Sidney Goldstein, MD

The announcement from Medtronic in January has apparently brought down the curtain on the much-heralded approach to the treatment of refractory hypertension using radio-frequency renal artery sympathetic nerve ablation (RASNA) applied through the tip of the Symplicity catheter.

This technology is being used widely around the world for the treatment of refractory hypertensive patients. The enthusiasm for RASNA was generated by a series of reports suggesting that an amazing decrease in systolic blood pressure of more than 30 mm Hg can be obtained in patients with resistant hypertension taking three or more antihypertensive drugs. However, the SYMPLICITY HTN-3 trial (Clin. Cardiol. 2012;35:528-35), which enrolled 535 patients with refractory hypertension, failed to achieve the primary endpoint of a significant decrease in systolic pressure in the radio-frequency (RF)-treated patients compared with the sham-operated patients. In the study, blinding was rigorously managed by renal artery catheterization of all 535 patients, with RF ablation instituted in two-thirds of the patients, and a sham operation conducted in one-third.

As a result of the observations in SYMPLICITY HTN-3, Medtronic is suspending enrollment in current trials using the Symplicity device throughout the world, and will "continue to ensure patients access to the Symplicity technology at the discretion of their physicians in countries where the device is approved," according to its statement.

Enthusiasm for RF ablation of the sympathetic nerves accompanying the renal artery was generated by a series of publications describing the physiologic and therapeutic effects. The first publications in this series described the metabolic changes that occurred after RF ablation carried out in one patient who experienced a decrease in systolic pressure of 20 mm Hg associated with modulation of sympathetic activity 30 days and 12 months after the procedure (N. Engl. J. Med. 2009;361:932-4). This study was followed by two subsequent reports of patients in whom RASNA was carried out. A proof-of-concept trial (SYMPLICITY HTN-1) in 153 patients reported a substantial decrease in blood pressure over a 2-year period (Hypertension 2011;57:911-7). A second trial (SYMPLICITY HTN-2) randomized 106 patients to either RASNA or standard therapy. That trial reported that 84% of the patients receiving RASNA had a reduction of blood pressure greater than 10 mm Hg within 6 months, compared with 35% of the control group (Lancet 2010;376:1903-9). Both studies reported a profound decrease in blood pressure that ensued over a 6-month period in 80%-90% of patients undergoing the therapy. In light of these reports, it is difficult to explain the fact that SYMPLICITY HTN-3 was a negative study.

Modulation of the sympathetic nervous system for the treatment of hypertension is not new. More than 60 years ago, Smithwick and colleagues carried out both surgical lumbar and sympathetic splanchnicectomy for its treatment with uncertain results (JAMA 1952;153:1501-4). In an era when all that we could offer hypertensive patients was a low-salt diet, the procedure became rather popular. However, the surgical risks, adverse side effects, and uncertainty of benefit led to both procedures being discontinued. Recently, there have been studies of the effect of stimulation of the carotid sinus nerve for the treatment of hypertension.

The potential benefit of modulation of the arterial sympathetic nerves, and particularly those located in the renal artery, became the focus of this recent interest. Nevertheless, a number of questions have arisen in regard to the mechanism of RASNA. And why does it take 6 months to achieve the blood pressure response? In addition, there is very little published data in regard to the changes in the renal artery and its adjacent tissue as a result of the RF ablation.

At the present, Medtronic has not provided any information beyond its indicating the lack of benefit. Further information will be reported at the upcoming American College of Cardiology scientific sessions. In the meantime, speculation is rampant as to whether the initial reports were purely placebo effects or if there is something intrinsically flawed in the SYMPLICITY HTN -3 trial.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The announcement from Medtronic in January has apparently brought down the curtain on the much-heralded approach to the treatment of refractory hypertension using radio-frequency renal artery sympathetic nerve ablation (RASNA) applied through the tip of the Symplicity catheter.

This technology is being used widely around the world for the treatment of refractory hypertensive patients. The enthusiasm for RASNA was generated by a series of reports suggesting that an amazing decrease in systolic blood pressure of more than 30 mm Hg can be obtained in patients with resistant hypertension taking three or more antihypertensive drugs. However, the SYMPLICITY HTN-3 trial (Clin. Cardiol. 2012;35:528-35), which enrolled 535 patients with refractory hypertension, failed to achieve the primary endpoint of a significant decrease in systolic pressure in the radio-frequency (RF)-treated patients compared with the sham-operated patients. In the study, blinding was rigorously managed by renal artery catheterization of all 535 patients, with RF ablation instituted in two-thirds of the patients, and a sham operation conducted in one-third.

As a result of the observations in SYMPLICITY HTN-3, Medtronic is suspending enrollment in current trials using the Symplicity device throughout the world, and will "continue to ensure patients access to the Symplicity technology at the discretion of their physicians in countries where the device is approved," according to its statement.

Enthusiasm for RF ablation of the sympathetic nerves accompanying the renal artery was generated by a series of publications describing the physiologic and therapeutic effects. The first publications in this series described the metabolic changes that occurred after RF ablation carried out in one patient who experienced a decrease in systolic pressure of 20 mm Hg associated with modulation of sympathetic activity 30 days and 12 months after the procedure (N. Engl. J. Med. 2009;361:932-4). This study was followed by two subsequent reports of patients in whom RASNA was carried out. A proof-of-concept trial (SYMPLICITY HTN-1) in 153 patients reported a substantial decrease in blood pressure over a 2-year period (Hypertension 2011;57:911-7). A second trial (SYMPLICITY HTN-2) randomized 106 patients to either RASNA or standard therapy. That trial reported that 84% of the patients receiving RASNA had a reduction of blood pressure greater than 10 mm Hg within 6 months, compared with 35% of the control group (Lancet 2010;376:1903-9). Both studies reported a profound decrease in blood pressure that ensued over a 6-month period in 80%-90% of patients undergoing the therapy. In light of these reports, it is difficult to explain the fact that SYMPLICITY HTN-3 was a negative study.

Modulation of the sympathetic nervous system for the treatment of hypertension is not new. More than 60 years ago, Smithwick and colleagues carried out both surgical lumbar and sympathetic splanchnicectomy for its treatment with uncertain results (JAMA 1952;153:1501-4). In an era when all that we could offer hypertensive patients was a low-salt diet, the procedure became rather popular. However, the surgical risks, adverse side effects, and uncertainty of benefit led to both procedures being discontinued. Recently, there have been studies of the effect of stimulation of the carotid sinus nerve for the treatment of hypertension.

The potential benefit of modulation of the arterial sympathetic nerves, and particularly those located in the renal artery, became the focus of this recent interest. Nevertheless, a number of questions have arisen in regard to the mechanism of RASNA. And why does it take 6 months to achieve the blood pressure response? In addition, there is very little published data in regard to the changes in the renal artery and its adjacent tissue as a result of the RF ablation.

At the present, Medtronic has not provided any information beyond its indicating the lack of benefit. Further information will be reported at the upcoming American College of Cardiology scientific sessions. In the meantime, speculation is rampant as to whether the initial reports were purely placebo effects or if there is something intrinsically flawed in the SYMPLICITY HTN -3 trial.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The announcement from Medtronic in January has apparently brought down the curtain on the much-heralded approach to the treatment of refractory hypertension using radio-frequency renal artery sympathetic nerve ablation (RASNA) applied through the tip of the Symplicity catheter.

This technology is being used widely around the world for the treatment of refractory hypertensive patients. The enthusiasm for RASNA was generated by a series of reports suggesting that an amazing decrease in systolic blood pressure of more than 30 mm Hg can be obtained in patients with resistant hypertension taking three or more antihypertensive drugs. However, the SYMPLICITY HTN-3 trial (Clin. Cardiol. 2012;35:528-35), which enrolled 535 patients with refractory hypertension, failed to achieve the primary endpoint of a significant decrease in systolic pressure in the radio-frequency (RF)-treated patients compared with the sham-operated patients. In the study, blinding was rigorously managed by renal artery catheterization of all 535 patients, with RF ablation instituted in two-thirds of the patients, and a sham operation conducted in one-third.

As a result of the observations in SYMPLICITY HTN-3, Medtronic is suspending enrollment in current trials using the Symplicity device throughout the world, and will "continue to ensure patients access to the Symplicity technology at the discretion of their physicians in countries where the device is approved," according to its statement.

Enthusiasm for RF ablation of the sympathetic nerves accompanying the renal artery was generated by a series of publications describing the physiologic and therapeutic effects. The first publications in this series described the metabolic changes that occurred after RF ablation carried out in one patient who experienced a decrease in systolic pressure of 20 mm Hg associated with modulation of sympathetic activity 30 days and 12 months after the procedure (N. Engl. J. Med. 2009;361:932-4). This study was followed by two subsequent reports of patients in whom RASNA was carried out. A proof-of-concept trial (SYMPLICITY HTN-1) in 153 patients reported a substantial decrease in blood pressure over a 2-year period (Hypertension 2011;57:911-7). A second trial (SYMPLICITY HTN-2) randomized 106 patients to either RASNA or standard therapy. That trial reported that 84% of the patients receiving RASNA had a reduction of blood pressure greater than 10 mm Hg within 6 months, compared with 35% of the control group (Lancet 2010;376:1903-9). Both studies reported a profound decrease in blood pressure that ensued over a 6-month period in 80%-90% of patients undergoing the therapy. In light of these reports, it is difficult to explain the fact that SYMPLICITY HTN-3 was a negative study.

Modulation of the sympathetic nervous system for the treatment of hypertension is not new. More than 60 years ago, Smithwick and colleagues carried out both surgical lumbar and sympathetic splanchnicectomy for its treatment with uncertain results (JAMA 1952;153:1501-4). In an era when all that we could offer hypertensive patients was a low-salt diet, the procedure became rather popular. However, the surgical risks, adverse side effects, and uncertainty of benefit led to both procedures being discontinued. Recently, there have been studies of the effect of stimulation of the carotid sinus nerve for the treatment of hypertension.

The potential benefit of modulation of the arterial sympathetic nerves, and particularly those located in the renal artery, became the focus of this recent interest. Nevertheless, a number of questions have arisen in regard to the mechanism of RASNA. And why does it take 6 months to achieve the blood pressure response? In addition, there is very little published data in regard to the changes in the renal artery and its adjacent tissue as a result of the RF ablation.

At the present, Medtronic has not provided any information beyond its indicating the lack of benefit. Further information will be reported at the upcoming American College of Cardiology scientific sessions. In the meantime, speculation is rampant as to whether the initial reports were purely placebo effects or if there is something intrinsically flawed in the SYMPLICITY HTN -3 trial.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

In the last 30 years, there have been immense advances in the treatment and prevention of sudden cardiac arrest, including beta-blocker therapy and automatic implantable cardiac defibrillators.

In addition, communities have organized emergency medical systems (EMS) designed to provide early cardiac care for the prevention and treatment of cardiac arrest occurring outside the hospital (OHCA). One of the great frustrations of physicians working in the EMS environment is the successful cardiac resuscitation for the patient who is left with severe neurological impairment or brain death. It is clear that resuscitation of the brain is very time dependent. Complete interruption of blood flow to the brain leads to the loss of consciousness within seconds and death of vulnerable neurons in several brain regions occurs within minutes, whereas 20-40 minutes of ischemia is required to kill cardiac myocytes.

To improve survival and prevent the neurological sequelae of OHCA, total body hypothermia is advised based on animal laboratory experiments and a few small clinical studies carried out in a total of 179 OHCA patients (N. Engl. J. Med. 2002;346:557-63 and 549-56).

Both studies show both a neurological and survival benefit – particularly in patients resuscitated from ventricular fibrillation – in comatose patients in whom resuscitation was achieved within 5-10 minutes after witnessed cardiac arrest when cooled to 32-34 degrees Celsius within 60 minutes of collapse. These studies led to the recommendation by the International Liaison Committee on Resuscitation (Circulation 2004;110;3385-97) that cooling to 32-34 degrees Celsius for 12-24 hours should be used in unconscious patients with OHCA with VF and possibly non-VF arrests.

These recommendations were supported by the AHA Guideline Committee (Circulation 2010;122:S768-86) As a result, cooling comatose OHCA patients after resuscitation is widely used in emergency departments in the United States and Europe with the use of a variety of devices and techniques including large volume saline, external cooling devices, intravenous catheter devices, and intranasal devices. When hypothermia was initially recommended, a number of questions were unanswered and remain unanswered despite multiple publications and wide clinical experience in the succeeding 12 years. Some of those questions include the timing, duration, and intensity of cooling, the preferable technique of cooling, and risk and benefits of the different cooling techniques.

In the United States, pressure infusion of 2 liters of ice cold saline is the usual initial method of cooling to 32-34 degrees Celsius followed by 12-36 hours with surface cooling.

Investigators in Seattle randomized OHCA patients prior to hypothermia or standard therapy with both VF and non-VF rhythms before hospitalization to improve the previous reported benefit when initiated in hospital (JAMA 2014;311;45-52).

The initiation of prehospital therapy achieved cooling 1 hour earlier than in previous hospitalization studies. The result in 1,359 OHCAs over a 5-year period raises important questions about the benefit of hypothermia. The researchers failed to find any benefit in regard to neurological outcomes or mortality. In VF OHCA, they observed a survival rate to hospital discharge of 62.7 % (intervention group) and 64.3% (controls). In the patients without VF, those rates were 19.2 and 16.3, respectively.

Neurological outcomes were also similar for patients with VF at 57.5% (intervention group) and 61.9% (controls), respectively. The non-VF rates were 14.4% (intervention) and 13.4 % (controls). Hypothermia was associated with significant adverse events, including pulmonary edema and increased use of diuretics.

These observations are contrary to previous observations and should provide an opportunity to reevaluate hypothermia for OHCA. These patients represent a series of complex metabolic issues that deserve careful research to provide answers to some of the outstanding issues. The recent studies provide an environment of equipoise where we can step back and revaluate this complex procedure in randomized control trials.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

In the last 30 years, there have been immense advances in the treatment and prevention of sudden cardiac arrest, including beta-blocker therapy and automatic implantable cardiac defibrillators.

In addition, communities have organized emergency medical systems (EMS) designed to provide early cardiac care for the prevention and treatment of cardiac arrest occurring outside the hospital (OHCA). One of the great frustrations of physicians working in the EMS environment is the successful cardiac resuscitation for the patient who is left with severe neurological impairment or brain death. It is clear that resuscitation of the brain is very time dependent. Complete interruption of blood flow to the brain leads to the loss of consciousness within seconds and death of vulnerable neurons in several brain regions occurs within minutes, whereas 20-40 minutes of ischemia is required to kill cardiac myocytes.

To improve survival and prevent the neurological sequelae of OHCA, total body hypothermia is advised based on animal laboratory experiments and a few small clinical studies carried out in a total of 179 OHCA patients (N. Engl. J. Med. 2002;346:557-63 and 549-56).

Both studies show both a neurological and survival benefit – particularly in patients resuscitated from ventricular fibrillation – in comatose patients in whom resuscitation was achieved within 5-10 minutes after witnessed cardiac arrest when cooled to 32-34 degrees Celsius within 60 minutes of collapse. These studies led to the recommendation by the International Liaison Committee on Resuscitation (Circulation 2004;110;3385-97) that cooling to 32-34 degrees Celsius for 12-24 hours should be used in unconscious patients with OHCA with VF and possibly non-VF arrests.

These recommendations were supported by the AHA Guideline Committee (Circulation 2010;122:S768-86) As a result, cooling comatose OHCA patients after resuscitation is widely used in emergency departments in the United States and Europe with the use of a variety of devices and techniques including large volume saline, external cooling devices, intravenous catheter devices, and intranasal devices. When hypothermia was initially recommended, a number of questions were unanswered and remain unanswered despite multiple publications and wide clinical experience in the succeeding 12 years. Some of those questions include the timing, duration, and intensity of cooling, the preferable technique of cooling, and risk and benefits of the different cooling techniques.

In the United States, pressure infusion of 2 liters of ice cold saline is the usual initial method of cooling to 32-34 degrees Celsius followed by 12-36 hours with surface cooling.

Investigators in Seattle randomized OHCA patients prior to hypothermia or standard therapy with both VF and non-VF rhythms before hospitalization to improve the previous reported benefit when initiated in hospital (JAMA 2014;311;45-52).

The initiation of prehospital therapy achieved cooling 1 hour earlier than in previous hospitalization studies. The result in 1,359 OHCAs over a 5-year period raises important questions about the benefit of hypothermia. The researchers failed to find any benefit in regard to neurological outcomes or mortality. In VF OHCA, they observed a survival rate to hospital discharge of 62.7 % (intervention group) and 64.3% (controls). In the patients without VF, those rates were 19.2 and 16.3, respectively.

Neurological outcomes were also similar for patients with VF at 57.5% (intervention group) and 61.9% (controls), respectively. The non-VF rates were 14.4% (intervention) and 13.4 % (controls). Hypothermia was associated with significant adverse events, including pulmonary edema and increased use of diuretics.

These observations are contrary to previous observations and should provide an opportunity to reevaluate hypothermia for OHCA. These patients represent a series of complex metabolic issues that deserve careful research to provide answers to some of the outstanding issues. The recent studies provide an environment of equipoise where we can step back and revaluate this complex procedure in randomized control trials.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

In the last 30 years, there have been immense advances in the treatment and prevention of sudden cardiac arrest, including beta-blocker therapy and automatic implantable cardiac defibrillators.

In addition, communities have organized emergency medical systems (EMS) designed to provide early cardiac care for the prevention and treatment of cardiac arrest occurring outside the hospital (OHCA). One of the great frustrations of physicians working in the EMS environment is the successful cardiac resuscitation for the patient who is left with severe neurological impairment or brain death. It is clear that resuscitation of the brain is very time dependent. Complete interruption of blood flow to the brain leads to the loss of consciousness within seconds and death of vulnerable neurons in several brain regions occurs within minutes, whereas 20-40 minutes of ischemia is required to kill cardiac myocytes.

To improve survival and prevent the neurological sequelae of OHCA, total body hypothermia is advised based on animal laboratory experiments and a few small clinical studies carried out in a total of 179 OHCA patients (N. Engl. J. Med. 2002;346:557-63 and 549-56).

Both studies show both a neurological and survival benefit – particularly in patients resuscitated from ventricular fibrillation – in comatose patients in whom resuscitation was achieved within 5-10 minutes after witnessed cardiac arrest when cooled to 32-34 degrees Celsius within 60 minutes of collapse. These studies led to the recommendation by the International Liaison Committee on Resuscitation (Circulation 2004;110;3385-97) that cooling to 32-34 degrees Celsius for 12-24 hours should be used in unconscious patients with OHCA with VF and possibly non-VF arrests.

These recommendations were supported by the AHA Guideline Committee (Circulation 2010;122:S768-86) As a result, cooling comatose OHCA patients after resuscitation is widely used in emergency departments in the United States and Europe with the use of a variety of devices and techniques including large volume saline, external cooling devices, intravenous catheter devices, and intranasal devices. When hypothermia was initially recommended, a number of questions were unanswered and remain unanswered despite multiple publications and wide clinical experience in the succeeding 12 years. Some of those questions include the timing, duration, and intensity of cooling, the preferable technique of cooling, and risk and benefits of the different cooling techniques.

In the United States, pressure infusion of 2 liters of ice cold saline is the usual initial method of cooling to 32-34 degrees Celsius followed by 12-36 hours with surface cooling.

Investigators in Seattle randomized OHCA patients prior to hypothermia or standard therapy with both VF and non-VF rhythms before hospitalization to improve the previous reported benefit when initiated in hospital (JAMA 2014;311;45-52).

The initiation of prehospital therapy achieved cooling 1 hour earlier than in previous hospitalization studies. The result in 1,359 OHCAs over a 5-year period raises important questions about the benefit of hypothermia. The researchers failed to find any benefit in regard to neurological outcomes or mortality. In VF OHCA, they observed a survival rate to hospital discharge of 62.7 % (intervention group) and 64.3% (controls). In the patients without VF, those rates were 19.2 and 16.3, respectively.

Neurological outcomes were also similar for patients with VF at 57.5% (intervention group) and 61.9% (controls), respectively. The non-VF rates were 14.4% (intervention) and 13.4 % (controls). Hypothermia was associated with significant adverse events, including pulmonary edema and increased use of diuretics.

These observations are contrary to previous observations and should provide an opportunity to reevaluate hypothermia for OHCA. These patients represent a series of complex metabolic issues that deserve careful research to provide answers to some of the outstanding issues. The recent studies provide an environment of equipoise where we can step back and revaluate this complex procedure in randomized control trials.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

I have been thinking about the recent cholesterol management guidelines offered by the American Heart Association and American College of Cardiology experts (J. Am. Coll. Cardiol. 2013;doi:10.1016/j.jacc.2013.11.002) and how they affect my approach to my patients. I am quick to agree to the first three points and the end of LDL targeted therapy in the guidelines, which focus now on the intensity of statins therapy in patients who have already expressed the complications of atherosclerotic cardiovascular disease (ASCVD).

However, I do question a cardiovascular prevention program that, for low-risk individuals with an LDL cholesterol level above 190 mg/dL, is largely driven by statin therapy based on a risk prediction model using age, sex, hypertension, smoking, HDL, and LDL cholesterol elevation. Of all risk factors, smoking and LDL are the only ones that we can modify. Although we have made a major attack on smoking, it would seem that the key to survival is that all of us should take a statin.

There is an abundant source of data on the benefit of statin therapy in patients who have already expressed ASCVD. Although data are limited in regard to very-low-risk groups without evidence of ASCVD, a meta-analysis by the Cholesterol Treatment Trialist Collaborators indicates that the lowering of LDL cholesterol by 40 mg/dL results in an approximate 12% decrease in vascular mortality and 20% decrease in cardiac deaths, regardless of regardless of risk category (Lancet 2012;380;581-90). This benefit was observed even in low-risk individuals despite the slight excess risk of hemorrhagic strokes and diabetes.

The prediction model appears to be the major point of controversy. Along with thousands other Americans, I went to the AHA website to see what my risk score was. I found that by modifying a few factors I could move from less than a 7.5% risk of a stroke or a heart attack in the next 10 years to a risk of well over that. I was not reassured that I was in the company of more than 45 million fellow Americans. Critics of the risk model suggest that based on a number of epidemiologic surveys, the risk model may double the number of individuals to whom the prevention guidelines apply (Lancet 2013;382:1762-5). If we expand the population so broadly, are we going to be a society of statin pill poppers?

Our attempts in the last half-century to develop prevention therapy for hypertension and diabetes have only been marginally successful. The cardiorenal scourge of hypertension remains, despite a plethora of effective drugs that have had little effect on chronic renal disease. Although therapy for diabetes has been supremely effective in treating the acute and chronic metabolic aspects of diabetes, insulin therapy has not been successful in preventing the long-term expression of the cardiovascular, ophthalmic, and renal events. And now we are trying to assess the role of statins for the prevention of cardiovascular events.

In comparison to hypertension and diabetes, statin therapy has the potential to be a sea change in the prevention of ASCVD by lowering serum cholesterol and thereby limiting the growth of the atherosclerotic plaque. A number of clinical trials support the cardiovascular benefit of statin therapy and its effect on lowering serum cholesterol. Although it is clear that we need to reflect on the reliability of the current risk factor model, the current guidelines are an important step forward in the integration of statin therapy into the prevention of cardiovascular disease.

However, talking to patients and telling them that they have greater than a 7.5% risk of having a stroke or a heart attack in the next 10 years remains an abstract concept. The guideline committee now urges me to sit down with my patients and have a heart-to-heart talk about risk and how to decrease it by changing their dangerous lifestyles rather than taking statins for the rest of their lives. When it comes down to it, lifestyle change loses and statins win.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

I have been thinking about the recent cholesterol management guidelines offered by the American Heart Association and American College of Cardiology experts (J. Am. Coll. Cardiol. 2013;doi:10.1016/j.jacc.2013.11.002) and how they affect my approach to my patients. I am quick to agree to the first three points and the end of LDL targeted therapy in the guidelines, which focus now on the intensity of statins therapy in patients who have already expressed the complications of atherosclerotic cardiovascular disease (ASCVD).

However, I do question a cardiovascular prevention program that, for low-risk individuals with an LDL cholesterol level above 190 mg/dL, is largely driven by statin therapy based on a risk prediction model using age, sex, hypertension, smoking, HDL, and LDL cholesterol elevation. Of all risk factors, smoking and LDL are the only ones that we can modify. Although we have made a major attack on smoking, it would seem that the key to survival is that all of us should take a statin.

There is an abundant source of data on the benefit of statin therapy in patients who have already expressed ASCVD. Although data are limited in regard to very-low-risk groups without evidence of ASCVD, a meta-analysis by the Cholesterol Treatment Trialist Collaborators indicates that the lowering of LDL cholesterol by 40 mg/dL results in an approximate 12% decrease in vascular mortality and 20% decrease in cardiac deaths, regardless of regardless of risk category (Lancet 2012;380;581-90). This benefit was observed even in low-risk individuals despite the slight excess risk of hemorrhagic strokes and diabetes.

The prediction model appears to be the major point of controversy. Along with thousands other Americans, I went to the AHA website to see what my risk score was. I found that by modifying a few factors I could move from less than a 7.5% risk of a stroke or a heart attack in the next 10 years to a risk of well over that. I was not reassured that I was in the company of more than 45 million fellow Americans. Critics of the risk model suggest that based on a number of epidemiologic surveys, the risk model may double the number of individuals to whom the prevention guidelines apply (Lancet 2013;382:1762-5). If we expand the population so broadly, are we going to be a society of statin pill poppers?

Our attempts in the last half-century to develop prevention therapy for hypertension and diabetes have only been marginally successful. The cardiorenal scourge of hypertension remains, despite a plethora of effective drugs that have had little effect on chronic renal disease. Although therapy for diabetes has been supremely effective in treating the acute and chronic metabolic aspects of diabetes, insulin therapy has not been successful in preventing the long-term expression of the cardiovascular, ophthalmic, and renal events. And now we are trying to assess the role of statins for the prevention of cardiovascular events.

In comparison to hypertension and diabetes, statin therapy has the potential to be a sea change in the prevention of ASCVD by lowering serum cholesterol and thereby limiting the growth of the atherosclerotic plaque. A number of clinical trials support the cardiovascular benefit of statin therapy and its effect on lowering serum cholesterol. Although it is clear that we need to reflect on the reliability of the current risk factor model, the current guidelines are an important step forward in the integration of statin therapy into the prevention of cardiovascular disease.

However, talking to patients and telling them that they have greater than a 7.5% risk of having a stroke or a heart attack in the next 10 years remains an abstract concept. The guideline committee now urges me to sit down with my patients and have a heart-to-heart talk about risk and how to decrease it by changing their dangerous lifestyles rather than taking statins for the rest of their lives. When it comes down to it, lifestyle change loses and statins win.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

I have been thinking about the recent cholesterol management guidelines offered by the American Heart Association and American College of Cardiology experts (J. Am. Coll. Cardiol. 2013;doi:10.1016/j.jacc.2013.11.002) and how they affect my approach to my patients. I am quick to agree to the first three points and the end of LDL targeted therapy in the guidelines, which focus now on the intensity of statins therapy in patients who have already expressed the complications of atherosclerotic cardiovascular disease (ASCVD).

However, I do question a cardiovascular prevention program that, for low-risk individuals with an LDL cholesterol level above 190 mg/dL, is largely driven by statin therapy based on a risk prediction model using age, sex, hypertension, smoking, HDL, and LDL cholesterol elevation. Of all risk factors, smoking and LDL are the only ones that we can modify. Although we have made a major attack on smoking, it would seem that the key to survival is that all of us should take a statin.

There is an abundant source of data on the benefit of statin therapy in patients who have already expressed ASCVD. Although data are limited in regard to very-low-risk groups without evidence of ASCVD, a meta-analysis by the Cholesterol Treatment Trialist Collaborators indicates that the lowering of LDL cholesterol by 40 mg/dL results in an approximate 12% decrease in vascular mortality and 20% decrease in cardiac deaths, regardless of regardless of risk category (Lancet 2012;380;581-90). This benefit was observed even in low-risk individuals despite the slight excess risk of hemorrhagic strokes and diabetes.

The prediction model appears to be the major point of controversy. Along with thousands other Americans, I went to the AHA website to see what my risk score was. I found that by modifying a few factors I could move from less than a 7.5% risk of a stroke or a heart attack in the next 10 years to a risk of well over that. I was not reassured that I was in the company of more than 45 million fellow Americans. Critics of the risk model suggest that based on a number of epidemiologic surveys, the risk model may double the number of individuals to whom the prevention guidelines apply (Lancet 2013;382:1762-5). If we expand the population so broadly, are we going to be a society of statin pill poppers?

Our attempts in the last half-century to develop prevention therapy for hypertension and diabetes have only been marginally successful. The cardiorenal scourge of hypertension remains, despite a plethora of effective drugs that have had little effect on chronic renal disease. Although therapy for diabetes has been supremely effective in treating the acute and chronic metabolic aspects of diabetes, insulin therapy has not been successful in preventing the long-term expression of the cardiovascular, ophthalmic, and renal events. And now we are trying to assess the role of statins for the prevention of cardiovascular events.

In comparison to hypertension and diabetes, statin therapy has the potential to be a sea change in the prevention of ASCVD by lowering serum cholesterol and thereby limiting the growth of the atherosclerotic plaque. A number of clinical trials support the cardiovascular benefit of statin therapy and its effect on lowering serum cholesterol. Although it is clear that we need to reflect on the reliability of the current risk factor model, the current guidelines are an important step forward in the integration of statin therapy into the prevention of cardiovascular disease.

However, talking to patients and telling them that they have greater than a 7.5% risk of having a stroke or a heart attack in the next 10 years remains an abstract concept. The guideline committee now urges me to sit down with my patients and have a heart-to-heart talk about risk and how to decrease it by changing their dangerous lifestyles rather than taking statins for the rest of their lives. When it comes down to it, lifestyle change loses and statins win.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The TOPCAT study, reported at the recent American Heart Association meeting in Dallas, examined the murky world of our understanding of heart failure occurring in patients with preserved left ventricular ejection fraction.

That seeming paradox has been the subject of physiologic and therapeutic controversy for some time. The realization that at least half of the patients admitted to the hospital with heart failure have normal or even supernormal left ventricular ejection fraction (HFpEF) has raised the therapeutic importance of this clinical entity. Of even more importance is the fact that patients with HFpEF exhibit morbidity and mortality similar to those heart failure patients with reduced left ventricular ejection fraction (HFrEF).

In an epidemiologic study in Olmsted County, Minnesota (N. Engl. J. Med. 2006;355:251-9), the 1-year mortality was 29% for HFpEF and 32% for HFrEF. Patients with HFpEF were more likely to be female (65.7% vs. 34.6%) and to have hypertension and atrial fibrillation than were those with HFrEF (62.7% vs. 48% and 41.3% vs. 28.5%, respectively).

Although we have significantly impacted mortality in patients who have HFrEF with the use of cardiac resynchronization therapy, implantable cardiac defibrillators, and medical therapy with beta-blockers and renin angiotensin inhibitors, we have failed to modify clinical outcomes in patients with HFpEF.

This has not been for a lack of trying. Several randomized clinical trials have been conducted with all of the drugs currently being used for HFrEF without any definitive results. An important problem in treating this population has been the heterogeneity of patients and multiple comorbidities, including chronic renal and pulmonary disease, acute hypertension, and atrial fibrillation that patients with HFpEF experience with the acute event. In addition, many of these patients are already receiving a multiplicity of concurrent therapies that have been approved for HFrEF for management.

Our understanding of the pathophysiology of HFpEF also remains cloudy. Both left and right ventricular hypertrophy with concomitant decrease in ventricular diastolic relaxation is the common observed echocardiographic abnormality. We have not as yet developed therapy for the treatment of diastolic dysfunction. Aldosterone antagonists, previously shown to be beneficial in patients with HFrEF, have emerged as likely candidates to improve HFpEF. Small clinical studies have shown improvement in diastolic function in elderly patients with hypertension and chronic renal disease. Consequently, the National Heart, Lung, and Blood Institute embarked on the TOPCAT study in 2006.

TOPCAT randomized 3,345 symptomatic heart failure patients who had a heart failure hospitalization in the previous year and with evidence of fluid retention, a left ventricular ejection fraction of more than 45%, controlled systolic blood pressure of less than 140 mm Hg, and elevated brain natriuretic peptide to treatment with placebo or spironolactone at 25 or 50 mg daily. A history of hypertension was present in 91%, coronary artery disease in 57%, atrial fibrillation in 35%, chronic renal disease in 35%, and diabetes in 32%. Patients included in the study had a mean LVEF of 56%; two thirds were in New York Heart Association class II and one third were in NYHA class III.

Over 80% of patients were receiving an ACE inhibitor or angiotensin receptor blocker, beta-blockers, and a diuretic. The mean dose of spironolactone was 25 mg. There was no significant difference in the primary outcome of cardiovascular death, nonfatal hospitalization or resuscitated cardiac arrest in the placebo and treated groups (20.4% and 18.6%, respectively). There was a significant decrease in heart failure hospitalization in the placebo compared to spironolactone patients (14.2% vs. 12.0%; P = .042). Both hyperkalemia greater than 5.5 mmol/L and an increase in serum creatinine were observed in the treated patients.

The striking observation in this trial, as it has been in previous trials, is the disparity between the epidemiologic mortality and the randomized controlled trial experience: 29% annual mortality in Olmsted County, compared with the 10.2% three-year mortality in TOPCAT. It appears that we are studying two separate diseases. And we are. After all the exclusion criteria included in the design of TOPCAT, we are unable to encapsulate the population at risk in this complex heart failure syndrome.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The TOPCAT study, reported at the recent American Heart Association meeting in Dallas, examined the murky world of our understanding of heart failure occurring in patients with preserved left ventricular ejection fraction.

That seeming paradox has been the subject of physiologic and therapeutic controversy for some time. The realization that at least half of the patients admitted to the hospital with heart failure have normal or even supernormal left ventricular ejection fraction (HFpEF) has raised the therapeutic importance of this clinical entity. Of even more importance is the fact that patients with HFpEF exhibit morbidity and mortality similar to those heart failure patients with reduced left ventricular ejection fraction (HFrEF).

In an epidemiologic study in Olmsted County, Minnesota (N. Engl. J. Med. 2006;355:251-9), the 1-year mortality was 29% for HFpEF and 32% for HFrEF. Patients with HFpEF were more likely to be female (65.7% vs. 34.6%) and to have hypertension and atrial fibrillation than were those with HFrEF (62.7% vs. 48% and 41.3% vs. 28.5%, respectively).

Although we have significantly impacted mortality in patients who have HFrEF with the use of cardiac resynchronization therapy, implantable cardiac defibrillators, and medical therapy with beta-blockers and renin angiotensin inhibitors, we have failed to modify clinical outcomes in patients with HFpEF.

This has not been for a lack of trying. Several randomized clinical trials have been conducted with all of the drugs currently being used for HFrEF without any definitive results. An important problem in treating this population has been the heterogeneity of patients and multiple comorbidities, including chronic renal and pulmonary disease, acute hypertension, and atrial fibrillation that patients with HFpEF experience with the acute event. In addition, many of these patients are already receiving a multiplicity of concurrent therapies that have been approved for HFrEF for management.

Our understanding of the pathophysiology of HFpEF also remains cloudy. Both left and right ventricular hypertrophy with concomitant decrease in ventricular diastolic relaxation is the common observed echocardiographic abnormality. We have not as yet developed therapy for the treatment of diastolic dysfunction. Aldosterone antagonists, previously shown to be beneficial in patients with HFrEF, have emerged as likely candidates to improve HFpEF. Small clinical studies have shown improvement in diastolic function in elderly patients with hypertension and chronic renal disease. Consequently, the National Heart, Lung, and Blood Institute embarked on the TOPCAT study in 2006.

TOPCAT randomized 3,345 symptomatic heart failure patients who had a heart failure hospitalization in the previous year and with evidence of fluid retention, a left ventricular ejection fraction of more than 45%, controlled systolic blood pressure of less than 140 mm Hg, and elevated brain natriuretic peptide to treatment with placebo or spironolactone at 25 or 50 mg daily. A history of hypertension was present in 91%, coronary artery disease in 57%, atrial fibrillation in 35%, chronic renal disease in 35%, and diabetes in 32%. Patients included in the study had a mean LVEF of 56%; two thirds were in New York Heart Association class II and one third were in NYHA class III.

Over 80% of patients were receiving an ACE inhibitor or angiotensin receptor blocker, beta-blockers, and a diuretic. The mean dose of spironolactone was 25 mg. There was no significant difference in the primary outcome of cardiovascular death, nonfatal hospitalization or resuscitated cardiac arrest in the placebo and treated groups (20.4% and 18.6%, respectively). There was a significant decrease in heart failure hospitalization in the placebo compared to spironolactone patients (14.2% vs. 12.0%; P = .042). Both hyperkalemia greater than 5.5 mmol/L and an increase in serum creatinine were observed in the treated patients.

The striking observation in this trial, as it has been in previous trials, is the disparity between the epidemiologic mortality and the randomized controlled trial experience: 29% annual mortality in Olmsted County, compared with the 10.2% three-year mortality in TOPCAT. It appears that we are studying two separate diseases. And we are. After all the exclusion criteria included in the design of TOPCAT, we are unable to encapsulate the population at risk in this complex heart failure syndrome.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The TOPCAT study, reported at the recent American Heart Association meeting in Dallas, examined the murky world of our understanding of heart failure occurring in patients with preserved left ventricular ejection fraction.

That seeming paradox has been the subject of physiologic and therapeutic controversy for some time. The realization that at least half of the patients admitted to the hospital with heart failure have normal or even supernormal left ventricular ejection fraction (HFpEF) has raised the therapeutic importance of this clinical entity. Of even more importance is the fact that patients with HFpEF exhibit morbidity and mortality similar to those heart failure patients with reduced left ventricular ejection fraction (HFrEF).

In an epidemiologic study in Olmsted County, Minnesota (N. Engl. J. Med. 2006;355:251-9), the 1-year mortality was 29% for HFpEF and 32% for HFrEF. Patients with HFpEF were more likely to be female (65.7% vs. 34.6%) and to have hypertension and atrial fibrillation than were those with HFrEF (62.7% vs. 48% and 41.3% vs. 28.5%, respectively).

Although we have significantly impacted mortality in patients who have HFrEF with the use of cardiac resynchronization therapy, implantable cardiac defibrillators, and medical therapy with beta-blockers and renin angiotensin inhibitors, we have failed to modify clinical outcomes in patients with HFpEF.

This has not been for a lack of trying. Several randomized clinical trials have been conducted with all of the drugs currently being used for HFrEF without any definitive results. An important problem in treating this population has been the heterogeneity of patients and multiple comorbidities, including chronic renal and pulmonary disease, acute hypertension, and atrial fibrillation that patients with HFpEF experience with the acute event. In addition, many of these patients are already receiving a multiplicity of concurrent therapies that have been approved for HFrEF for management.

Our understanding of the pathophysiology of HFpEF also remains cloudy. Both left and right ventricular hypertrophy with concomitant decrease in ventricular diastolic relaxation is the common observed echocardiographic abnormality. We have not as yet developed therapy for the treatment of diastolic dysfunction. Aldosterone antagonists, previously shown to be beneficial in patients with HFrEF, have emerged as likely candidates to improve HFpEF. Small clinical studies have shown improvement in diastolic function in elderly patients with hypertension and chronic renal disease. Consequently, the National Heart, Lung, and Blood Institute embarked on the TOPCAT study in 2006.

TOPCAT randomized 3,345 symptomatic heart failure patients who had a heart failure hospitalization in the previous year and with evidence of fluid retention, a left ventricular ejection fraction of more than 45%, controlled systolic blood pressure of less than 140 mm Hg, and elevated brain natriuretic peptide to treatment with placebo or spironolactone at 25 or 50 mg daily. A history of hypertension was present in 91%, coronary artery disease in 57%, atrial fibrillation in 35%, chronic renal disease in 35%, and diabetes in 32%. Patients included in the study had a mean LVEF of 56%; two thirds were in New York Heart Association class II and one third were in NYHA class III.

Over 80% of patients were receiving an ACE inhibitor or angiotensin receptor blocker, beta-blockers, and a diuretic. The mean dose of spironolactone was 25 mg. There was no significant difference in the primary outcome of cardiovascular death, nonfatal hospitalization or resuscitated cardiac arrest in the placebo and treated groups (20.4% and 18.6%, respectively). There was a significant decrease in heart failure hospitalization in the placebo compared to spironolactone patients (14.2% vs. 12.0%; P = .042). Both hyperkalemia greater than 5.5 mmol/L and an increase in serum creatinine were observed in the treated patients.

The striking observation in this trial, as it has been in previous trials, is the disparity between the epidemiologic mortality and the randomized controlled trial experience: 29% annual mortality in Olmsted County, compared with the 10.2% three-year mortality in TOPCAT. It appears that we are studying two separate diseases. And we are. After all the exclusion criteria included in the design of TOPCAT, we are unable to encapsulate the population at risk in this complex heart failure syndrome.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

Getting the right therapeutic dose of any drug is not always easy. Using antibiotics to treat infection or antihypertensive drugs to lower blood pressure can be measured easily by simple physiologic measurements.

The treatment of heart failure with beta-blockers or ACE inhibitors, however, has been largely defined by clinical trials, which by their nature use one dosage and usually provide the clinician with limited information about the range of the best and most effective dosages. The rigor of choosing the correct dosage in clinical trials is often limited to small, underpowered phase II studies carried out well before the major phase III trials, which are designed to support efficacy and safety, usually at that one dosage. And still, physicians usually pick the lowest dose, following Hippocrates’ dictum to "do no harm." This dilemma has particular importance in picking the best dose of a beta-blocker in heart failure.

A recent presentation at the annual congress of the European Society of Cardiology by Dr. L. Brent Mitchell ("Full-dose beta-blockers still show benefit," October 2013, p. 26) sheds some important light on the benefit of maximum dosing with beta-blockers in heart failure patients treated with cardiac resynchronization therapy (CRT) or implantable cardiac defibrillators (ICDs) in whom bradycardia escape pacing was present.

Although all patients received standard drug therapy, patients receiving less than 50% of the full recommended dose of beta-blocker had a worse outcome in regard to mortality and rehospitalization when compared with patients receiving the full recommended dose, regardless of the beta-blocker used. Roughly one-half of these heart failure ICD/CRT patients were receiving less than half of the recommended dose for heart failure therapy. Older patients and those with more advance heart failure tended to receive the lower dose. In this patient population with pacemaker-controlled low heart rate, the issue of beta-blocker–induced bradycardia is no longer an issue: the higher the better.

In patients with atrial-controlled heart rates with sinus rhythm or atrial fibrillation, however, the induction of bradycardia has been an issue as physicians up-titrate dosages. The effect on morbidity and mortality of varying doses of metoprolol succinate (Toprol) was examined in the MERIT-HF trial (J. Am. Coll. Cardiol. 2002;40:491-8), in which physicians were encouraged to up-titrate to the highest dose. The limitation of up-titration was bradycardia. The high-dose (greater than 100 mg/day) and low-dose (100 mg/day or less) patients received 192 mg and 76 mg/day, respectively. Despite the different maximal doses, the final heart rate achieved with the up-titration was 68 beats/min. Patients receiving the high dose and low dose achieved the same relative benefit of therapy. The low-dose patient group was older and had a higher New York Heart Association functional class.

These observations suggest that there was a significant variability in the patient’s sensitivity to beta-blocker therapy, but the achievement of a low heart rate, regardless of dose, was effective in achieving the best therapeutic benefit. In a small dose-ranging study, patients were randomized to receive 50 or 200 mg/day of Toprol. The patients receiving 200 mg demonstrated an increase in ejection fraction and a decrease in end systolic volume, compared with the 50 mg–dose patients, who failed to evidence any hemodynamic improvement (Circulation 2007;116:49-56).

These observations emphasize the uncertainties of drug dosing in heart failure with our standard therapy. The benefit of high doses of beta-blockers in the ICD/CRT trial in patients whose heart rate was controlled with bradycardia pacing provides important support for the use of high doses in these individuals. In patients whose heart rate was controlled by atrial rhythms in the MERIT-HF trial, heart rate became the major limitation of drug therapy. In these patients, up-titration to maximal heart rate expressed the presence of a variable sensitivity to beta-blockade. The achievement of a slow heart rate, regardless of dose, appeared to achieve a similar benefit on heart failure outcomes.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies, and was the co-principal investigator of the MERIT-HF trial.

Getting the right therapeutic dose of any drug is not always easy. Using antibiotics to treat infection or antihypertensive drugs to lower blood pressure can be measured easily by simple physiologic measurements.

The treatment of heart failure with beta-blockers or ACE inhibitors, however, has been largely defined by clinical trials, which by their nature use one dosage and usually provide the clinician with limited information about the range of the best and most effective dosages. The rigor of choosing the correct dosage in clinical trials is often limited to small, underpowered phase II studies carried out well before the major phase III trials, which are designed to support efficacy and safety, usually at that one dosage. And still, physicians usually pick the lowest dose, following Hippocrates’ dictum to "do no harm." This dilemma has particular importance in picking the best dose of a beta-blocker in heart failure.

A recent presentation at the annual congress of the European Society of Cardiology by Dr. L. Brent Mitchell ("Full-dose beta-blockers still show benefit," October 2013, p. 26) sheds some important light on the benefit of maximum dosing with beta-blockers in heart failure patients treated with cardiac resynchronization therapy (CRT) or implantable cardiac defibrillators (ICDs) in whom bradycardia escape pacing was present.

Although all patients received standard drug therapy, patients receiving less than 50% of the full recommended dose of beta-blocker had a worse outcome in regard to mortality and rehospitalization when compared with patients receiving the full recommended dose, regardless of the beta-blocker used. Roughly one-half of these heart failure ICD/CRT patients were receiving less than half of the recommended dose for heart failure therapy. Older patients and those with more advance heart failure tended to receive the lower dose. In this patient population with pacemaker-controlled low heart rate, the issue of beta-blocker–induced bradycardia is no longer an issue: the higher the better.

In patients with atrial-controlled heart rates with sinus rhythm or atrial fibrillation, however, the induction of bradycardia has been an issue as physicians up-titrate dosages. The effect on morbidity and mortality of varying doses of metoprolol succinate (Toprol) was examined in the MERIT-HF trial (J. Am. Coll. Cardiol. 2002;40:491-8), in which physicians were encouraged to up-titrate to the highest dose. The limitation of up-titration was bradycardia. The high-dose (greater than 100 mg/day) and low-dose (100 mg/day or less) patients received 192 mg and 76 mg/day, respectively. Despite the different maximal doses, the final heart rate achieved with the up-titration was 68 beats/min. Patients receiving the high dose and low dose achieved the same relative benefit of therapy. The low-dose patient group was older and had a higher New York Heart Association functional class.

These observations suggest that there was a significant variability in the patient’s sensitivity to beta-blocker therapy, but the achievement of a low heart rate, regardless of dose, was effective in achieving the best therapeutic benefit. In a small dose-ranging study, patients were randomized to receive 50 or 200 mg/day of Toprol. The patients receiving 200 mg demonstrated an increase in ejection fraction and a decrease in end systolic volume, compared with the 50 mg–dose patients, who failed to evidence any hemodynamic improvement (Circulation 2007;116:49-56).

These observations emphasize the uncertainties of drug dosing in heart failure with our standard therapy. The benefit of high doses of beta-blockers in the ICD/CRT trial in patients whose heart rate was controlled with bradycardia pacing provides important support for the use of high doses in these individuals. In patients whose heart rate was controlled by atrial rhythms in the MERIT-HF trial, heart rate became the major limitation of drug therapy. In these patients, up-titration to maximal heart rate expressed the presence of a variable sensitivity to beta-blockade. The achievement of a slow heart rate, regardless of dose, appeared to achieve a similar benefit on heart failure outcomes.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies, and was the co-principal investigator of the MERIT-HF trial.

Getting the right therapeutic dose of any drug is not always easy. Using antibiotics to treat infection or antihypertensive drugs to lower blood pressure can be measured easily by simple physiologic measurements.

The treatment of heart failure with beta-blockers or ACE inhibitors, however, has been largely defined by clinical trials, which by their nature use one dosage and usually provide the clinician with limited information about the range of the best and most effective dosages. The rigor of choosing the correct dosage in clinical trials is often limited to small, underpowered phase II studies carried out well before the major phase III trials, which are designed to support efficacy and safety, usually at that one dosage. And still, physicians usually pick the lowest dose, following Hippocrates’ dictum to "do no harm." This dilemma has particular importance in picking the best dose of a beta-blocker in heart failure.

A recent presentation at the annual congress of the European Society of Cardiology by Dr. L. Brent Mitchell ("Full-dose beta-blockers still show benefit," October 2013, p. 26) sheds some important light on the benefit of maximum dosing with beta-blockers in heart failure patients treated with cardiac resynchronization therapy (CRT) or implantable cardiac defibrillators (ICDs) in whom bradycardia escape pacing was present.

Although all patients received standard drug therapy, patients receiving less than 50% of the full recommended dose of beta-blocker had a worse outcome in regard to mortality and rehospitalization when compared with patients receiving the full recommended dose, regardless of the beta-blocker used. Roughly one-half of these heart failure ICD/CRT patients were receiving less than half of the recommended dose for heart failure therapy. Older patients and those with more advance heart failure tended to receive the lower dose. In this patient population with pacemaker-controlled low heart rate, the issue of beta-blocker–induced bradycardia is no longer an issue: the higher the better.

In patients with atrial-controlled heart rates with sinus rhythm or atrial fibrillation, however, the induction of bradycardia has been an issue as physicians up-titrate dosages. The effect on morbidity and mortality of varying doses of metoprolol succinate (Toprol) was examined in the MERIT-HF trial (J. Am. Coll. Cardiol. 2002;40:491-8), in which physicians were encouraged to up-titrate to the highest dose. The limitation of up-titration was bradycardia. The high-dose (greater than 100 mg/day) and low-dose (100 mg/day or less) patients received 192 mg and 76 mg/day, respectively. Despite the different maximal doses, the final heart rate achieved with the up-titration was 68 beats/min. Patients receiving the high dose and low dose achieved the same relative benefit of therapy. The low-dose patient group was older and had a higher New York Heart Association functional class.

These observations suggest that there was a significant variability in the patient’s sensitivity to beta-blocker therapy, but the achievement of a low heart rate, regardless of dose, was effective in achieving the best therapeutic benefit. In a small dose-ranging study, patients were randomized to receive 50 or 200 mg/day of Toprol. The patients receiving 200 mg demonstrated an increase in ejection fraction and a decrease in end systolic volume, compared with the 50 mg–dose patients, who failed to evidence any hemodynamic improvement (Circulation 2007;116:49-56).

These observations emphasize the uncertainties of drug dosing in heart failure with our standard therapy. The benefit of high doses of beta-blockers in the ICD/CRT trial in patients whose heart rate was controlled with bradycardia pacing provides important support for the use of high doses in these individuals. In patients whose heart rate was controlled by atrial rhythms in the MERIT-HF trial, heart rate became the major limitation of drug therapy. In these patients, up-titration to maximal heart rate expressed the presence of a variable sensitivity to beta-blockade. The achievement of a slow heart rate, regardless of dose, appeared to achieve a similar benefit on heart failure outcomes.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies, and was the co-principal investigator of the MERIT-HF trial.

For over a half a century, the vitamin K antagonists coumarin and warfarin have been the only anticoagulants available to prevent clot formation in a variety of cardiovascular clinical settings. They are now about to be replaced with direct thrombin and factor Xa inhibitors. Vitamin K antagonists have not only dominated anticoagulant therapy, they have created an entire industry within the cardiovascular domain for the monitoring and control of its dose administration.

The story began in 1933 when Karl Paul Link, Ph.D., working in a laboratory at the University of Wisconsin School of Agriculture, was asked to examine the blood of cows dying of hemorrhage thought to be due to the ingestion of spoiled sweet clover. After years of research, Link was able to isolate an anticoagulant from the clover feed, called dicumarol, and he initially patented it in 1941 as rat poison. The marketed drug was called warfarin, after the Wisconsin Agricultural Research Foundation (WARF). Based on that patent, billions of dollars were generated for future research at the WARF.

Warfarin began to be used in the 1950s by a number of clinical investigators to prevent pulmonary embolism in the setting of an acute myocardial infarction (Lancet 1954;266:92-5). At that time, 1 month of complete bed rest was standard therapy for an AMI, and thrombophlebitis together with pulmonary and systemic embolism were the main causes of mortality. When early ambulation became acceptable for AMI patients, warfarin use tapered off. As clinicians became more focused on the prevention of intravascular thrombus formation after prosthetic valve surgery, and to prevent thromboembolism in patients with atrial fibrillation, warfarin therapy became more widely used, and the definition of the therapeutic dose of warfarin became important.

It soon became evident that vitamin K antagonists had a very narrow therapeutic window, framed by excessive bleeding at high doses and inefficacy at lower dose. As a result, the need for closer dose monitoring became important, and this led to the establishment of anticoagulant clinics. However, even with the establishment of these clinics, it became obvious that the clinical status of patients and dietary variability played major roles in dosing. The need for frequent blood sampling and the logistics of dose management were frustrations for both the patient and physician for decades.

As the need for better anticoagulant therapy became evident, drugs were developed that had a wider therapeutic range and that could be administered orally without the need of blood monitoring. The development of direct-acting thrombin and factor Xa inhibitors have led to major advances in anticoagulant therapy, resulting in safer oral fixed-dose drugs with therapeutic efficacy comparable to or better than vitamin K antagonists. In addition, they appear to be free from the effects of dietary variation. The factor Xa inhibitors apixaban and rivaroxaban have been approved by the Food and Drug Administration for the prevention of systemic emboli in patients with atrial fibrillation. Rivaroxaban is also indicated for preventing and treating deep vein thrombosis and pulmonary embolism. The direct thrombin inhibitor dabigatran has also been approved for the prevention of thromboembolism in patients with atrial fibrillation. The only settings for which the new anticoagulants have not been approved are acute coronary syndrome and prevention of thromboembolism with prosthetic valves.

The development of new anticoagulants provides an opportunity to improve therapy and witness the retirement of a ponderous and complicated dosing program that has been inconvenient to both patients and doctors. The retirement of warfarin and the death of the anticoagulant clinic will be appreciated by all.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

For over a half a century, the vitamin K antagonists coumarin and warfarin have been the only anticoagulants available to prevent clot formation in a variety of cardiovascular clinical settings. They are now about to be replaced with direct thrombin and factor Xa inhibitors. Vitamin K antagonists have not only dominated anticoagulant therapy, they have created an entire industry within the cardiovascular domain for the monitoring and control of its dose administration.

The story began in 1933 when Karl Paul Link, Ph.D., working in a laboratory at the University of Wisconsin School of Agriculture, was asked to examine the blood of cows dying of hemorrhage thought to be due to the ingestion of spoiled sweet clover. After years of research, Link was able to isolate an anticoagulant from the clover feed, called dicumarol, and he initially patented it in 1941 as rat poison. The marketed drug was called warfarin, after the Wisconsin Agricultural Research Foundation (WARF). Based on that patent, billions of dollars were generated for future research at the WARF.

Warfarin began to be used in the 1950s by a number of clinical investigators to prevent pulmonary embolism in the setting of an acute myocardial infarction (Lancet 1954;266:92-5). At that time, 1 month of complete bed rest was standard therapy for an AMI, and thrombophlebitis together with pulmonary and systemic embolism were the main causes of mortality. When early ambulation became acceptable for AMI patients, warfarin use tapered off. As clinicians became more focused on the prevention of intravascular thrombus formation after prosthetic valve surgery, and to prevent thromboembolism in patients with atrial fibrillation, warfarin therapy became more widely used, and the definition of the therapeutic dose of warfarin became important.

It soon became evident that vitamin K antagonists had a very narrow therapeutic window, framed by excessive bleeding at high doses and inefficacy at lower dose. As a result, the need for closer dose monitoring became important, and this led to the establishment of anticoagulant clinics. However, even with the establishment of these clinics, it became obvious that the clinical status of patients and dietary variability played major roles in dosing. The need for frequent blood sampling and the logistics of dose management were frustrations for both the patient and physician for decades.

As the need for better anticoagulant therapy became evident, drugs were developed that had a wider therapeutic range and that could be administered orally without the need of blood monitoring. The development of direct-acting thrombin and factor Xa inhibitors have led to major advances in anticoagulant therapy, resulting in safer oral fixed-dose drugs with therapeutic efficacy comparable to or better than vitamin K antagonists. In addition, they appear to be free from the effects of dietary variation. The factor Xa inhibitors apixaban and rivaroxaban have been approved by the Food and Drug Administration for the prevention of systemic emboli in patients with atrial fibrillation. Rivaroxaban is also indicated for preventing and treating deep vein thrombosis and pulmonary embolism. The direct thrombin inhibitor dabigatran has also been approved for the prevention of thromboembolism in patients with atrial fibrillation. The only settings for which the new anticoagulants have not been approved are acute coronary syndrome and prevention of thromboembolism with prosthetic valves.

The development of new anticoagulants provides an opportunity to improve therapy and witness the retirement of a ponderous and complicated dosing program that has been inconvenient to both patients and doctors. The retirement of warfarin and the death of the anticoagulant clinic will be appreciated by all.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

For over a half a century, the vitamin K antagonists coumarin and warfarin have been the only anticoagulants available to prevent clot formation in a variety of cardiovascular clinical settings. They are now about to be replaced with direct thrombin and factor Xa inhibitors. Vitamin K antagonists have not only dominated anticoagulant therapy, they have created an entire industry within the cardiovascular domain for the monitoring and control of its dose administration.

The story began in 1933 when Karl Paul Link, Ph.D., working in a laboratory at the University of Wisconsin School of Agriculture, was asked to examine the blood of cows dying of hemorrhage thought to be due to the ingestion of spoiled sweet clover. After years of research, Link was able to isolate an anticoagulant from the clover feed, called dicumarol, and he initially patented it in 1941 as rat poison. The marketed drug was called warfarin, after the Wisconsin Agricultural Research Foundation (WARF). Based on that patent, billions of dollars were generated for future research at the WARF.

Warfarin began to be used in the 1950s by a number of clinical investigators to prevent pulmonary embolism in the setting of an acute myocardial infarction (Lancet 1954;266:92-5). At that time, 1 month of complete bed rest was standard therapy for an AMI, and thrombophlebitis together with pulmonary and systemic embolism were the main causes of mortality. When early ambulation became acceptable for AMI patients, warfarin use tapered off. As clinicians became more focused on the prevention of intravascular thrombus formation after prosthetic valve surgery, and to prevent thromboembolism in patients with atrial fibrillation, warfarin therapy became more widely used, and the definition of the therapeutic dose of warfarin became important.

It soon became evident that vitamin K antagonists had a very narrow therapeutic window, framed by excessive bleeding at high doses and inefficacy at lower dose. As a result, the need for closer dose monitoring became important, and this led to the establishment of anticoagulant clinics. However, even with the establishment of these clinics, it became obvious that the clinical status of patients and dietary variability played major roles in dosing. The need for frequent blood sampling and the logistics of dose management were frustrations for both the patient and physician for decades.

As the need for better anticoagulant therapy became evident, drugs were developed that had a wider therapeutic range and that could be administered orally without the need of blood monitoring. The development of direct-acting thrombin and factor Xa inhibitors have led to major advances in anticoagulant therapy, resulting in safer oral fixed-dose drugs with therapeutic efficacy comparable to or better than vitamin K antagonists. In addition, they appear to be free from the effects of dietary variation. The factor Xa inhibitors apixaban and rivaroxaban have been approved by the Food and Drug Administration for the prevention of systemic emboli in patients with atrial fibrillation. Rivaroxaban is also indicated for preventing and treating deep vein thrombosis and pulmonary embolism. The direct thrombin inhibitor dabigatran has also been approved for the prevention of thromboembolism in patients with atrial fibrillation. The only settings for which the new anticoagulants have not been approved are acute coronary syndrome and prevention of thromboembolism with prosthetic valves.

The development of new anticoagulants provides an opportunity to improve therapy and witness the retirement of a ponderous and complicated dosing program that has been inconvenient to both patients and doctors. The retirement of warfarin and the death of the anticoagulant clinic will be appreciated by all.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

A recent report at the American College of Cardiology annual meeting concluded that handheld ultrasound was superior to a group of trained cardiologists in the determination of cardiac pathology and function (J. Am. Coll. Cardiol. 2013;61:E1442).

This sort of information immediately raised my hackles. I am all for technological advances, but this proclamation struck close to my heart. I have progressed from cardiac catheterization using "red glass" accommodation for fluoroscopy to high-intensity multiplane angiography. I have even participated in the development of biventricular pacemakers for the treatment of heart failure and defibrillation. But the suggestion that a cardiologist can be replaced by a toy activated my Luddite receptors.

For those of you who are unaware of who or what a Luddite is, I refer you to England in the year 1811, when Edward (Ned) Ludd protested the replacement of hand-loom workers with a mechanized knitting process that threw thousands of English weavers out of work. He started a protest movement by Luddites that led to attacks on weaving mills and ultimately the hanging of some of his followers as terrorists in 1817. At about that time, in 1816, Rene Laennec developed the stethoscope by using a "quire" of paper rolled into a cylinder to listen to an obese young lady’s heart rather than his naked ear placed on her chest, which was the practice at that time.

From that paper tube has evolved the stethoscope as we know it today. Occasionally it is used to listen to the heart and lungs of patients, but it is seen mostly as a professional "necktie" in TV dramas. The fact that cardiologists and the stethoscope were to be replaced by the handheld ultrasound just as the loom weavers were replaced by the knitting machine led me to respond to the challenge.

I believe that the author, Dr. Manish Mehta of Oregon Health and Science University, Portland, spoke to an important issue. I would agree that many cardiologists are more comfortable using an echocardiogram than a stethoscope. The value of auscultation skills can be judged by the fact that cardiology board examinations do not include testing of auscultation skills but provide numerous questions on the interpretation of echocardiograms. Of course, there are the economic benefits of performing an echocardiogram compared with auscultation, which does not come up on my charge sheet.

I would grant that a handheld ultrasound can identify whether a pericardial effusion is present, a physical diagnostic challenge that I have frequently failed, particularly in thick-chested individuals. But give me a thin, young guy and I’ll get it every time. But does the presence of a leaking or stenotic valve or an enlarged heart, both easily identified by the handheld ultrasound, indicate heart failure? Give me an S3 gallop or distended neck veins and I can make the diagnosis of heart failure without a B-type natriuretic peptide level. The problem is that no one – well, very few of us – teaches how to examine the heart.

There is also the importance of the physician actually touching the patient as part of the examination. Not only examining the heart; but how about the abdomen? If we followed the path led by the BS echo, we could take the nurse’s recorded chief complaint and send the patient directly to radiology for a CT or an MRI. The fact that this is what the patient really wants does not escape this skeptic. But is this what medicine is really about? Much has been written about physician-patient interaction, but has it come to doctors being only a triage to the radiology department?

I am not going to break up the nearest echo machine with my stethoscope and end up on the hospital director’s "scaffolds" like the 18th century Luddites did. Echocardiography clearly provides a wonderful view of the heart and its valves, and can guide us to the surgical correction of valvular and muscular defects. Some technology, such as Doppler imaging, actually does provide information about physiologic phenomena including myocardial function and ischemia. But if the cardiologists lose in a contest with handheld ultrasound, it is because we have lost our bedside skills as a result of our overreliance on technology and have been blinded to its limitations.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

A recent report at the American College of Cardiology annual meeting concluded that handheld ultrasound was superior to a group of trained cardiologists in the determination of cardiac pathology and function (J. Am. Coll. Cardiol. 2013;61:E1442).

This sort of information immediately raised my hackles. I am all for technological advances, but this proclamation struck close to my heart. I have progressed from cardiac catheterization using "red glass" accommodation for fluoroscopy to high-intensity multiplane angiography. I have even participated in the development of biventricular pacemakers for the treatment of heart failure and defibrillation. But the suggestion that a cardiologist can be replaced by a toy activated my Luddite receptors.

For those of you who are unaware of who or what a Luddite is, I refer you to England in the year 1811, when Edward (Ned) Ludd protested the replacement of hand-loom workers with a mechanized knitting process that threw thousands of English weavers out of work. He started a protest movement by Luddites that led to attacks on weaving mills and ultimately the hanging of some of his followers as terrorists in 1817. At about that time, in 1816, Rene Laennec developed the stethoscope by using a "quire" of paper rolled into a cylinder to listen to an obese young lady’s heart rather than his naked ear placed on her chest, which was the practice at that time.

From that paper tube has evolved the stethoscope as we know it today. Occasionally it is used to listen to the heart and lungs of patients, but it is seen mostly as a professional "necktie" in TV dramas. The fact that cardiologists and the stethoscope were to be replaced by the handheld ultrasound just as the loom weavers were replaced by the knitting machine led me to respond to the challenge.

I believe that the author, Dr. Manish Mehta of Oregon Health and Science University, Portland, spoke to an important issue. I would agree that many cardiologists are more comfortable using an echocardiogram than a stethoscope. The value of auscultation skills can be judged by the fact that cardiology board examinations do not include testing of auscultation skills but provide numerous questions on the interpretation of echocardiograms. Of course, there are the economic benefits of performing an echocardiogram compared with auscultation, which does not come up on my charge sheet.

I would grant that a handheld ultrasound can identify whether a pericardial effusion is present, a physical diagnostic challenge that I have frequently failed, particularly in thick-chested individuals. But give me a thin, young guy and I’ll get it every time. But does the presence of a leaking or stenotic valve or an enlarged heart, both easily identified by the handheld ultrasound, indicate heart failure? Give me an S3 gallop or distended neck veins and I can make the diagnosis of heart failure without a B-type natriuretic peptide level. The problem is that no one – well, very few of us – teaches how to examine the heart.

There is also the importance of the physician actually touching the patient as part of the examination. Not only examining the heart; but how about the abdomen? If we followed the path led by the BS echo, we could take the nurse’s recorded chief complaint and send the patient directly to radiology for a CT or an MRI. The fact that this is what the patient really wants does not escape this skeptic. But is this what medicine is really about? Much has been written about physician-patient interaction, but has it come to doctors being only a triage to the radiology department?

I am not going to break up the nearest echo machine with my stethoscope and end up on the hospital director’s "scaffolds" like the 18th century Luddites did. Echocardiography clearly provides a wonderful view of the heart and its valves, and can guide us to the surgical correction of valvular and muscular defects. Some technology, such as Doppler imaging, actually does provide information about physiologic phenomena including myocardial function and ischemia. But if the cardiologists lose in a contest with handheld ultrasound, it is because we have lost our bedside skills as a result of our overreliance on technology and have been blinded to its limitations.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

A recent report at the American College of Cardiology annual meeting concluded that handheld ultrasound was superior to a group of trained cardiologists in the determination of cardiac pathology and function (J. Am. Coll. Cardiol. 2013;61:E1442).

This sort of information immediately raised my hackles. I am all for technological advances, but this proclamation struck close to my heart. I have progressed from cardiac catheterization using "red glass" accommodation for fluoroscopy to high-intensity multiplane angiography. I have even participated in the development of biventricular pacemakers for the treatment of heart failure and defibrillation. But the suggestion that a cardiologist can be replaced by a toy activated my Luddite receptors.

For those of you who are unaware of who or what a Luddite is, I refer you to England in the year 1811, when Edward (Ned) Ludd protested the replacement of hand-loom workers with a mechanized knitting process that threw thousands of English weavers out of work. He started a protest movement by Luddites that led to attacks on weaving mills and ultimately the hanging of some of his followers as terrorists in 1817. At about that time, in 1816, Rene Laennec developed the stethoscope by using a "quire" of paper rolled into a cylinder to listen to an obese young lady’s heart rather than his naked ear placed on her chest, which was the practice at that time.

From that paper tube has evolved the stethoscope as we know it today. Occasionally it is used to listen to the heart and lungs of patients, but it is seen mostly as a professional "necktie" in TV dramas. The fact that cardiologists and the stethoscope were to be replaced by the handheld ultrasound just as the loom weavers were replaced by the knitting machine led me to respond to the challenge.

I believe that the author, Dr. Manish Mehta of Oregon Health and Science University, Portland, spoke to an important issue. I would agree that many cardiologists are more comfortable using an echocardiogram than a stethoscope. The value of auscultation skills can be judged by the fact that cardiology board examinations do not include testing of auscultation skills but provide numerous questions on the interpretation of echocardiograms. Of course, there are the economic benefits of performing an echocardiogram compared with auscultation, which does not come up on my charge sheet.

I would grant that a handheld ultrasound can identify whether a pericardial effusion is present, a physical diagnostic challenge that I have frequently failed, particularly in thick-chested individuals. But give me a thin, young guy and I’ll get it every time. But does the presence of a leaking or stenotic valve or an enlarged heart, both easily identified by the handheld ultrasound, indicate heart failure? Give me an S3 gallop or distended neck veins and I can make the diagnosis of heart failure without a B-type natriuretic peptide level. The problem is that no one – well, very few of us – teaches how to examine the heart.

There is also the importance of the physician actually touching the patient as part of the examination. Not only examining the heart; but how about the abdomen? If we followed the path led by the BS echo, we could take the nurse’s recorded chief complaint and send the patient directly to radiology for a CT or an MRI. The fact that this is what the patient really wants does not escape this skeptic. But is this what medicine is really about? Much has been written about physician-patient interaction, but has it come to doctors being only a triage to the radiology department?

I am not going to break up the nearest echo machine with my stethoscope and end up on the hospital director’s "scaffolds" like the 18th century Luddites did. Echocardiography clearly provides a wonderful view of the heart and its valves, and can guide us to the surgical correction of valvular and muscular defects. Some technology, such as Doppler imaging, actually does provide information about physiologic phenomena including myocardial function and ischemia. But if the cardiologists lose in a contest with handheld ultrasound, it is because we have lost our bedside skills as a result of our overreliance on technology and have been blinded to its limitations.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The successful treatment of cancer with chemotherapeutic agents has led to a new set of cardiac problems related to their acute and chronic cardiac toxicity. It should not be surprising that drugs that impact so potently on intrinsic cell function and energy production to cause tumor cell death also impact on other systems, including the heart. An unfortunate by-product of the success of adjuvant therapy has been development of cardiomyocyte dysfunction and death and the development of heart failure.

Current estimates indicate that cardiovascular disease has become a competing comortality risk in women undergoing cancer chemotherapy. Cohort studies indicate that breast cancer patients who have undergone chemotherapy are at an increased cardiovascular mortality risk, compared with age matched controls. The National Cancer Institute and the Centers for Disease Control and Prevention estimate that there are more than 10 million cancer survivors in the United States and that 60% of adults newly diagnosed with cancer will be alive 5 or more years later. Many of these survivors will have significant heart failure as a result of their "successful" chemotherapy (J. Clin. Oncol. 2007;25:3991-4008).

Most of these survivors will have been treated either acutely or chronically with anthracycline drugs (such as doxorubicin), drugs directed at HER2 monoclonal antibodies (trastuzumab), or endocrine-like drugs (tamoxifen). Treatment protocols vary widely and have focused primarily on the acute, chronic, and recurrent therapy for tumor eradication with limited regard – until recently – for the acute or chronic cardiotoxic effects of the drugs. The precise incidence of cardiac toxicity is poorly understood since there are very few long-term follow-up data regarding cardiac morbidity and mortality. In these long-term survivors, cardiovascular mortality will be the predominant cause of death in women over age 60 treated for breast cancer (Circulation 2012;126:2749-63). It is estimated that half of the patients treated with anthracyclines will exhibit some cardiac dysfunction within 10-20 years and 5% will develop overt heart failure.

The mechanism by which cardiac dysfunction occurs varies depending upon the drug used. Anthracycline drugs cause ultrastructural cell changes, vacuolar degeneration, myofibrillar loss, and apoptosis. This change can be observed during early administration but may manifest years later, seemingly without any early evidence of dysfunction. Trastuzumab causes cardiac function as a result of deletion of HER2, which is essential for cardiomyocyte survival and stress adaptation. Tamoxifen-like drugs can lead to the acceleration of typical cardiac risk factors. Interaction of any of these classes of drugs when used in combination for recurrent or resistant disease can accelerate the occurrence of cardiac pathology.

The degree of adverse acute and chronic cardiac effects is related to the dose and duration of therapy. Early recognition of cardiac toxicity appears to be critical in order to mitigate the toxic drug effects. Clinical data suggest that early administration of ACE inhibitors or beta-blockers may limit or reverse cardiac dysfunction (Circulation 2006;114:2474-81). The measurement of LVEF has been used to identify early cardiac dysfunction. A symptomatic decrease in LVEF from 5% to 55% or an asymptomatic decrease of 10% is considered to be diagnostic of cardiac toxicity. Serum troponin I of greater than 0.08% also has been reported to increase the occurrence of cardiac toxicity 24-fold. Recent studies suggest that measurement of myocardial contractile velocity and strain and rate of strain by tissue Doppler imaging may provide earlier identification of myocardial dysfunction than that achieved with LVEF alone (Circulation 2012;126:2749-63).

The increased development of heart failure as a result of cancer chemotherapy has largely slipped under the cardiologist’s radar. The recent awareness of the adverse cardiac effect of these agents has generated investigation into the development of early and more sensitive biological markers and methods of mitigating cell dysfunction with concomitant medical therapy.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The successful treatment of cancer with chemotherapeutic agents has led to a new set of cardiac problems related to their acute and chronic cardiac toxicity. It should not be surprising that drugs that impact so potently on intrinsic cell function and energy production to cause tumor cell death also impact on other systems, including the heart. An unfortunate by-product of the success of adjuvant therapy has been development of cardiomyocyte dysfunction and death and the development of heart failure.

Current estimates indicate that cardiovascular disease has become a competing comortality risk in women undergoing cancer chemotherapy. Cohort studies indicate that breast cancer patients who have undergone chemotherapy are at an increased cardiovascular mortality risk, compared with age matched controls. The National Cancer Institute and the Centers for Disease Control and Prevention estimate that there are more than 10 million cancer survivors in the United States and that 60% of adults newly diagnosed with cancer will be alive 5 or more years later. Many of these survivors will have significant heart failure as a result of their "successful" chemotherapy (J. Clin. Oncol. 2007;25:3991-4008).

Most of these survivors will have been treated either acutely or chronically with anthracycline drugs (such as doxorubicin), drugs directed at HER2 monoclonal antibodies (trastuzumab), or endocrine-like drugs (tamoxifen). Treatment protocols vary widely and have focused primarily on the acute, chronic, and recurrent therapy for tumor eradication with limited regard – until recently – for the acute or chronic cardiotoxic effects of the drugs. The precise incidence of cardiac toxicity is poorly understood since there are very few long-term follow-up data regarding cardiac morbidity and mortality. In these long-term survivors, cardiovascular mortality will be the predominant cause of death in women over age 60 treated for breast cancer (Circulation 2012;126:2749-63). It is estimated that half of the patients treated with anthracyclines will exhibit some cardiac dysfunction within 10-20 years and 5% will develop overt heart failure.

The mechanism by which cardiac dysfunction occurs varies depending upon the drug used. Anthracycline drugs cause ultrastructural cell changes, vacuolar degeneration, myofibrillar loss, and apoptosis. This change can be observed during early administration but may manifest years later, seemingly without any early evidence of dysfunction. Trastuzumab causes cardiac function as a result of deletion of HER2, which is essential for cardiomyocyte survival and stress adaptation. Tamoxifen-like drugs can lead to the acceleration of typical cardiac risk factors. Interaction of any of these classes of drugs when used in combination for recurrent or resistant disease can accelerate the occurrence of cardiac pathology.

The degree of adverse acute and chronic cardiac effects is related to the dose and duration of therapy. Early recognition of cardiac toxicity appears to be critical in order to mitigate the toxic drug effects. Clinical data suggest that early administration of ACE inhibitors or beta-blockers may limit or reverse cardiac dysfunction (Circulation 2006;114:2474-81). The measurement of LVEF has been used to identify early cardiac dysfunction. A symptomatic decrease in LVEF from 5% to 55% or an asymptomatic decrease of 10% is considered to be diagnostic of cardiac toxicity. Serum troponin I of greater than 0.08% also has been reported to increase the occurrence of cardiac toxicity 24-fold. Recent studies suggest that measurement of myocardial contractile velocity and strain and rate of strain by tissue Doppler imaging may provide earlier identification of myocardial dysfunction than that achieved with LVEF alone (Circulation 2012;126:2749-63).

The increased development of heart failure as a result of cancer chemotherapy has largely slipped under the cardiologist’s radar. The recent awareness of the adverse cardiac effect of these agents has generated investigation into the development of early and more sensitive biological markers and methods of mitigating cell dysfunction with concomitant medical therapy.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The successful treatment of cancer with chemotherapeutic agents has led to a new set of cardiac problems related to their acute and chronic cardiac toxicity. It should not be surprising that drugs that impact so potently on intrinsic cell function and energy production to cause tumor cell death also impact on other systems, including the heart. An unfortunate by-product of the success of adjuvant therapy has been development of cardiomyocyte dysfunction and death and the development of heart failure.

Current estimates indicate that cardiovascular disease has become a competing comortality risk in women undergoing cancer chemotherapy. Cohort studies indicate that breast cancer patients who have undergone chemotherapy are at an increased cardiovascular mortality risk, compared with age matched controls. The National Cancer Institute and the Centers for Disease Control and Prevention estimate that there are more than 10 million cancer survivors in the United States and that 60% of adults newly diagnosed with cancer will be alive 5 or more years later. Many of these survivors will have significant heart failure as a result of their "successful" chemotherapy (J. Clin. Oncol. 2007;25:3991-4008).

Most of these survivors will have been treated either acutely or chronically with anthracycline drugs (such as doxorubicin), drugs directed at HER2 monoclonal antibodies (trastuzumab), or endocrine-like drugs (tamoxifen). Treatment protocols vary widely and have focused primarily on the acute, chronic, and recurrent therapy for tumor eradication with limited regard – until recently – for the acute or chronic cardiotoxic effects of the drugs. The precise incidence of cardiac toxicity is poorly understood since there are very few long-term follow-up data regarding cardiac morbidity and mortality. In these long-term survivors, cardiovascular mortality will be the predominant cause of death in women over age 60 treated for breast cancer (Circulation 2012;126:2749-63). It is estimated that half of the patients treated with anthracyclines will exhibit some cardiac dysfunction within 10-20 years and 5% will develop overt heart failure.

The mechanism by which cardiac dysfunction occurs varies depending upon the drug used. Anthracycline drugs cause ultrastructural cell changes, vacuolar degeneration, myofibrillar loss, and apoptosis. This change can be observed during early administration but may manifest years later, seemingly without any early evidence of dysfunction. Trastuzumab causes cardiac function as a result of deletion of HER2, which is essential for cardiomyocyte survival and stress adaptation. Tamoxifen-like drugs can lead to the acceleration of typical cardiac risk factors. Interaction of any of these classes of drugs when used in combination for recurrent or resistant disease can accelerate the occurrence of cardiac pathology.

The degree of adverse acute and chronic cardiac effects is related to the dose and duration of therapy. Early recognition of cardiac toxicity appears to be critical in order to mitigate the toxic drug effects. Clinical data suggest that early administration of ACE inhibitors or beta-blockers may limit or reverse cardiac dysfunction (Circulation 2006;114:2474-81). The measurement of LVEF has been used to identify early cardiac dysfunction. A symptomatic decrease in LVEF from 5% to 55% or an asymptomatic decrease of 10% is considered to be diagnostic of cardiac toxicity. Serum troponin I of greater than 0.08% also has been reported to increase the occurrence of cardiac toxicity 24-fold. Recent studies suggest that measurement of myocardial contractile velocity and strain and rate of strain by tissue Doppler imaging may provide earlier identification of myocardial dysfunction than that achieved with LVEF alone (Circulation 2012;126:2749-63).

The increased development of heart failure as a result of cancer chemotherapy has largely slipped under the cardiologist’s radar. The recent awareness of the adverse cardiac effect of these agents has generated investigation into the development of early and more sensitive biological markers and methods of mitigating cell dysfunction with concomitant medical therapy.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

We have recently been informed by an American Heart Association committee that owning a pet decreases your cardiovascular risk. Since I am of the age when a coronary event is almost inevitable, the opinion of the committee caught my attention.

I am not much into pets, and I am not what you would call a dog lover; but I have had a dog that I really loved. Her name was Cassiopeia, "Cassie" for short, named after my then–10-year-old son’s favorite constellation. She was a warm and attentive golden retriever who jumped up on my car to greet me every evening when I came home from the hospital. My wife, who dutifully walked her every day, rarely got so much as a tail wag. She was clearly "my" dog and, like any person or animal that comes up to you at the end of the day with a lick or a kiss, was someone to be cherished.

In her 10th year, Cassie’s kidneys failed. After several weeks of daily administration of intravenous fluids, I gave up and took her to the vet to be euthanized. I freely admit that I was mildly depressed for a few weeks after she died. We never got another dog because my wife refused to continue to take care of an animal that never showed any appreciation.

The American Heart Association’s position on the benefit of pet ownership in the reduction of cardiovascular risk is one of at least three scientific statements that the organization makes each month. It did bring to mind the effect of Cassie on my psyche and the potentially beneficial effect that she had on my coronary arteries. However, I would have to admit I have failed to pay much attention to previous proclamations by well-meaning scientific bodies like the AHA committees. I have ignored the advice about my large coffee intake, my lack of daily exercise, and the amount of salt I put on my steak.

This particular statement by the AHA, however, was cautious about the justification of the canine-human interaction and indicated that there are scant randomized data to support the claim, and what existed related to cats, a species to which my wife is allergic. The recent dog–heart disease statement had come about as a result of a "growing number of news reports and medical studies" that purported to show a beneficial relationship between pet ownership and heart disease. It is amazing how one fails to notice a brouhaha right in our own midst. According to the New York Times account, the public uproar had reached such a "point that it would be reasonable to formally investigate" the issue.

But how would you ever try to design a trial testing the hypothesis that owning a dog was a panacea for cardiovascular disease? It is not clear what mechanism of action could be attributed to the presence of the dog. Was it exercise or depression? Of course, members of the committee jumped to the obvious relationship between exercising the dog and exercising the human. The particular species of dog certainly could have importance. Should it be a big friendly golden lab, a huge Great Dane, or a little Pekingese? Did its weight or disposition have any importance? How could you ever get rid of all of the variables? Forget the idea of a randomized trial; let’s just deal with the science of the matter.

I still could not forget Cassie and I tried to see how a new dog could help me. I thought about how my wife would take this, but I decided that her unhappiness would tip the balance against getting another dog. Another Cassie to bolster my psyche just doesn’t seem to be in the cards. In my own situation I wasn’t going to exercise the dog anyway. I had already assigned that responsibility to my wife, and I am not prepared to take that from her, even though she was willing to pass it on to someone else. I think that I will do without a dog and just try to carry on.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

We have recently been informed by an American Heart Association committee that owning a pet decreases your cardiovascular risk. Since I am of the age when a coronary event is almost inevitable, the opinion of the committee caught my attention.

I am not much into pets, and I am not what you would call a dog lover; but I have had a dog that I really loved. Her name was Cassiopeia, "Cassie" for short, named after my then–10-year-old son’s favorite constellation. She was a warm and attentive golden retriever who jumped up on my car to greet me every evening when I came home from the hospital. My wife, who dutifully walked her every day, rarely got so much as a tail wag. She was clearly "my" dog and, like any person or animal that comes up to you at the end of the day with a lick or a kiss, was someone to be cherished.

In her 10th year, Cassie’s kidneys failed. After several weeks of daily administration of intravenous fluids, I gave up and took her to the vet to be euthanized. I freely admit that I was mildly depressed for a few weeks after she died. We never got another dog because my wife refused to continue to take care of an animal that never showed any appreciation.

The American Heart Association’s position on the benefit of pet ownership in the reduction of cardiovascular risk is one of at least three scientific statements that the organization makes each month. It did bring to mind the effect of Cassie on my psyche and the potentially beneficial effect that she had on my coronary arteries. However, I would have to admit I have failed to pay much attention to previous proclamations by well-meaning scientific bodies like the AHA committees. I have ignored the advice about my large coffee intake, my lack of daily exercise, and the amount of salt I put on my steak.

This particular statement by the AHA, however, was cautious about the justification of the canine-human interaction and indicated that there are scant randomized data to support the claim, and what existed related to cats, a species to which my wife is allergic. The recent dog–heart disease statement had come about as a result of a "growing number of news reports and medical studies" that purported to show a beneficial relationship between pet ownership and heart disease. It is amazing how one fails to notice a brouhaha right in our own midst. According to the New York Times account, the public uproar had reached such a "point that it would be reasonable to formally investigate" the issue.

But how would you ever try to design a trial testing the hypothesis that owning a dog was a panacea for cardiovascular disease? It is not clear what mechanism of action could be attributed to the presence of the dog. Was it exercise or depression? Of course, members of the committee jumped to the obvious relationship between exercising the dog and exercising the human. The particular species of dog certainly could have importance. Should it be a big friendly golden lab, a huge Great Dane, or a little Pekingese? Did its weight or disposition have any importance? How could you ever get rid of all of the variables? Forget the idea of a randomized trial; let’s just deal with the science of the matter.

I still could not forget Cassie and I tried to see how a new dog could help me. I thought about how my wife would take this, but I decided that her unhappiness would tip the balance against getting another dog. Another Cassie to bolster my psyche just doesn’t seem to be in the cards. In my own situation I wasn’t going to exercise the dog anyway. I had already assigned that responsibility to my wife, and I am not prepared to take that from her, even though she was willing to pass it on to someone else. I think that I will do without a dog and just try to carry on.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

We have recently been informed by an American Heart Association committee that owning a pet decreases your cardiovascular risk. Since I am of the age when a coronary event is almost inevitable, the opinion of the committee caught my attention.

I am not much into pets, and I am not what you would call a dog lover; but I have had a dog that I really loved. Her name was Cassiopeia, "Cassie" for short, named after my then–10-year-old son’s favorite constellation. She was a warm and attentive golden retriever who jumped up on my car to greet me every evening when I came home from the hospital. My wife, who dutifully walked her every day, rarely got so much as a tail wag. She was clearly "my" dog and, like any person or animal that comes up to you at the end of the day with a lick or a kiss, was someone to be cherished.

In her 10th year, Cassie’s kidneys failed. After several weeks of daily administration of intravenous fluids, I gave up and took her to the vet to be euthanized. I freely admit that I was mildly depressed for a few weeks after she died. We never got another dog because my wife refused to continue to take care of an animal that never showed any appreciation.

The American Heart Association’s position on the benefit of pet ownership in the reduction of cardiovascular risk is one of at least three scientific statements that the organization makes each month. It did bring to mind the effect of Cassie on my psyche and the potentially beneficial effect that she had on my coronary arteries. However, I would have to admit I have failed to pay much attention to previous proclamations by well-meaning scientific bodies like the AHA committees. I have ignored the advice about my large coffee intake, my lack of daily exercise, and the amount of salt I put on my steak.

This particular statement by the AHA, however, was cautious about the justification of the canine-human interaction and indicated that there are scant randomized data to support the claim, and what existed related to cats, a species to which my wife is allergic. The recent dog–heart disease statement had come about as a result of a "growing number of news reports and medical studies" that purported to show a beneficial relationship between pet ownership and heart disease. It is amazing how one fails to notice a brouhaha right in our own midst. According to the New York Times account, the public uproar had reached such a "point that it would be reasonable to formally investigate" the issue.

But how would you ever try to design a trial testing the hypothesis that owning a dog was a panacea for cardiovascular disease? It is not clear what mechanism of action could be attributed to the presence of the dog. Was it exercise or depression? Of course, members of the committee jumped to the obvious relationship between exercising the dog and exercising the human. The particular species of dog certainly could have importance. Should it be a big friendly golden lab, a huge Great Dane, or a little Pekingese? Did its weight or disposition have any importance? How could you ever get rid of all of the variables? Forget the idea of a randomized trial; let’s just deal with the science of the matter.

I still could not forget Cassie and I tried to see how a new dog could help me. I thought about how my wife would take this, but I decided that her unhappiness would tip the balance against getting another dog. Another Cassie to bolster my psyche just doesn’t seem to be in the cards. In my own situation I wasn’t going to exercise the dog anyway. I had already assigned that responsibility to my wife, and I am not prepared to take that from her, even though she was willing to pass it on to someone else. I think that I will do without a dog and just try to carry on.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.