Heart of the Matter

In the past 25 years, there has been an explosion of investment by the pharmaceutical and medical-device industries in basic and applied medical research, from $2 billion in 1980 to $39 billion in 2004.

This support has had a profound influence on academia. It has changed the atmosphere in academic research from one of altruism to one with an entrepreneurial edge, as evidenced by the burgeoning numbers of invention disclosures and new patent applications from academic institutions. It has resulted in a significant increase in commercialization of academic medical centers and their faculties. It has also led to a natural desire for a greater ownership of concepts and profits by both the physician investigator and the sponsoring institution. In clinical trials, the boundary between the patient and the physician as an investigator and the physician as an inventor and entrepreneur has become more complex—particularly when they are the same person or the same institution.

There has been a recent spate of publicity about the financial relationships between physicians, academic research institutions, and companies developing new drugs and devices. Charges and countercharges have been made suggesting inappropriate involvement by physicians and medical institutions in devices or drugs that could result in significant financial return to them.

What is involved here is not obvious unethical behavior but the appearance that such behavior is taking place. It is not unusual that a clinical investigator would seek external high-risk financial support in order to carry an idea forward. The investigator who has invested in the research project would like to profit from that investment should the project become successful. Medical institutions, knowledgeable about new concepts, wish to invest in their development.

The patient who is asked to participate in a clinical trial knows nothing about the financial strings attached to the research project he or she is enrolled in. The patient is told there is a reasonable possibility, but no certainty, that the study could benefit them. The contract that the patient and physician sign, articulated in the consent form, indicates that scientific equipoise exists between active therapy and conventional therapy. The patient is motivated by the possibility of personally benefiting from the new therapy or at least the belief that it might benefit future patients. It is a contract founded on personal benefit and altruism. The injection of a profit motive by either the physician or the institution has the potential to contaminate the entire consent process.

The high road is one in which the inventor or institution has no patient contact in a research project from which either might profit financially. Physician scientists who wish to have their ideas tested should delegate the study and the analysis to more objective researchers. Likewise, institutions that have invested in the product should not participate in the investigation, to avoid the possibility of influencing staff participation in the trial and recruitment of patients. Anything short of this opens the investigator and institution to criticism of bias.

In the past 25 years, there has been an explosion of investment by the pharmaceutical and medical-device industries in basic and applied medical research, from $2 billion in 1980 to $39 billion in 2004.

This support has had a profound influence on academia. It has changed the atmosphere in academic research from one of altruism to one with an entrepreneurial edge, as evidenced by the burgeoning numbers of invention disclosures and new patent applications from academic institutions. It has resulted in a significant increase in commercialization of academic medical centers and their faculties. It has also led to a natural desire for a greater ownership of concepts and profits by both the physician investigator and the sponsoring institution. In clinical trials, the boundary between the patient and the physician as an investigator and the physician as an inventor and entrepreneur has become more complex—particularly when they are the same person or the same institution.

There has been a recent spate of publicity about the financial relationships between physicians, academic research institutions, and companies developing new drugs and devices. Charges and countercharges have been made suggesting inappropriate involvement by physicians and medical institutions in devices or drugs that could result in significant financial return to them.

What is involved here is not obvious unethical behavior but the appearance that such behavior is taking place. It is not unusual that a clinical investigator would seek external high-risk financial support in order to carry an idea forward. The investigator who has invested in the research project would like to profit from that investment should the project become successful. Medical institutions, knowledgeable about new concepts, wish to invest in their development.

The patient who is asked to participate in a clinical trial knows nothing about the financial strings attached to the research project he or she is enrolled in. The patient is told there is a reasonable possibility, but no certainty, that the study could benefit them. The contract that the patient and physician sign, articulated in the consent form, indicates that scientific equipoise exists between active therapy and conventional therapy. The patient is motivated by the possibility of personally benefiting from the new therapy or at least the belief that it might benefit future patients. It is a contract founded on personal benefit and altruism. The injection of a profit motive by either the physician or the institution has the potential to contaminate the entire consent process.

The high road is one in which the inventor or institution has no patient contact in a research project from which either might profit financially. Physician scientists who wish to have their ideas tested should delegate the study and the analysis to more objective researchers. Likewise, institutions that have invested in the product should not participate in the investigation, to avoid the possibility of influencing staff participation in the trial and recruitment of patients. Anything short of this opens the investigator and institution to criticism of bias.

In the past 25 years, there has been an explosion of investment by the pharmaceutical and medical-device industries in basic and applied medical research, from $2 billion in 1980 to $39 billion in 2004.

This support has had a profound influence on academia. It has changed the atmosphere in academic research from one of altruism to one with an entrepreneurial edge, as evidenced by the burgeoning numbers of invention disclosures and new patent applications from academic institutions. It has resulted in a significant increase in commercialization of academic medical centers and their faculties. It has also led to a natural desire for a greater ownership of concepts and profits by both the physician investigator and the sponsoring institution. In clinical trials, the boundary between the patient and the physician as an investigator and the physician as an inventor and entrepreneur has become more complex—particularly when they are the same person or the same institution.

There has been a recent spate of publicity about the financial relationships between physicians, academic research institutions, and companies developing new drugs and devices. Charges and countercharges have been made suggesting inappropriate involvement by physicians and medical institutions in devices or drugs that could result in significant financial return to them.

What is involved here is not obvious unethical behavior but the appearance that such behavior is taking place. It is not unusual that a clinical investigator would seek external high-risk financial support in order to carry an idea forward. The investigator who has invested in the research project would like to profit from that investment should the project become successful. Medical institutions, knowledgeable about new concepts, wish to invest in their development.

The patient who is asked to participate in a clinical trial knows nothing about the financial strings attached to the research project he or she is enrolled in. The patient is told there is a reasonable possibility, but no certainty, that the study could benefit them. The contract that the patient and physician sign, articulated in the consent form, indicates that scientific equipoise exists between active therapy and conventional therapy. The patient is motivated by the possibility of personally benefiting from the new therapy or at least the belief that it might benefit future patients. It is a contract founded on personal benefit and altruism. The injection of a profit motive by either the physician or the institution has the potential to contaminate the entire consent process.

The high road is one in which the inventor or institution has no patient contact in a research project from which either might profit financially. Physician scientists who wish to have their ideas tested should delegate the study and the analysis to more objective researchers. Likewise, institutions that have invested in the product should not participate in the investigation, to avoid the possibility of influencing staff participation in the trial and recruitment of patients. Anything short of this opens the investigator and institution to criticism of bias.

America is facing a major shortage of nurses and doctors, with no real solution in sight. For more than a half a century, we have depended on the foreign health professionals to satisfy our domestic requirements. U.S. medical and nursing schools have failed to respond to this need.

According to data from the 2004 U.S. Physician Masterfile, more than 200,000 physicians, or 25% of those practicing in the United States, were trained outside this country. More than 60% of those were trained in low-income countries such as India, the Philippines, and Pakistan (N. Engl. J. Med. 2005;353:1810–8). Another 25,000 were U.S. citizens who received their medical training abroad.

Not until this year has there been any significant change in the number of students entering U.S. medical schools. Between 1971 and 1985, American medical school graduates increased from approximately 10,000 to 16,000 per year. Since 1985, the number of medical graduates has been flat.

Over the past 20 years, there has been a significant change in the makeup of medical school classes as the number of female graduates has increased and the number of male graduates has decreased. In 2004, there were just 1,000 fewer female graduates than male graduates. During the same period, there has been a gradual increase in both African American and Hispanic students.

According to a recent report from the Association of American Medical Colleges, this year, for the first time in almost two decades, there has been an increase of 2.1% in medical school enrollees, to more than 17,000 first-year medical students.

Even with this overall increase in enrollments, demand far outstrips supply. By failing to train enough American doctors for our needs, we are siphoning off foreign-trained doctors from developing countries, thus contributing to the lowering of public health standards in those countries.

As economics and immigration policies change, both here and around the world, we may not be able to rely on a continuing supply of doctors from abroad, especially considering that a shortfall of more than 200,000 doctors is projected by 2020.

The outlook for nursing is even worse. We continue to meet much of our need for nurses by recruiting from underdeveloped countries. However, this is an international problem. Recent legislation passed by Congress has made it easier for foreign-trained nurses to work in this country, which, as with the doctors, has aggravated the shortfall of nurses in their countries of origin. The number of nurses working in the United States has remained relatively flat over the last few years, at about 2 million, but there is a projected 50% increase over the next decade in the demand for nurses. As the nurse-patient ratios decrease by legislation, as they have in California, this short supply will be exacerbated. In addition, as our population ages, so will more nurses retire, placing further pressure on the shortage.

The Association of American Medical Colleges and the American Nurses Association should play a role in solving to these manpower issues, but there has been little evidence of their leadership at the national level. Practicing physicians have little recourse other than wringing their hands and wishing for help.

America is facing a major shortage of nurses and doctors, with no real solution in sight. For more than a half a century, we have depended on the foreign health professionals to satisfy our domestic requirements. U.S. medical and nursing schools have failed to respond to this need.

According to data from the 2004 U.S. Physician Masterfile, more than 200,000 physicians, or 25% of those practicing in the United States, were trained outside this country. More than 60% of those were trained in low-income countries such as India, the Philippines, and Pakistan (N. Engl. J. Med. 2005;353:1810–8). Another 25,000 were U.S. citizens who received their medical training abroad.

Not until this year has there been any significant change in the number of students entering U.S. medical schools. Between 1971 and 1985, American medical school graduates increased from approximately 10,000 to 16,000 per year. Since 1985, the number of medical graduates has been flat.

Over the past 20 years, there has been a significant change in the makeup of medical school classes as the number of female graduates has increased and the number of male graduates has decreased. In 2004, there were just 1,000 fewer female graduates than male graduates. During the same period, there has been a gradual increase in both African American and Hispanic students.

According to a recent report from the Association of American Medical Colleges, this year, for the first time in almost two decades, there has been an increase of 2.1% in medical school enrollees, to more than 17,000 first-year medical students.

Even with this overall increase in enrollments, demand far outstrips supply. By failing to train enough American doctors for our needs, we are siphoning off foreign-trained doctors from developing countries, thus contributing to the lowering of public health standards in those countries.

As economics and immigration policies change, both here and around the world, we may not be able to rely on a continuing supply of doctors from abroad, especially considering that a shortfall of more than 200,000 doctors is projected by 2020.

The outlook for nursing is even worse. We continue to meet much of our need for nurses by recruiting from underdeveloped countries. However, this is an international problem. Recent legislation passed by Congress has made it easier for foreign-trained nurses to work in this country, which, as with the doctors, has aggravated the shortfall of nurses in their countries of origin. The number of nurses working in the United States has remained relatively flat over the last few years, at about 2 million, but there is a projected 50% increase over the next decade in the demand for nurses. As the nurse-patient ratios decrease by legislation, as they have in California, this short supply will be exacerbated. In addition, as our population ages, so will more nurses retire, placing further pressure on the shortage.

The Association of American Medical Colleges and the American Nurses Association should play a role in solving to these manpower issues, but there has been little evidence of their leadership at the national level. Practicing physicians have little recourse other than wringing their hands and wishing for help.

America is facing a major shortage of nurses and doctors, with no real solution in sight. For more than a half a century, we have depended on the foreign health professionals to satisfy our domestic requirements. U.S. medical and nursing schools have failed to respond to this need.

According to data from the 2004 U.S. Physician Masterfile, more than 200,000 physicians, or 25% of those practicing in the United States, were trained outside this country. More than 60% of those were trained in low-income countries such as India, the Philippines, and Pakistan (N. Engl. J. Med. 2005;353:1810–8). Another 25,000 were U.S. citizens who received their medical training abroad.

Not until this year has there been any significant change in the number of students entering U.S. medical schools. Between 1971 and 1985, American medical school graduates increased from approximately 10,000 to 16,000 per year. Since 1985, the number of medical graduates has been flat.

Over the past 20 years, there has been a significant change in the makeup of medical school classes as the number of female graduates has increased and the number of male graduates has decreased. In 2004, there were just 1,000 fewer female graduates than male graduates. During the same period, there has been a gradual increase in both African American and Hispanic students.

According to a recent report from the Association of American Medical Colleges, this year, for the first time in almost two decades, there has been an increase of 2.1% in medical school enrollees, to more than 17,000 first-year medical students.

Even with this overall increase in enrollments, demand far outstrips supply. By failing to train enough American doctors for our needs, we are siphoning off foreign-trained doctors from developing countries, thus contributing to the lowering of public health standards in those countries.

As economics and immigration policies change, both here and around the world, we may not be able to rely on a continuing supply of doctors from abroad, especially considering that a shortfall of more than 200,000 doctors is projected by 2020.

The outlook for nursing is even worse. We continue to meet much of our need for nurses by recruiting from underdeveloped countries. However, this is an international problem. Recent legislation passed by Congress has made it easier for foreign-trained nurses to work in this country, which, as with the doctors, has aggravated the shortfall of nurses in their countries of origin. The number of nurses working in the United States has remained relatively flat over the last few years, at about 2 million, but there is a projected 50% increase over the next decade in the demand for nurses. As the nurse-patient ratios decrease by legislation, as they have in California, this short supply will be exacerbated. In addition, as our population ages, so will more nurses retire, placing further pressure on the shortage.

The Association of American Medical Colleges and the American Nurses Association should play a role in solving to these manpower issues, but there has been little evidence of their leadership at the national level. Practicing physicians have little recourse other than wringing their hands and wishing for help.

By all appearances, we have reached a plateau in our attack on heart disease, and the recent meeting of the American Heart Association in Dallas provided ample evidence of this.

Numerous presentations and clinical trials were reported at the meeting, and some are included in this issue of CARDIOLOGY NEWS. But the findings reported have not moved us very far forward. Clinical trials spanning a variety of targets failed to show any significant benefits. Much of what was reported compared one drug or device with another, with an eye to safety rather than showing any improvement in mortality or morbidity.

In many cases, investigators examined new stents and antithrombotic drugs, but provided no reason to deviate from current practice. Some studies suggested that one stent might be better than another, but were often conducted in differing patient populations, which modulated most of the observed benefits and negated the differences.

In the device area, a variety of new techniques directed at improving the marginal benefits of ablation therapy for atrial fibrillation were reported. Several studies focused on trying to identify those patients who benefit the most from biventricular pacing.

More surprisingly, the results of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) indicated that heart failure mortality increased significantly after a single discharge of the defibrillator. These observations suggested that the MADIT II patients were trading sudden death for progressive heart failure. There was no ready explanation for these observations, which generated considerable discussion among attendees about the trade-off.

The results of two clinical trials with levosimendan, a calcium-sensitizing drug for heart failure that is available in Europe but not approved in the United States, were also reported. Although patients seemed to experience improvement in symptoms acutely, morbidity and mortality were not significantly improved. It seems that current heart failure therapy with intravenous inotropic drugs supports patients through the acute episode, only to expose them to repeat and progressive failure. The cost of this support is further myocardial damage. It is becoming clear that there is a need for drugs that will improve cardiac function without causing cell damage in the setting of acute heart failure, a syndrome that is drawing increasing interest from investigators.

In the area of lipid therapy, fenofibrate was studied in patients with type 2 diabetes. There was a significant decrease in nonfatal MIs, but also a nonsignificant increase in total mortality.

With some certainty, our major therapeutic tools have stood the test of examination during the last year, but they have not provided a window to any new therapies. It seems that we have lowered cardiac mortality to a level that might make it difficult to demonstrate drug benefit.

Perhaps these observations will become more pertinent to the future of cardiology as costs and reimbursements begin to play an even greater role in our decision making. It is possible that we may be pricing ourselves out of the market as the numbers in our uninsured population burgeon.

By all appearances, we have reached a plateau in our attack on heart disease, and the recent meeting of the American Heart Association in Dallas provided ample evidence of this.

Numerous presentations and clinical trials were reported at the meeting, and some are included in this issue of CARDIOLOGY NEWS. But the findings reported have not moved us very far forward. Clinical trials spanning a variety of targets failed to show any significant benefits. Much of what was reported compared one drug or device with another, with an eye to safety rather than showing any improvement in mortality or morbidity.

In many cases, investigators examined new stents and antithrombotic drugs, but provided no reason to deviate from current practice. Some studies suggested that one stent might be better than another, but were often conducted in differing patient populations, which modulated most of the observed benefits and negated the differences.

In the device area, a variety of new techniques directed at improving the marginal benefits of ablation therapy for atrial fibrillation were reported. Several studies focused on trying to identify those patients who benefit the most from biventricular pacing.

More surprisingly, the results of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) indicated that heart failure mortality increased significantly after a single discharge of the defibrillator. These observations suggested that the MADIT II patients were trading sudden death for progressive heart failure. There was no ready explanation for these observations, which generated considerable discussion among attendees about the trade-off.

The results of two clinical trials with levosimendan, a calcium-sensitizing drug for heart failure that is available in Europe but not approved in the United States, were also reported. Although patients seemed to experience improvement in symptoms acutely, morbidity and mortality were not significantly improved. It seems that current heart failure therapy with intravenous inotropic drugs supports patients through the acute episode, only to expose them to repeat and progressive failure. The cost of this support is further myocardial damage. It is becoming clear that there is a need for drugs that will improve cardiac function without causing cell damage in the setting of acute heart failure, a syndrome that is drawing increasing interest from investigators.

In the area of lipid therapy, fenofibrate was studied in patients with type 2 diabetes. There was a significant decrease in nonfatal MIs, but also a nonsignificant increase in total mortality.

With some certainty, our major therapeutic tools have stood the test of examination during the last year, but they have not provided a window to any new therapies. It seems that we have lowered cardiac mortality to a level that might make it difficult to demonstrate drug benefit.

Perhaps these observations will become more pertinent to the future of cardiology as costs and reimbursements begin to play an even greater role in our decision making. It is possible that we may be pricing ourselves out of the market as the numbers in our uninsured population burgeon.

By all appearances, we have reached a plateau in our attack on heart disease, and the recent meeting of the American Heart Association in Dallas provided ample evidence of this.

Numerous presentations and clinical trials were reported at the meeting, and some are included in this issue of CARDIOLOGY NEWS. But the findings reported have not moved us very far forward. Clinical trials spanning a variety of targets failed to show any significant benefits. Much of what was reported compared one drug or device with another, with an eye to safety rather than showing any improvement in mortality or morbidity.

In many cases, investigators examined new stents and antithrombotic drugs, but provided no reason to deviate from current practice. Some studies suggested that one stent might be better than another, but were often conducted in differing patient populations, which modulated most of the observed benefits and negated the differences.

In the device area, a variety of new techniques directed at improving the marginal benefits of ablation therapy for atrial fibrillation were reported. Several studies focused on trying to identify those patients who benefit the most from biventricular pacing.

More surprisingly, the results of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) indicated that heart failure mortality increased significantly after a single discharge of the defibrillator. These observations suggested that the MADIT II patients were trading sudden death for progressive heart failure. There was no ready explanation for these observations, which generated considerable discussion among attendees about the trade-off.

The results of two clinical trials with levosimendan, a calcium-sensitizing drug for heart failure that is available in Europe but not approved in the United States, were also reported. Although patients seemed to experience improvement in symptoms acutely, morbidity and mortality were not significantly improved. It seems that current heart failure therapy with intravenous inotropic drugs supports patients through the acute episode, only to expose them to repeat and progressive failure. The cost of this support is further myocardial damage. It is becoming clear that there is a need for drugs that will improve cardiac function without causing cell damage in the setting of acute heart failure, a syndrome that is drawing increasing interest from investigators.

In the area of lipid therapy, fenofibrate was studied in patients with type 2 diabetes. There was a significant decrease in nonfatal MIs, but also a nonsignificant increase in total mortality.

With some certainty, our major therapeutic tools have stood the test of examination during the last year, but they have not provided a window to any new therapies. It seems that we have lowered cardiac mortality to a level that might make it difficult to demonstrate drug benefit.

Perhaps these observations will become more pertinent to the future of cardiology as costs and reimbursements begin to play an even greater role in our decision making. It is possible that we may be pricing ourselves out of the market as the numbers in our uninsured population burgeon.

In this issue of CARDIOLOGY NEWS, observations reported at the meeting of the European Society of Cardiology in Stockholm provide insights into the real-world use of drug-eluting stents.

Much of our knowledge of DESs has come from carefully controlled clinical trials using highly selected patients and conducted in academic institutions. What happens after the device is approved and introduced for use in everyday medical practice is often very different.

Human nature drives interventional cardiologists to use the latest new toy, regardless of price, while patients are educated by the media to demand state-of-the-art stents.

At the same time, cardiologists tend to expand the indications for use of the device or drug beyond the patient inclusion criteria used to established efficacy and safety. In addition, information about the application of new therapies after the FDA has approved them is scarce. In some cases, drugs have been used in patients who differed from those in the seminal clinical trial, resulting in increased major adverse clinical events (MACE).

Gregory J. Mishkel, M.D., described how he and his associates observed that in more than 3,000 patients in a general cardiology practice, most of those who received DESs did not fit the criteria used in the trials that established the benefits of the stents. (See page 23.) As the patients' characteristics were expanded beyond the initial inclusion criteria, the incidence of MACE increased. The more risk factors the patients had, the more likely was the occurrence of MACE. In the context of patients demanding the latest procedure to get the best results, the investigators found that the patients were, in fact, being shortchanged.

The investigators suggest that enthusiasm for DESs also led to stenting when coronary bypass surgery might have been a better choice, but they did not provide data to support that possibility.

Another result of the overuse of DESs has been the impact on health care costs. The actual cost of stents varies from institution to institution. Current estimates suggest that a bare-metal stent (BMS) costs about $1,000, whereas a DES costs about three times that. If one considers that it usually takes at least two stents to completely treat stenosis, then the cost of DES implantation, compared with that of BMS implantation, begins to mount up.

In the Basel Stent Cost Effectiveness Trial (BASKET, page 1), researchers compared the costs and efficacy of the implantation of the paclitaxel-eluting Taxus and sirolimus-eluting Cypher stents with the Vision stent, a cobalt-chromium-based BMS. Although the DESs resulted in an improved target vessel revascularization, they also tacked on almost $90,000 per year of quality-adjusted life-year gained by the DES.

These reports provide an unusual glimpse into how new devices are actually being used in clinical medicine, as well as how drugs and devices are applied to the general populations based on data from narrowly defined patient samples in clinical trials. Patients in enrolled in clinical trials are recruited to answer specific questions, which results in the exclusion of many in the general population with complicating illnesses. Unfortunately, those complicating illnesses that exclude patients from clinical trials are the problems that the physician deals with every day.

In this issue of CARDIOLOGY NEWS, observations reported at the meeting of the European Society of Cardiology in Stockholm provide insights into the real-world use of drug-eluting stents.

Much of our knowledge of DESs has come from carefully controlled clinical trials using highly selected patients and conducted in academic institutions. What happens after the device is approved and introduced for use in everyday medical practice is often very different.

Human nature drives interventional cardiologists to use the latest new toy, regardless of price, while patients are educated by the media to demand state-of-the-art stents.

At the same time, cardiologists tend to expand the indications for use of the device or drug beyond the patient inclusion criteria used to established efficacy and safety. In addition, information about the application of new therapies after the FDA has approved them is scarce. In some cases, drugs have been used in patients who differed from those in the seminal clinical trial, resulting in increased major adverse clinical events (MACE).

Gregory J. Mishkel, M.D., described how he and his associates observed that in more than 3,000 patients in a general cardiology practice, most of those who received DESs did not fit the criteria used in the trials that established the benefits of the stents. (See page 23.) As the patients' characteristics were expanded beyond the initial inclusion criteria, the incidence of MACE increased. The more risk factors the patients had, the more likely was the occurrence of MACE. In the context of patients demanding the latest procedure to get the best results, the investigators found that the patients were, in fact, being shortchanged.

The investigators suggest that enthusiasm for DESs also led to stenting when coronary bypass surgery might have been a better choice, but they did not provide data to support that possibility.

Another result of the overuse of DESs has been the impact on health care costs. The actual cost of stents varies from institution to institution. Current estimates suggest that a bare-metal stent (BMS) costs about $1,000, whereas a DES costs about three times that. If one considers that it usually takes at least two stents to completely treat stenosis, then the cost of DES implantation, compared with that of BMS implantation, begins to mount up.

In the Basel Stent Cost Effectiveness Trial (BASKET, page 1), researchers compared the costs and efficacy of the implantation of the paclitaxel-eluting Taxus and sirolimus-eluting Cypher stents with the Vision stent, a cobalt-chromium-based BMS. Although the DESs resulted in an improved target vessel revascularization, they also tacked on almost $90,000 per year of quality-adjusted life-year gained by the DES.

These reports provide an unusual glimpse into how new devices are actually being used in clinical medicine, as well as how drugs and devices are applied to the general populations based on data from narrowly defined patient samples in clinical trials. Patients in enrolled in clinical trials are recruited to answer specific questions, which results in the exclusion of many in the general population with complicating illnesses. Unfortunately, those complicating illnesses that exclude patients from clinical trials are the problems that the physician deals with every day.

In this issue of CARDIOLOGY NEWS, observations reported at the meeting of the European Society of Cardiology in Stockholm provide insights into the real-world use of drug-eluting stents.

Much of our knowledge of DESs has come from carefully controlled clinical trials using highly selected patients and conducted in academic institutions. What happens after the device is approved and introduced for use in everyday medical practice is often very different.

Human nature drives interventional cardiologists to use the latest new toy, regardless of price, while patients are educated by the media to demand state-of-the-art stents.

At the same time, cardiologists tend to expand the indications for use of the device or drug beyond the patient inclusion criteria used to established efficacy and safety. In addition, information about the application of new therapies after the FDA has approved them is scarce. In some cases, drugs have been used in patients who differed from those in the seminal clinical trial, resulting in increased major adverse clinical events (MACE).

Gregory J. Mishkel, M.D., described how he and his associates observed that in more than 3,000 patients in a general cardiology practice, most of those who received DESs did not fit the criteria used in the trials that established the benefits of the stents. (See page 23.) As the patients' characteristics were expanded beyond the initial inclusion criteria, the incidence of MACE increased. The more risk factors the patients had, the more likely was the occurrence of MACE. In the context of patients demanding the latest procedure to get the best results, the investigators found that the patients were, in fact, being shortchanged.

The investigators suggest that enthusiasm for DESs also led to stenting when coronary bypass surgery might have been a better choice, but they did not provide data to support that possibility.

Another result of the overuse of DESs has been the impact on health care costs. The actual cost of stents varies from institution to institution. Current estimates suggest that a bare-metal stent (BMS) costs about $1,000, whereas a DES costs about three times that. If one considers that it usually takes at least two stents to completely treat stenosis, then the cost of DES implantation, compared with that of BMS implantation, begins to mount up.

In the Basel Stent Cost Effectiveness Trial (BASKET, page 1), researchers compared the costs and efficacy of the implantation of the paclitaxel-eluting Taxus and sirolimus-eluting Cypher stents with the Vision stent, a cobalt-chromium-based BMS. Although the DESs resulted in an improved target vessel revascularization, they also tacked on almost $90,000 per year of quality-adjusted life-year gained by the DES.

These reports provide an unusual glimpse into how new devices are actually being used in clinical medicine, as well as how drugs and devices are applied to the general populations based on data from narrowly defined patient samples in clinical trials. Patients in enrolled in clinical trials are recruited to answer specific questions, which results in the exclusion of many in the general population with complicating illnesses. Unfortunately, those complicating illnesses that exclude patients from clinical trials are the problems that the physician deals with every day.

A significant shift in recent years to treating heart failure with device implantation and surgery has made its way into clinical guidelines, published last month by the American College of Cardiology and the American Heart Association. The value of these therapies is most apparent in young patients with little concomitant disease and in whom the long-term risks and benefits can be measured in many symptom-free years.

The decision to implant a cardioverter-defibrillator in a young patient with an ejection fraction of 20% and with active ventricular ectopia is easy, as is the choice of mitral valve surgery in a similar patient with symptomatic heart failure. However, physicians using the heart failure-guideline update should appreciate that many of our heart failure patients to whom these guidelines will be applied are elderly. The summary article recommends and deems it “reasonable” to consider a wide range of therapies, including surgery and devices. But the full text, which includes the background discussions of the decision-making process, makes it clear that the authors struggled with the universality of their application to all ages and all persons. (Both articles are available at www.acc.org/clinical/statements.htm

There is concern that some elderly patients will be persuaded to accept these therapies as essential to survival, as they well may be. But at what cost to quality of survival?

It is important to understand that these are indeed guidelines and not requirements. However, there are concerns that they will become imperatives for the measurement of quality, like β-blockers, aspirin, and ACE inhibitors, and thus fall into the gun sights of aggressive medical administrators who will penalize hospitals and doctors who do not comply. In the realm of quality improvement, variation is not appreciated.

Some questions can be raised about the class I recommendation for the use of biventricular pacing with patients with prolonged QRS intervals at a time when we are still learning about the physiology of the device, where the electrodes should be implanted, and which patients will benefit most. The results of those studies will determine who will receive the most benefit. This information will be essential for cardiologists as they make their recommendations to individual patients. Similarly, the advisory class I for mitral valve replacement in “severe” mitral insufficiency in patients with asymptomatic left ventricular dysfunction is puzzling without a definition of severity and without any randomized clinical trial to support the procedure.

The application of these technical advances to elderly patients, who make up a large part of heart failure population, should be a concern of physicians. Some writing to this newspaper are worried that any deviation from the published guidelines will make them vulnerable to litigation. To those who have those concerns—and they are indeed real—I would suggest they read beyond the guideline summary and appreciate the gray zones that surround many of the recommendations. And the writing committee should try to bring its recommendations into a somewhat “grayer” reality of care and perhaps reemphasize the need for the physician's judgment in applying them.

A significant shift in recent years to treating heart failure with device implantation and surgery has made its way into clinical guidelines, published last month by the American College of Cardiology and the American Heart Association. The value of these therapies is most apparent in young patients with little concomitant disease and in whom the long-term risks and benefits can be measured in many symptom-free years.

The decision to implant a cardioverter-defibrillator in a young patient with an ejection fraction of 20% and with active ventricular ectopia is easy, as is the choice of mitral valve surgery in a similar patient with symptomatic heart failure. However, physicians using the heart failure-guideline update should appreciate that many of our heart failure patients to whom these guidelines will be applied are elderly. The summary article recommends and deems it “reasonable” to consider a wide range of therapies, including surgery and devices. But the full text, which includes the background discussions of the decision-making process, makes it clear that the authors struggled with the universality of their application to all ages and all persons. (Both articles are available at www.acc.org/clinical/statements.htm

There is concern that some elderly patients will be persuaded to accept these therapies as essential to survival, as they well may be. But at what cost to quality of survival?

It is important to understand that these are indeed guidelines and not requirements. However, there are concerns that they will become imperatives for the measurement of quality, like β-blockers, aspirin, and ACE inhibitors, and thus fall into the gun sights of aggressive medical administrators who will penalize hospitals and doctors who do not comply. In the realm of quality improvement, variation is not appreciated.

Some questions can be raised about the class I recommendation for the use of biventricular pacing with patients with prolonged QRS intervals at a time when we are still learning about the physiology of the device, where the electrodes should be implanted, and which patients will benefit most. The results of those studies will determine who will receive the most benefit. This information will be essential for cardiologists as they make their recommendations to individual patients. Similarly, the advisory class I for mitral valve replacement in “severe” mitral insufficiency in patients with asymptomatic left ventricular dysfunction is puzzling without a definition of severity and without any randomized clinical trial to support the procedure.

The application of these technical advances to elderly patients, who make up a large part of heart failure population, should be a concern of physicians. Some writing to this newspaper are worried that any deviation from the published guidelines will make them vulnerable to litigation. To those who have those concerns—and they are indeed real—I would suggest they read beyond the guideline summary and appreciate the gray zones that surround many of the recommendations. And the writing committee should try to bring its recommendations into a somewhat “grayer” reality of care and perhaps reemphasize the need for the physician's judgment in applying them.

A significant shift in recent years to treating heart failure with device implantation and surgery has made its way into clinical guidelines, published last month by the American College of Cardiology and the American Heart Association. The value of these therapies is most apparent in young patients with little concomitant disease and in whom the long-term risks and benefits can be measured in many symptom-free years.

The decision to implant a cardioverter-defibrillator in a young patient with an ejection fraction of 20% and with active ventricular ectopia is easy, as is the choice of mitral valve surgery in a similar patient with symptomatic heart failure. However, physicians using the heart failure-guideline update should appreciate that many of our heart failure patients to whom these guidelines will be applied are elderly. The summary article recommends and deems it “reasonable” to consider a wide range of therapies, including surgery and devices. But the full text, which includes the background discussions of the decision-making process, makes it clear that the authors struggled with the universality of their application to all ages and all persons. (Both articles are available at www.acc.org/clinical/statements.htm

There is concern that some elderly patients will be persuaded to accept these therapies as essential to survival, as they well may be. But at what cost to quality of survival?

It is important to understand that these are indeed guidelines and not requirements. However, there are concerns that they will become imperatives for the measurement of quality, like β-blockers, aspirin, and ACE inhibitors, and thus fall into the gun sights of aggressive medical administrators who will penalize hospitals and doctors who do not comply. In the realm of quality improvement, variation is not appreciated.

Some questions can be raised about the class I recommendation for the use of biventricular pacing with patients with prolonged QRS intervals at a time when we are still learning about the physiology of the device, where the electrodes should be implanted, and which patients will benefit most. The results of those studies will determine who will receive the most benefit. This information will be essential for cardiologists as they make their recommendations to individual patients. Similarly, the advisory class I for mitral valve replacement in “severe” mitral insufficiency in patients with asymptomatic left ventricular dysfunction is puzzling without a definition of severity and without any randomized clinical trial to support the procedure.

The application of these technical advances to elderly patients, who make up a large part of heart failure population, should be a concern of physicians. Some writing to this newspaper are worried that any deviation from the published guidelines will make them vulnerable to litigation. To those who have those concerns—and they are indeed real—I would suggest they read beyond the guideline summary and appreciate the gray zones that surround many of the recommendations. And the writing committee should try to bring its recommendations into a somewhat “grayer” reality of care and perhaps reemphasize the need for the physician's judgment in applying them.

In the beginning, randomized clinical trials were designed to move the observations made at the bench and from small clinical studies to the community at large.

One example of this transition was the Beta-Blocker Heart Attack Trial, which evolved from positive observations in small clinical studies of 100 patients or less. Because of intense skepticism, recruitment was difficult since many felt that β-blockers were dangerous. The positive benefit reported in 1982 was a surprise to everyone, including the investigators. Even though the results were replicated by at least two other RCTs, the incorporation of β-blocker therapy in post-MI patients took more than a decade to gain traction in contemporary therapy. It was difficult to get the ear of the practicing physician, but no one ever thought that one day physicians would be forced, much less given a bonus, to prescribe β-blockers after an MI.

Concern about the inconsistency of the application of beneficial therapy and in the desire to insure that every American was appropriately treated, guidelines based on RCTs were created to help physicians make the best therapeutic choices. Largely as a result of ACC/AHA guideline, β-blockers became accepted therapy following an acute myocardial infarction. From an average use of 30% in the 1990s, utilization rates began to climb 65% by the beginning of this century. Physician education was the mechanism by which this advance occurred. β-Blocker utilization became an important quality measure advanced by a variety of private and federal insurers. Now utilization rates approach 80%–85% of patients discharged after an MI, and the percent of patients receiving β-blocker therapy became part of the well-publicized quality standards that measure the performance of hospitals and clinics nationwide.

RCTs became the foundation of what is now called evidence-based medicine. We are bombarded by RCTs supporting the use of a plethora of drugs and devices that improve the lives of cardiac patients. It no longer takes a decade to incorporate these therapies into clinical practice; they are now certified within months. Guidelines committees that at one time met every 2–3 years are now in almost continuous session.

Now in the interest of uniformity, education is no longer regarded as sufficient to influence physicians, but economic incentives are proposed to prevent variation, the enemy of the “quality gurus,” in order to ensure uniformity. Physicians and their representatives are now considering accepting payment incentives in order to achieve uniformity and expedite adherence to evidence-based medicine. Variation in the application of these guidelines will lead to financial penalties.

Much of this is motivated by the idea that by achieving uniformity of care, health care costs will decrease at a time when almost 45 million Americans do not have health insurance to pay for it. In an era in which postgraduate medical education is funded largely by the pharmaceutical industry, education is no longer important. Financial incentives are the only answer to compliance. Something just doesn't sound right. Is it really no longer possible to educate physicians about how to treat their patients?

In the beginning, randomized clinical trials were designed to move the observations made at the bench and from small clinical studies to the community at large.

One example of this transition was the Beta-Blocker Heart Attack Trial, which evolved from positive observations in small clinical studies of 100 patients or less. Because of intense skepticism, recruitment was difficult since many felt that β-blockers were dangerous. The positive benefit reported in 1982 was a surprise to everyone, including the investigators. Even though the results were replicated by at least two other RCTs, the incorporation of β-blocker therapy in post-MI patients took more than a decade to gain traction in contemporary therapy. It was difficult to get the ear of the practicing physician, but no one ever thought that one day physicians would be forced, much less given a bonus, to prescribe β-blockers after an MI.

Concern about the inconsistency of the application of beneficial therapy and in the desire to insure that every American was appropriately treated, guidelines based on RCTs were created to help physicians make the best therapeutic choices. Largely as a result of ACC/AHA guideline, β-blockers became accepted therapy following an acute myocardial infarction. From an average use of 30% in the 1990s, utilization rates began to climb 65% by the beginning of this century. Physician education was the mechanism by which this advance occurred. β-Blocker utilization became an important quality measure advanced by a variety of private and federal insurers. Now utilization rates approach 80%–85% of patients discharged after an MI, and the percent of patients receiving β-blocker therapy became part of the well-publicized quality standards that measure the performance of hospitals and clinics nationwide.

RCTs became the foundation of what is now called evidence-based medicine. We are bombarded by RCTs supporting the use of a plethora of drugs and devices that improve the lives of cardiac patients. It no longer takes a decade to incorporate these therapies into clinical practice; they are now certified within months. Guidelines committees that at one time met every 2–3 years are now in almost continuous session.

Now in the interest of uniformity, education is no longer regarded as sufficient to influence physicians, but economic incentives are proposed to prevent variation, the enemy of the “quality gurus,” in order to ensure uniformity. Physicians and their representatives are now considering accepting payment incentives in order to achieve uniformity and expedite adherence to evidence-based medicine. Variation in the application of these guidelines will lead to financial penalties.

Much of this is motivated by the idea that by achieving uniformity of care, health care costs will decrease at a time when almost 45 million Americans do not have health insurance to pay for it. In an era in which postgraduate medical education is funded largely by the pharmaceutical industry, education is no longer important. Financial incentives are the only answer to compliance. Something just doesn't sound right. Is it really no longer possible to educate physicians about how to treat their patients?

In the beginning, randomized clinical trials were designed to move the observations made at the bench and from small clinical studies to the community at large.

One example of this transition was the Beta-Blocker Heart Attack Trial, which evolved from positive observations in small clinical studies of 100 patients or less. Because of intense skepticism, recruitment was difficult since many felt that β-blockers were dangerous. The positive benefit reported in 1982 was a surprise to everyone, including the investigators. Even though the results were replicated by at least two other RCTs, the incorporation of β-blocker therapy in post-MI patients took more than a decade to gain traction in contemporary therapy. It was difficult to get the ear of the practicing physician, but no one ever thought that one day physicians would be forced, much less given a bonus, to prescribe β-blockers after an MI.

Concern about the inconsistency of the application of beneficial therapy and in the desire to insure that every American was appropriately treated, guidelines based on RCTs were created to help physicians make the best therapeutic choices. Largely as a result of ACC/AHA guideline, β-blockers became accepted therapy following an acute myocardial infarction. From an average use of 30% in the 1990s, utilization rates began to climb 65% by the beginning of this century. Physician education was the mechanism by which this advance occurred. β-Blocker utilization became an important quality measure advanced by a variety of private and federal insurers. Now utilization rates approach 80%–85% of patients discharged after an MI, and the percent of patients receiving β-blocker therapy became part of the well-publicized quality standards that measure the performance of hospitals and clinics nationwide.

RCTs became the foundation of what is now called evidence-based medicine. We are bombarded by RCTs supporting the use of a plethora of drugs and devices that improve the lives of cardiac patients. It no longer takes a decade to incorporate these therapies into clinical practice; they are now certified within months. Guidelines committees that at one time met every 2–3 years are now in almost continuous session.

Now in the interest of uniformity, education is no longer regarded as sufficient to influence physicians, but economic incentives are proposed to prevent variation, the enemy of the “quality gurus,” in order to ensure uniformity. Physicians and their representatives are now considering accepting payment incentives in order to achieve uniformity and expedite adherence to evidence-based medicine. Variation in the application of these guidelines will lead to financial penalties.

Much of this is motivated by the idea that by achieving uniformity of care, health care costs will decrease at a time when almost 45 million Americans do not have health insurance to pay for it. In an era in which postgraduate medical education is funded largely by the pharmaceutical industry, education is no longer important. Financial incentives are the only answer to compliance. Something just doesn't sound right. Is it really no longer possible to educate physicians about how to treat their patients?

The recalls of Vioxx and implantable cardioverter defibrillators have beset the cardiology community with a cloud of uncertainty on how to advise our patients in a variety of areas.

Any patient who is the least bit aware of current events and has an ICD or has been taking Vioxx (rofecoxib) knows of the dangers they face. Some are grateful that they “dodged the bullet” before they stopped taking the pill. Others will have to make more complex decisions about the removal of an ICD.

Drug and device recalls are not new to cardiology. In the 1980s and 1990s, several “magic” antiarrhythmic drugs were recalled after they were shown to be proarrhythmic. Even now, there are patients with Björk-Shiley aortic valves in place who remain under radiologic surveillance to ensure the integrity of the faulty devices.

What has changed is the magnitude of the problem, as well as public awareness of the issues. Drugs advertised on television as a panacea for pain have now been shown to cause heart attacks, and devices presumed to prevent sudden cardiac death can fail.

People have been led to believe that there is no downside to therapy. Even though we have no data on the long-term benefits and safety of many devices or drugs, patients and doctors have ignored long-term risks. Those who raised caution flags were dismissed as “nattering nabobs” of nonconformity. The Food and Drug Administration has relied on the pharmaceutical manufacturers and device makers to disclose negative information about their products. Such naiveté hardly befits a governmental agency charged with such an important safety role.

What should we expect from regulatory agencies and the pharmaceutical and device industry to assure us that products are safe? Transparency, at the least. We should be able to see within the industrial databases in order to understand what is going on. We also need to have simpler surveillance procedures, so that we understand the issues. It is clear that, as reported widely in the press, Guidant erred greatly when it continued to sell a product it knew was defective and that Merck was less than forthcoming about Vioxx. It is also disingenuous of both physicians and industry to recommend that patients make their own decisions. It is equally mindless to suggest that physicians decide which of their patients—whom they have already defined as being at high risk of sudden death and in need of an ICD—are at the highest risk when advising device replacement.

It is just possible that patients and physicians will learn that there is no free lunch and that all devices and drugs carry some degree of risk. Beyond the immediate risks of implantation in high-risk patients, adverse effects may take years to emerge.

In the meantime, it is imperative that the FDA and the Centers for Medicare and Medicaid Services establish surveillance procedures and registries that will ensure the safety of the products being implanted and ingested. Clinical trials, on which we rely for safety and efficacy data, often are too short and frequently are conducted in populations too small and specific to determine safety in a larger and more heterogeneous population over a lifetime of therapy.

The recalls of Vioxx and implantable cardioverter defibrillators have beset the cardiology community with a cloud of uncertainty on how to advise our patients in a variety of areas.

Any patient who is the least bit aware of current events and has an ICD or has been taking Vioxx (rofecoxib) knows of the dangers they face. Some are grateful that they “dodged the bullet” before they stopped taking the pill. Others will have to make more complex decisions about the removal of an ICD.

Drug and device recalls are not new to cardiology. In the 1980s and 1990s, several “magic” antiarrhythmic drugs were recalled after they were shown to be proarrhythmic. Even now, there are patients with Björk-Shiley aortic valves in place who remain under radiologic surveillance to ensure the integrity of the faulty devices.

What has changed is the magnitude of the problem, as well as public awareness of the issues. Drugs advertised on television as a panacea for pain have now been shown to cause heart attacks, and devices presumed to prevent sudden cardiac death can fail.

People have been led to believe that there is no downside to therapy. Even though we have no data on the long-term benefits and safety of many devices or drugs, patients and doctors have ignored long-term risks. Those who raised caution flags were dismissed as “nattering nabobs” of nonconformity. The Food and Drug Administration has relied on the pharmaceutical manufacturers and device makers to disclose negative information about their products. Such naiveté hardly befits a governmental agency charged with such an important safety role.

What should we expect from regulatory agencies and the pharmaceutical and device industry to assure us that products are safe? Transparency, at the least. We should be able to see within the industrial databases in order to understand what is going on. We also need to have simpler surveillance procedures, so that we understand the issues. It is clear that, as reported widely in the press, Guidant erred greatly when it continued to sell a product it knew was defective and that Merck was less than forthcoming about Vioxx. It is also disingenuous of both physicians and industry to recommend that patients make their own decisions. It is equally mindless to suggest that physicians decide which of their patients—whom they have already defined as being at high risk of sudden death and in need of an ICD—are at the highest risk when advising device replacement.

It is just possible that patients and physicians will learn that there is no free lunch and that all devices and drugs carry some degree of risk. Beyond the immediate risks of implantation in high-risk patients, adverse effects may take years to emerge.

In the meantime, it is imperative that the FDA and the Centers for Medicare and Medicaid Services establish surveillance procedures and registries that will ensure the safety of the products being implanted and ingested. Clinical trials, on which we rely for safety and efficacy data, often are too short and frequently are conducted in populations too small and specific to determine safety in a larger and more heterogeneous population over a lifetime of therapy.

The recalls of Vioxx and implantable cardioverter defibrillators have beset the cardiology community with a cloud of uncertainty on how to advise our patients in a variety of areas.

Any patient who is the least bit aware of current events and has an ICD or has been taking Vioxx (rofecoxib) knows of the dangers they face. Some are grateful that they “dodged the bullet” before they stopped taking the pill. Others will have to make more complex decisions about the removal of an ICD.

Drug and device recalls are not new to cardiology. In the 1980s and 1990s, several “magic” antiarrhythmic drugs were recalled after they were shown to be proarrhythmic. Even now, there are patients with Björk-Shiley aortic valves in place who remain under radiologic surveillance to ensure the integrity of the faulty devices.

What has changed is the magnitude of the problem, as well as public awareness of the issues. Drugs advertised on television as a panacea for pain have now been shown to cause heart attacks, and devices presumed to prevent sudden cardiac death can fail.

People have been led to believe that there is no downside to therapy. Even though we have no data on the long-term benefits and safety of many devices or drugs, patients and doctors have ignored long-term risks. Those who raised caution flags were dismissed as “nattering nabobs” of nonconformity. The Food and Drug Administration has relied on the pharmaceutical manufacturers and device makers to disclose negative information about their products. Such naiveté hardly befits a governmental agency charged with such an important safety role.

What should we expect from regulatory agencies and the pharmaceutical and device industry to assure us that products are safe? Transparency, at the least. We should be able to see within the industrial databases in order to understand what is going on. We also need to have simpler surveillance procedures, so that we understand the issues. It is clear that, as reported widely in the press, Guidant erred greatly when it continued to sell a product it knew was defective and that Merck was less than forthcoming about Vioxx. It is also disingenuous of both physicians and industry to recommend that patients make their own decisions. It is equally mindless to suggest that physicians decide which of their patients—whom they have already defined as being at high risk of sudden death and in need of an ICD—are at the highest risk when advising device replacement.

It is just possible that patients and physicians will learn that there is no free lunch and that all devices and drugs carry some degree of risk. Beyond the immediate risks of implantation in high-risk patients, adverse effects may take years to emerge.

In the meantime, it is imperative that the FDA and the Centers for Medicare and Medicaid Services establish surveillance procedures and registries that will ensure the safety of the products being implanted and ingested. Clinical trials, on which we rely for safety and efficacy data, often are too short and frequently are conducted in populations too small and specific to determine safety in a larger and more heterogeneous population over a lifetime of therapy.

With the approval of BiDil for the treatment of heart failure in African Americans, the Food and Drug Administration has essentially excluded the use of this combination of isosorbide dinitrate and hydralazine in non-African Americans.

In the African-American Heart Failure Trial (A-HeFT), BiDil decreased mortality in 1,050 exclusively African American patients with New York Heart Association class III and IV heart failure randomized to the drug or a placebo. Most impressively, this benefit occurred in the presence of concomitant therapy with ACE inhibitors and β-blockers within 10 months (N. Engl. J. Med. 2004;351:2049–57).

A major question remains whether this approval should indicate that its use be limited to African American patients only or extended also to all patients. Now that it is approved, it will almost certainly be used in heart failure patients regardless of race. The two drugs are readily available as generic preparations in any pharmacy.

Much has been made of the observation that the antihypertensive effects of ACE inhibitors are less in African Americans than in whites. In addition, the mortality benefit observed in African Americans, compared with whites, in the Vasodilator Heart Failure Trial (V-HeFT I) provides additional foundation for A-HeFT. If a differential blood pressure response was the cause of improved response in A-HeFT, there is little evidence for that. Very minimal decreases of systolic (0.7 mm Hg) and diastolic (1.6 mm Hg) pressure in diastole were seen in the BiDil-treated patients.

It has been suggested that the benefit of BiDil may be related to the antioxidant effect of hydralazine. This theory is supported in part by observation that African Americans may be deficient in nitric oxide, a major source of oxidant metabolism. A lack of nitric oxide at the cellular level as a result of a decrease in endothelial nitric oxide synthase (eNOS) is thought to be a potential putative process of heart failure. If African Americans with heart failure were more deficient in eNOS, they could be more likely to benefit from chronic therapy with BiDil. However, if not, one would expect the effect to be the same, regardless of race.

Some aspects of the therapy are puzzling. The drug was rather poorly tolerated, with only 68% of the BiDil patients staying on the drug, compared with 89% in the placebo group during the 10 months of follow-up. Much of this was presumably due to headache and dizziness, which occurred in 48% and 29% of the patients, respectively. In addition, long-term hydralazine use has been reported to result in a lupus-like syndrome with arthritis at doses greater than 200 mg/day, particularly in patients with renal dysfunction. The dose used in A-HeFT was 225 mg/day. Unfortunately, the duration A-HeFT was short, owing to its observed benefit.

The A-HeFT findings provide a new approach to treating heart failure, regardless of race. If the antioxidant hypothesis is correct, its application should not be limited to African Americans. Given that previous clinical trials in heart failure—which, unfortunately, have been dominated by whites—have been applied to all heart failure patients, regardless of race, it is reasonable that the results in A-HeFT should also be applied to all heart failure patients.

With the approval of BiDil for the treatment of heart failure in African Americans, the Food and Drug Administration has essentially excluded the use of this combination of isosorbide dinitrate and hydralazine in non-African Americans.

In the African-American Heart Failure Trial (A-HeFT), BiDil decreased mortality in 1,050 exclusively African American patients with New York Heart Association class III and IV heart failure randomized to the drug or a placebo. Most impressively, this benefit occurred in the presence of concomitant therapy with ACE inhibitors and β-blockers within 10 months (N. Engl. J. Med. 2004;351:2049–57).

A major question remains whether this approval should indicate that its use be limited to African American patients only or extended also to all patients. Now that it is approved, it will almost certainly be used in heart failure patients regardless of race. The two drugs are readily available as generic preparations in any pharmacy.

Much has been made of the observation that the antihypertensive effects of ACE inhibitors are less in African Americans than in whites. In addition, the mortality benefit observed in African Americans, compared with whites, in the Vasodilator Heart Failure Trial (V-HeFT I) provides additional foundation for A-HeFT. If a differential blood pressure response was the cause of improved response in A-HeFT, there is little evidence for that. Very minimal decreases of systolic (0.7 mm Hg) and diastolic (1.6 mm Hg) pressure in diastole were seen in the BiDil-treated patients.

It has been suggested that the benefit of BiDil may be related to the antioxidant effect of hydralazine. This theory is supported in part by observation that African Americans may be deficient in nitric oxide, a major source of oxidant metabolism. A lack of nitric oxide at the cellular level as a result of a decrease in endothelial nitric oxide synthase (eNOS) is thought to be a potential putative process of heart failure. If African Americans with heart failure were more deficient in eNOS, they could be more likely to benefit from chronic therapy with BiDil. However, if not, one would expect the effect to be the same, regardless of race.

Some aspects of the therapy are puzzling. The drug was rather poorly tolerated, with only 68% of the BiDil patients staying on the drug, compared with 89% in the placebo group during the 10 months of follow-up. Much of this was presumably due to headache and dizziness, which occurred in 48% and 29% of the patients, respectively. In addition, long-term hydralazine use has been reported to result in a lupus-like syndrome with arthritis at doses greater than 200 mg/day, particularly in patients with renal dysfunction. The dose used in A-HeFT was 225 mg/day. Unfortunately, the duration A-HeFT was short, owing to its observed benefit.

The A-HeFT findings provide a new approach to treating heart failure, regardless of race. If the antioxidant hypothesis is correct, its application should not be limited to African Americans. Given that previous clinical trials in heart failure—which, unfortunately, have been dominated by whites—have been applied to all heart failure patients, regardless of race, it is reasonable that the results in A-HeFT should also be applied to all heart failure patients.

With the approval of BiDil for the treatment of heart failure in African Americans, the Food and Drug Administration has essentially excluded the use of this combination of isosorbide dinitrate and hydralazine in non-African Americans.

In the African-American Heart Failure Trial (A-HeFT), BiDil decreased mortality in 1,050 exclusively African American patients with New York Heart Association class III and IV heart failure randomized to the drug or a placebo. Most impressively, this benefit occurred in the presence of concomitant therapy with ACE inhibitors and β-blockers within 10 months (N. Engl. J. Med. 2004;351:2049–57).

A major question remains whether this approval should indicate that its use be limited to African American patients only or extended also to all patients. Now that it is approved, it will almost certainly be used in heart failure patients regardless of race. The two drugs are readily available as generic preparations in any pharmacy.

Much has been made of the observation that the antihypertensive effects of ACE inhibitors are less in African Americans than in whites. In addition, the mortality benefit observed in African Americans, compared with whites, in the Vasodilator Heart Failure Trial (V-HeFT I) provides additional foundation for A-HeFT. If a differential blood pressure response was the cause of improved response in A-HeFT, there is little evidence for that. Very minimal decreases of systolic (0.7 mm Hg) and diastolic (1.6 mm Hg) pressure in diastole were seen in the BiDil-treated patients.

It has been suggested that the benefit of BiDil may be related to the antioxidant effect of hydralazine. This theory is supported in part by observation that African Americans may be deficient in nitric oxide, a major source of oxidant metabolism. A lack of nitric oxide at the cellular level as a result of a decrease in endothelial nitric oxide synthase (eNOS) is thought to be a potential putative process of heart failure. If African Americans with heart failure were more deficient in eNOS, they could be more likely to benefit from chronic therapy with BiDil. However, if not, one would expect the effect to be the same, regardless of race.

Some aspects of the therapy are puzzling. The drug was rather poorly tolerated, with only 68% of the BiDil patients staying on the drug, compared with 89% in the placebo group during the 10 months of follow-up. Much of this was presumably due to headache and dizziness, which occurred in 48% and 29% of the patients, respectively. In addition, long-term hydralazine use has been reported to result in a lupus-like syndrome with arthritis at doses greater than 200 mg/day, particularly in patients with renal dysfunction. The dose used in A-HeFT was 225 mg/day. Unfortunately, the duration A-HeFT was short, owing to its observed benefit.

The A-HeFT findings provide a new approach to treating heart failure, regardless of race. If the antioxidant hypothesis is correct, its application should not be limited to African Americans. Given that previous clinical trials in heart failure—which, unfortunately, have been dominated by whites—have been applied to all heart failure patients, regardless of race, it is reasonable that the results in A-HeFT should also be applied to all heart failure patients.

There was a time when one could almost explain what a cardiologist does. But things are changing. The boundaries of professional performance and competence are expanding and becoming increasingly blurred.

The traditional domain of the interventional cardiologist has been expanded to include the carotid artery and peripheral vessels. If we can dilate and stent a coronary artery, why not do the same to the carotid or femoral artery? The improvement in imaging also has led to the cardiologists invading areas traditionally assigned to radiologists. And in a very short period of time we have challenged the turf of many of our colleagues in vascular, cardiac, and neurologic surgery.

Many of these changes are driven by new technologies that have expanded the clinical parameters of skilled physicians. They also have occurred as a result of the dynamic changes in therapy that have evolved at the same time. The urgency for care and the desire for cardiovascular “one-stop” therapy have made accessibility an important driving force. If you saw a tight iliac lesion as you passed a catheter toward the coronary artery in a patient with claudication, wouldn't you take care of it?

The shifting of therapeutic boundaries also has occurred within cardiology as we see the transfer of clinical responsibility from the electrophysiologists to the general cardiologists for pacemaker and defibrillator implantation to meet the increased demand for these devices. We may even see cardiac surgeons implanting these devices as they did in years past as they find time on their hands.

As the parameters of cardiology expand, it is becoming clear that we are unable to meet the demands for our core clinical services. Emergency and internal medicine physicians, who can now be trained and certified in echocardiography, play a large role in providing echocardiographic services. This has occurred as a result of the availability of inexpensive and portable echocardiograph equipment. The need for heart failure care has led to the training of internal medicine physicians outside of the cardiology fellowship tract in this field.

These unrestrained movements are reflected in cardiology training programs. Young physicians who wish to become cardiologists are limited by the scarcity of training positions. Many trainees find that the programs are inflexible, making it impossible to concentrate in certain areas of interest. Significant changes in training programs must be made to address the needs of trainees who wish to pursue training exclusive of interventional procedures. Every cardiologist does not need to know how to push a catheter. In fact, pushing a catheter may become a lost art as MRI and CT technologies advance.

The direction of patient care will remain with the physician who provides the care. For the most part, the treatment of cardiovascular disease in the broadest sense remains in the hands of the cardiologist. It is the cardiologist who answers the call at 3 in the morning. No one is going to call the neighborhood radiologist for chest pain or the neurosurgeon for syncope. The cardiology community must ensure the availability of a sufficient number of cardiologists for the future. It will also need to provide more flexibility in training to provide the diversity of services for the 21st century.

There was a time when one could almost explain what a cardiologist does. But things are changing. The boundaries of professional performance and competence are expanding and becoming increasingly blurred.

The traditional domain of the interventional cardiologist has been expanded to include the carotid artery and peripheral vessels. If we can dilate and stent a coronary artery, why not do the same to the carotid or femoral artery? The improvement in imaging also has led to the cardiologists invading areas traditionally assigned to radiologists. And in a very short period of time we have challenged the turf of many of our colleagues in vascular, cardiac, and neurologic surgery.

Many of these changes are driven by new technologies that have expanded the clinical parameters of skilled physicians. They also have occurred as a result of the dynamic changes in therapy that have evolved at the same time. The urgency for care and the desire for cardiovascular “one-stop” therapy have made accessibility an important driving force. If you saw a tight iliac lesion as you passed a catheter toward the coronary artery in a patient with claudication, wouldn't you take care of it?

The shifting of therapeutic boundaries also has occurred within cardiology as we see the transfer of clinical responsibility from the electrophysiologists to the general cardiologists for pacemaker and defibrillator implantation to meet the increased demand for these devices. We may even see cardiac surgeons implanting these devices as they did in years past as they find time on their hands.

As the parameters of cardiology expand, it is becoming clear that we are unable to meet the demands for our core clinical services. Emergency and internal medicine physicians, who can now be trained and certified in echocardiography, play a large role in providing echocardiographic services. This has occurred as a result of the availability of inexpensive and portable echocardiograph equipment. The need for heart failure care has led to the training of internal medicine physicians outside of the cardiology fellowship tract in this field.

These unrestrained movements are reflected in cardiology training programs. Young physicians who wish to become cardiologists are limited by the scarcity of training positions. Many trainees find that the programs are inflexible, making it impossible to concentrate in certain areas of interest. Significant changes in training programs must be made to address the needs of trainees who wish to pursue training exclusive of interventional procedures. Every cardiologist does not need to know how to push a catheter. In fact, pushing a catheter may become a lost art as MRI and CT technologies advance.

The direction of patient care will remain with the physician who provides the care. For the most part, the treatment of cardiovascular disease in the broadest sense remains in the hands of the cardiologist. It is the cardiologist who answers the call at 3 in the morning. No one is going to call the neighborhood radiologist for chest pain or the neurosurgeon for syncope. The cardiology community must ensure the availability of a sufficient number of cardiologists for the future. It will also need to provide more flexibility in training to provide the diversity of services for the 21st century.

There was a time when one could almost explain what a cardiologist does. But things are changing. The boundaries of professional performance and competence are expanding and becoming increasingly blurred.

The traditional domain of the interventional cardiologist has been expanded to include the carotid artery and peripheral vessels. If we can dilate and stent a coronary artery, why not do the same to the carotid or femoral artery? The improvement in imaging also has led to the cardiologists invading areas traditionally assigned to radiologists. And in a very short period of time we have challenged the turf of many of our colleagues in vascular, cardiac, and neurologic surgery.

Many of these changes are driven by new technologies that have expanded the clinical parameters of skilled physicians. They also have occurred as a result of the dynamic changes in therapy that have evolved at the same time. The urgency for care and the desire for cardiovascular “one-stop” therapy have made accessibility an important driving force. If you saw a tight iliac lesion as you passed a catheter toward the coronary artery in a patient with claudication, wouldn't you take care of it?

The shifting of therapeutic boundaries also has occurred within cardiology as we see the transfer of clinical responsibility from the electrophysiologists to the general cardiologists for pacemaker and defibrillator implantation to meet the increased demand for these devices. We may even see cardiac surgeons implanting these devices as they did in years past as they find time on their hands.

As the parameters of cardiology expand, it is becoming clear that we are unable to meet the demands for our core clinical services. Emergency and internal medicine physicians, who can now be trained and certified in echocardiography, play a large role in providing echocardiographic services. This has occurred as a result of the availability of inexpensive and portable echocardiograph equipment. The need for heart failure care has led to the training of internal medicine physicians outside of the cardiology fellowship tract in this field.

These unrestrained movements are reflected in cardiology training programs. Young physicians who wish to become cardiologists are limited by the scarcity of training positions. Many trainees find that the programs are inflexible, making it impossible to concentrate in certain areas of interest. Significant changes in training programs must be made to address the needs of trainees who wish to pursue training exclusive of interventional procedures. Every cardiologist does not need to know how to push a catheter. In fact, pushing a catheter may become a lost art as MRI and CT technologies advance.

The direction of patient care will remain with the physician who provides the care. For the most part, the treatment of cardiovascular disease in the broadest sense remains in the hands of the cardiologist. It is the cardiologist who answers the call at 3 in the morning. No one is going to call the neighborhood radiologist for chest pain or the neurosurgeon for syncope. The cardiology community must ensure the availability of a sufficient number of cardiologists for the future. It will also need to provide more flexibility in training to provide the diversity of services for the 21st century.

Randomized clinical trials have had an immense effect on the practice of medicine. However, in order to answer the questions posed in such trials, relevant and sufficient patient populations and treatments must be identified.

Large RCTs, or megatrials, can identify small differences in populations but tend to exaggerate their significance. Several megatrials have questionable relevance to clinical care.

The recent COMMIT/CCS-2 study examined the role of early intravenous metoprolol in nearly 46,000 Chinese patients with Killip class I-III ST-segment-elevation MI (STEMI). But in contrast to U.S. treatment practices, fibrinolysis was common and percutaneous coronary intervention (PCI) was uncommon. In addition, the trial design included intravenous metoprolol for patients with Killip class III with heart failure, a treatment that many U.S. physicians would have been reluctant to give. The data indicated that this reluctance was well founded. Metoprolol caused an increase in death due to shock and heart failure in the Killip class III patients, which counterbalanced the decrease in arrhythmic deaths observed in the Killip I and II patients. Overall, there was no benefit associated with intravenous metoprolol in STEMI patients.

The GUSTO I trial, reported in 1993, randomized 41,021 patients with STEMI to compare the benefit of thrombolysis with streptokinase with accelerated tissue plasminogen activator (TPA), both combined with intravenous heparin. The 30-day mortality was 7.4% in streptokinase-treated patients and 6.3% in TPA patients. Despite this meager absolute difference of 1.1% (P = .001) and in the face of increased hemorrhagic strokes in the TPA-treated patients (P = .03), TPA, at a cost 10 times that of streptokinase, became the U.S. standard of therapy, while streptokinase remains the most common thrombolytic therapy in the rest of the world.

The HOPE trial enrolled 9,297 patients to test the benefit of the ACE inhibitor ramipril in patients at a high risk of CAD on the composite end point of ischemic events including death. In 2000, after 5 years of follow-up, the event rates were 17.8% in the placebo group and 14.0% in the ramipril group (P < .001). These results led to the rapid inclusion of ACE inhibitor therapy in any patients with or at risk of CAD. But meanwhile, another RCT, PEACE, had enrolled 8,290 similar patients to test the benefit of the ACE inhibitor trandolapril in patients who were being treated with β-blockers, statins, and PCI. PEACE reported its findings in 2004 and found no benefit of ACE inhibitors, largely due the more aggressive concomitant therapy, which resulted in a lower placebo event rate. In just a few short years, therapy had changed so rapidly that ACE inhibitors no longer appeared to have an impact on the outcome in patients at risk of ischemic events. In retrospect, HOPE was dated even before it was reported.

RCTs continue to impact on our bedside decisions. These experiences with megatrials, however, give reason to be critical of their importance in the care of our patients. It is best to remember that today's scientific “truths” may be shown to be “false” tomorrow.

Randomized clinical trials have had an immense effect on the practice of medicine. However, in order to answer the questions posed in such trials, relevant and sufficient patient populations and treatments must be identified.

Large RCTs, or megatrials, can identify small differences in populations but tend to exaggerate their significance. Several megatrials have questionable relevance to clinical care.

The recent COMMIT/CCS-2 study examined the role of early intravenous metoprolol in nearly 46,000 Chinese patients with Killip class I-III ST-segment-elevation MI (STEMI). But in contrast to U.S. treatment practices, fibrinolysis was common and percutaneous coronary intervention (PCI) was uncommon. In addition, the trial design included intravenous metoprolol for patients with Killip class III with heart failure, a treatment that many U.S. physicians would have been reluctant to give. The data indicated that this reluctance was well founded. Metoprolol caused an increase in death due to shock and heart failure in the Killip class III patients, which counterbalanced the decrease in arrhythmic deaths observed in the Killip I and II patients. Overall, there was no benefit associated with intravenous metoprolol in STEMI patients.

The GUSTO I trial, reported in 1993, randomized 41,021 patients with STEMI to compare the benefit of thrombolysis with streptokinase with accelerated tissue plasminogen activator (TPA), both combined with intravenous heparin. The 30-day mortality was 7.4% in streptokinase-treated patients and 6.3% in TPA patients. Despite this meager absolute difference of 1.1% (P = .001) and in the face of increased hemorrhagic strokes in the TPA-treated patients (P = .03), TPA, at a cost 10 times that of streptokinase, became the U.S. standard of therapy, while streptokinase remains the most common thrombolytic therapy in the rest of the world.

The HOPE trial enrolled 9,297 patients to test the benefit of the ACE inhibitor ramipril in patients at a high risk of CAD on the composite end point of ischemic events including death. In 2000, after 5 years of follow-up, the event rates were 17.8% in the placebo group and 14.0% in the ramipril group (P < .001). These results led to the rapid inclusion of ACE inhibitor therapy in any patients with or at risk of CAD. But meanwhile, another RCT, PEACE, had enrolled 8,290 similar patients to test the benefit of the ACE inhibitor trandolapril in patients who were being treated with β-blockers, statins, and PCI. PEACE reported its findings in 2004 and found no benefit of ACE inhibitors, largely due the more aggressive concomitant therapy, which resulted in a lower placebo event rate. In just a few short years, therapy had changed so rapidly that ACE inhibitors no longer appeared to have an impact on the outcome in patients at risk of ischemic events. In retrospect, HOPE was dated even before it was reported.

RCTs continue to impact on our bedside decisions. These experiences with megatrials, however, give reason to be critical of their importance in the care of our patients. It is best to remember that today's scientific “truths” may be shown to be “false” tomorrow.

Randomized clinical trials have had an immense effect on the practice of medicine. However, in order to answer the questions posed in such trials, relevant and sufficient patient populations and treatments must be identified.

Large RCTs, or megatrials, can identify small differences in populations but tend to exaggerate their significance. Several megatrials have questionable relevance to clinical care.

The recent COMMIT/CCS-2 study examined the role of early intravenous metoprolol in nearly 46,000 Chinese patients with Killip class I-III ST-segment-elevation MI (STEMI). But in contrast to U.S. treatment practices, fibrinolysis was common and percutaneous coronary intervention (PCI) was uncommon. In addition, the trial design included intravenous metoprolol for patients with Killip class III with heart failure, a treatment that many U.S. physicians would have been reluctant to give. The data indicated that this reluctance was well founded. Metoprolol caused an increase in death due to shock and heart failure in the Killip class III patients, which counterbalanced the decrease in arrhythmic deaths observed in the Killip I and II patients. Overall, there was no benefit associated with intravenous metoprolol in STEMI patients.

The GUSTO I trial, reported in 1993, randomized 41,021 patients with STEMI to compare the benefit of thrombolysis with streptokinase with accelerated tissue plasminogen activator (TPA), both combined with intravenous heparin. The 30-day mortality was 7.4% in streptokinase-treated patients and 6.3% in TPA patients. Despite this meager absolute difference of 1.1% (P = .001) and in the face of increased hemorrhagic strokes in the TPA-treated patients (P = .03), TPA, at a cost 10 times that of streptokinase, became the U.S. standard of therapy, while streptokinase remains the most common thrombolytic therapy in the rest of the world.

The HOPE trial enrolled 9,297 patients to test the benefit of the ACE inhibitor ramipril in patients at a high risk of CAD on the composite end point of ischemic events including death. In 2000, after 5 years of follow-up, the event rates were 17.8% in the placebo group and 14.0% in the ramipril group (P < .001). These results led to the rapid inclusion of ACE inhibitor therapy in any patients with or at risk of CAD. But meanwhile, another RCT, PEACE, had enrolled 8,290 similar patients to test the benefit of the ACE inhibitor trandolapril in patients who were being treated with β-blockers, statins, and PCI. PEACE reported its findings in 2004 and found no benefit of ACE inhibitors, largely due the more aggressive concomitant therapy, which resulted in a lower placebo event rate. In just a few short years, therapy had changed so rapidly that ACE inhibitors no longer appeared to have an impact on the outcome in patients at risk of ischemic events. In retrospect, HOPE was dated even before it was reported.

RCTs continue to impact on our bedside decisions. These experiences with megatrials, however, give reason to be critical of their importance in the care of our patients. It is best to remember that today's scientific “truths” may be shown to be “false” tomorrow.