the area of the left ventricle is getting smaller.

In contrast, during inspiration and expiration in a patient with restrictive cardiomyopathy, as the right ventricle gets smaller, so does the left ventricle.

“The ratio of the right ventricle to left ventricle area under the curve during inspiration versus expiration gives a very nice distinction between constrictive pericarditis and restrictive cardiomyopathy. Enhanced ventricular interaction is the most sensitive and specific finding for constrictive pericarditis,” according to Dr. Nishimura.

He added that, in addition to constrictive pericarditis and restrictive cardiomyopathy, there is a third and underappreciated cause of right heart failure with a normal ejection fraction: severe tricuspid regurgitation. This abnormality may not be readily apparent upon echocardiography in a patient with a pacemaker lead or automatic implantable cardioverter-defibrillator lead, which can cause acoustic shadowing that results in underestimation of the severity of tricuspid regurgitation. The clue here is the observation of hepatic vein systolic flow reversal, which can only be caused by severe tricuspid regurgitation.

“Think tricuspid regurgitation in patients who have a pacemaker lead or AICD, and also in older women with longstanding atrial fibrillation who dilate their tricuspid annulus and develop more and more tricuspid regurgitation. Take those patients to the cath lab and do a right ventriculogram, which will show tricuspid regurgitation,” Dr. Nishimura advised.

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Differentiating constrictive pericarditis from restrictive cardiomyopathy in patients with right heart failure with a normal ejection fraction is “one of the most difficult diagnostic challenges in cardiology today,” but reliable results can be achieved using a careful step-by-step approach, Dr. Rick A. Nishimura said at the Annual Cardiovascular Conference at Snowmass.

Under current terminology for heart failure, cardiologists speak of HFrEF, or heart failure with reduced ejection fraction, and HFpEF, or heart failure with preserved ejection fraction. But there is a third group of patients who are often mistakenly thought to have HFpEF: those with severe right heart failure and a normal ejection fraction, classically caused by constrictive pericarditis or restrictive cardiomyopathy.

Unlike patients with HFpEF, these people are not hypertensive and they don’t have pulmonary congestion. Instead, they present predominantly with ascites, peripheral edema, fatigue, and marked elevation in jugular venous pressure, noted Dr. Nishimura, professor of medicine at the Mayo Clinic in Rochester, Minn.

Before elaborating on his own tried-and-true, step-by-step approach, he highlighted several diagnostic procedures he considers less than reliable. One is advanced imaging with CT or MRI looking for the pericardial thickening that is widely viewed as an anatomic hallmark of constrictive pericarditis.

“Remember, 22% of patients with proven constrictive pericarditis actually have a normal pericardium on CT or MRI, because it’s their fibrotic epicardium that’s causing the constrictive pericarditis. And roughly 70% of patients are going to have some thickened pericardium after radiation therapy or coronary artery bypass graft surgery without having constrictive pericarditis. So CT and MRI are helpful, but they’re not going to be diagnostic,” according to the cardiologist.

Similarly, while it’s often been said that constrictive pericarditis can be diagnosed based upon a classic trio of hemodynamic findings obtained through heart catheterization – namely, early rapid filling with a left ventricular end-diastolic pressure equal to the right ventricular end-diastolic pressure, a right ventricular end-diastolic pressure greater than one-third of the right ventricular systolic pressure, and a pulmonary artery pressure below 50 mm Hg – these criteria didn’t reliably separate the last 100 patients who came to the catheterization lab at the Mayo Clinic with either constrictive pericarditis or restrictive cardiomyopathy, he continued.

Dr. Nishimura’s approach to the work-up of patients with unexplained right heart failure and a normal ejection begins with the history and physical examination. The history in a patient with constrictive pericarditis is classically one of radiation therapy years earlier for a malignancy, or prior CABG surgery. And the physical exam has to reveal the presence of high neck veins.

“If you don’t see high neck veins due to elevated jugular venous pressure with rapid x and y descents, the patient doesn’t have constrictive pericarditis, no matter what the echocardiogram shows,” Dr. Nishimura asserted.

If those findings are present, however, then on 2-D echocardiography he’s looking for three things that point to constrictive pericarditis: a brisk septal shudder due to rapid filling in early diastole with every heart beat; an early diastolic posterior motion of the intraventricular septum, known as the septal bounce, that occurs as a consequence of the less compliant ventricular walls; and dilation of the inferior vena cava indicative of increased right atrial pressure.

When all three findings are present on 2-D echo, he turns to Doppler echo for hemodynamic information. If Doppler shows a reduction in transmitral driving pressure from the lungs to the heart during inspiration, as the intrathoracic pressure drops but the left ventricular pressure does not, the work-up is done. That patient has constrictive pericarditis and needs to be referred to surgery for pericardiectomy, which will bring rapid improvement.

In roughly one-quarter of patients with constrictive pericarditis, however, that full constellation of 2-D and Doppler echocardiographic findings isn’t present. It then becomes necessary to move on to cardiac catheterization. The first two things to look for in the cath lab are elevated end-equalization of diastolic pressures and low cardiac output.

“If they’re in the cath lab and they’ve got normal filling pressures and a normal cardiac output, they do not have clinically significant constrictive pericarditis, no matter what the echo shows. So those two things are necessary to see, but of course they’re not diagnostic. So we go further,” Dr. Nishimura said.

A patient with constrictive pericarditis will have enhanced ventricular interaction arising from the restraint imposed by a rigid, diseased pericardium. That’s crucial. This increased ventricular interaction is manifest as an increase in the size of the right ventricle during inspiration while the area of the left ventricle is getting smaller.

In contrast, during inspiration and expiration in a patient with restrictive cardiomyopathy, as the right ventricle gets smaller, so does the left ventricle.

“The ratio of the right ventricle to left ventricle area under the curve during inspiration versus expiration gives a very nice distinction between constrictive pericarditis and restrictive cardiomyopathy. Enhanced ventricular interaction is the most sensitive and specific finding for constrictive pericarditis,” according to Dr. Nishimura.

He added that, in addition to constrictive pericarditis and restrictive cardiomyopathy, there is a third and underappreciated cause of right heart failure with a normal ejection fraction: severe tricuspid regurgitation. This abnormality may not be readily apparent upon echocardiography in a patient with a pacemaker lead or automatic implantable cardioverter-defibrillator lead, which can cause acoustic shadowing that results in underestimation of the severity of tricuspid regurgitation. The clue here is the observation of hepatic vein systolic flow reversal, which can only be caused by severe tricuspid regurgitation.

“Think tricuspid regurgitation in patients who have a pacemaker lead or AICD, and also in older women with longstanding atrial fibrillation who dilate their tricuspid annulus and develop more and more tricuspid regurgitation. Take those patients to the cath lab and do a right ventriculogram, which will show tricuspid regurgitation,” Dr. Nishimura advised.

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

The survival benefit conferred by implantable cardioverter-defibrillators (ICDs) persists with increasing patient age, but does attenuate, according to a report published online Feb.10 in Circulation: Cardiovascular Quality and Outcomes.

This indicates that “age per se should not be a contraindication to ICD placement. Rather, clinical judgment should take into account other factors, including patient preference, periprocedural risk, and comorbidity burden,” said Dr. Paul L. Hess of Duke Clinical Research Institute, Durham N.C., and his associates.

It is uncertain whether ICDs are effective at reducing sudden cardiac death in patients aged 75 years and older, largely because this age group has been underrepresented in clinical trials. Yet more than 40% of new ICDs are placed in older patients, including 10% placed in patients aged 80 years and older. Dr. Hess and his colleagues pooled data from five major clinical trials of ICDs to increase the sample size of older patients, allowing better appraisal of treatment effects in this age group. They retrospectively assessed survival outcomes in 3,530 patients who participated in the MADIT-I, MUSTT, MADIT-II, DEFINITE, and SCD-HeFT studies conducted in the United States, Canada, Italy, Germany, the Netherlands, and Israel.

The median age in this pooled sample was 62 years. There were 390 patients (11%) aged 75 years and older. Median follow-up after ICD placement was 2.6 years.

The primary outcome of interest – all-cause mortality – was 21.3% among ICD recipients, compared with 30.6% in patients who didn’t receive ICDs. “After adjusting for patient demographics, medical comorbidities, and laboratory values, point estimates indicated that the survival benefit of ICD therapy persists across the age spectrum,” the investigators said (Circ. Cardiovasc. Qual. Outcomes 2015 Feb. 10; [doi:10.1161/circoutcomes.114.001306]).

The survival benefit attenuated with increasing patient age. This may be because of an increase in competing causes of death as patients aged. However, the total number of participants aged 75 years and older was “modest” despite the pooling of data, “and this may have affected the corresponding efficacy estimates and the observed attenuation of ICD survival benefit,” Dr. Hess and his associates wrote.

The study also found no evidence that age influences the risk of rehospitalization after ICD placement.

The survival benefit conferred by implantable cardioverter-defibrillators (ICDs) persists with increasing patient age, but does attenuate, according to a report published online Feb.10 in Circulation: Cardiovascular Quality and Outcomes.

This indicates that “age per se should not be a contraindication to ICD placement. Rather, clinical judgment should take into account other factors, including patient preference, periprocedural risk, and comorbidity burden,” said Dr. Paul L. Hess of Duke Clinical Research Institute, Durham N.C., and his associates.

It is uncertain whether ICDs are effective at reducing sudden cardiac death in patients aged 75 years and older, largely because this age group has been underrepresented in clinical trials. Yet more than 40% of new ICDs are placed in older patients, including 10% placed in patients aged 80 years and older. Dr. Hess and his colleagues pooled data from five major clinical trials of ICDs to increase the sample size of older patients, allowing better appraisal of treatment effects in this age group. They retrospectively assessed survival outcomes in 3,530 patients who participated in the MADIT-I, MUSTT, MADIT-II, DEFINITE, and SCD-HeFT studies conducted in the United States, Canada, Italy, Germany, the Netherlands, and Israel.

The median age in this pooled sample was 62 years. There were 390 patients (11%) aged 75 years and older. Median follow-up after ICD placement was 2.6 years.

The primary outcome of interest – all-cause mortality – was 21.3% among ICD recipients, compared with 30.6% in patients who didn’t receive ICDs. “After adjusting for patient demographics, medical comorbidities, and laboratory values, point estimates indicated that the survival benefit of ICD therapy persists across the age spectrum,” the investigators said (Circ. Cardiovasc. Qual. Outcomes 2015 Feb. 10; [doi:10.1161/circoutcomes.114.001306]).

The survival benefit attenuated with increasing patient age. This may be because of an increase in competing causes of death as patients aged. However, the total number of participants aged 75 years and older was “modest” despite the pooling of data, “and this may have affected the corresponding efficacy estimates and the observed attenuation of ICD survival benefit,” Dr. Hess and his associates wrote.

The study also found no evidence that age influences the risk of rehospitalization after ICD placement.

The survival benefit conferred by implantable cardioverter-defibrillators (ICDs) persists with increasing patient age, but does attenuate, according to a report published online Feb.10 in Circulation: Cardiovascular Quality and Outcomes.

This indicates that “age per se should not be a contraindication to ICD placement. Rather, clinical judgment should take into account other factors, including patient preference, periprocedural risk, and comorbidity burden,” said Dr. Paul L. Hess of Duke Clinical Research Institute, Durham N.C., and his associates.

It is uncertain whether ICDs are effective at reducing sudden cardiac death in patients aged 75 years and older, largely because this age group has been underrepresented in clinical trials. Yet more than 40% of new ICDs are placed in older patients, including 10% placed in patients aged 80 years and older. Dr. Hess and his colleagues pooled data from five major clinical trials of ICDs to increase the sample size of older patients, allowing better appraisal of treatment effects in this age group. They retrospectively assessed survival outcomes in 3,530 patients who participated in the MADIT-I, MUSTT, MADIT-II, DEFINITE, and SCD-HeFT studies conducted in the United States, Canada, Italy, Germany, the Netherlands, and Israel.

The median age in this pooled sample was 62 years. There were 390 patients (11%) aged 75 years and older. Median follow-up after ICD placement was 2.6 years.

The primary outcome of interest – all-cause mortality – was 21.3% among ICD recipients, compared with 30.6% in patients who didn’t receive ICDs. “After adjusting for patient demographics, medical comorbidities, and laboratory values, point estimates indicated that the survival benefit of ICD therapy persists across the age spectrum,” the investigators said (Circ. Cardiovasc. Qual. Outcomes 2015 Feb. 10; [doi:10.1161/circoutcomes.114.001306]).

The survival benefit attenuated with increasing patient age. This may be because of an increase in competing causes of death as patients aged. However, the total number of participants aged 75 years and older was “modest” despite the pooling of data, “and this may have affected the corresponding efficacy estimates and the observed attenuation of ICD survival benefit,” Dr. Hess and his associates wrote.

The study also found no evidence that age influences the risk of rehospitalization after ICD placement.