Editorial

The article by Hagerty and Rich in this issue of the Cleveland Clinic Journal of Medicine¹ covers an important topic—whether elderly patients with atrial fibrillation should receive anticoagulant therapy for it, or whether the risk of bleeding with this therapy outweighs the benefit of preventing stroke.

See related article

BETTER RISK PREDICTORS ARE NEEDED

Prediction tools are available for estimating the risk of stroke in patients with atrial fibrillation without anticoagulation^2,3 and to estimate bleeding risk from anticoagulation^4–7 (Table 1). Both tools have limitations, but as Hagerty and Rich point out, the stroke risk scales are likely better than the bleeding risk scales.

For example, Fang et al⁸ note that the risk of intracranial hemorrhage increases significantly after age 85. The bleeding risk scales use lower age cutoffs than this, perhaps increasing their sensitivity but decreasing their specificity.

Although HAS-BLED^5,6 includes antiplatelet drugs such as nonsteroidal anti-inflammatory drugs and aspirin as risk factors for bleeding, ATRIA⁴ and HEMORR₂HAGES⁷ do not.

Other drugs such as macrolides, quinolones, and high-dose corticosteroids raise the international normalized ratio (INR). These are typically used short-term, but can cause major fluctuations in the INR that may not be detected by monthly INR checks. Incorporating the short-term use of such drugs into bleeding risk scales would be difficult if not impossible a priori. Yet clinicians should be aware that these drugs can affect bleeding risk.

As Hagerty and Rich note,¹ the bleeding risk scores were developed for warfarin, and their applicability to patients treated with novel oral anticoagulants is uncertain.

All three of the available bleeding risk scales consider prior bleeding as a risk factor, but the severity of the prior bleeding varies. Although it is understandable to include major bleeding as a risk factor since it carries an increased risk of death, minor bleeding can affect morbidity and quality of life. Only the ATRIA score⁴ considers both major and minor bleeding, while HEMORR₂HAGES⁷ does not specify bleeding severity, and HAS-BLED^5,6 considers only major bleeding. Clearly, there is a need to update these existing bleeding risk scores so that they can apply to novel oral anticoagulants and consider both major and minor bleeding.

As the authors note, for predicting the risk of stroke, the CHA₂DS₂-VASc score³ provides more precision than the CHADS₂ score² at the lower end of the benefit spectrum. Unfortunately, there is no similar screening tool to predict bleeding risk from anticoagulation with greater precision in the middle to lower part of the risk spectrum.

THE PATIENT’S PREFERENCES MATTER

The patient’s life expectancy and personal preferences are important independent factors that affect the decision of whether to anticoagulate or not. It is the responsibility of clinicians who care for older adults to make sure that these two important considerations are included in any anticoagulation decision-making for this group of patients.

The article by Hagerty and Rich in this issue of the Cleveland Clinic Journal of Medicine¹ covers an important topic—whether elderly patients with atrial fibrillation should receive anticoagulant therapy for it, or whether the risk of bleeding with this therapy outweighs the benefit of preventing stroke.

See related article

BETTER RISK PREDICTORS ARE NEEDED

Prediction tools are available for estimating the risk of stroke in patients with atrial fibrillation without anticoagulation^2,3 and to estimate bleeding risk from anticoagulation^4–7 (Table 1). Both tools have limitations, but as Hagerty and Rich point out, the stroke risk scales are likely better than the bleeding risk scales.

For example, Fang et al⁸ note that the risk of intracranial hemorrhage increases significantly after age 85. The bleeding risk scales use lower age cutoffs than this, perhaps increasing their sensitivity but decreasing their specificity.

Although HAS-BLED^5,6 includes antiplatelet drugs such as nonsteroidal anti-inflammatory drugs and aspirin as risk factors for bleeding, ATRIA⁴ and HEMORR₂HAGES⁷ do not.

Other drugs such as macrolides, quinolones, and high-dose corticosteroids raise the international normalized ratio (INR). These are typically used short-term, but can cause major fluctuations in the INR that may not be detected by monthly INR checks. Incorporating the short-term use of such drugs into bleeding risk scales would be difficult if not impossible a priori. Yet clinicians should be aware that these drugs can affect bleeding risk.

As Hagerty and Rich note,¹ the bleeding risk scores were developed for warfarin, and their applicability to patients treated with novel oral anticoagulants is uncertain.

All three of the available bleeding risk scales consider prior bleeding as a risk factor, but the severity of the prior bleeding varies. Although it is understandable to include major bleeding as a risk factor since it carries an increased risk of death, minor bleeding can affect morbidity and quality of life. Only the ATRIA score⁴ considers both major and minor bleeding, while HEMORR₂HAGES⁷ does not specify bleeding severity, and HAS-BLED^5,6 considers only major bleeding. Clearly, there is a need to update these existing bleeding risk scores so that they can apply to novel oral anticoagulants and consider both major and minor bleeding.

As the authors note, for predicting the risk of stroke, the CHA₂DS₂-VASc score³ provides more precision than the CHADS₂ score² at the lower end of the benefit spectrum. Unfortunately, there is no similar screening tool to predict bleeding risk from anticoagulation with greater precision in the middle to lower part of the risk spectrum.

THE PATIENT’S PREFERENCES MATTER

The patient’s life expectancy and personal preferences are important independent factors that affect the decision of whether to anticoagulate or not. It is the responsibility of clinicians who care for older adults to make sure that these two important considerations are included in any anticoagulation decision-making for this group of patients.

The article by Hagerty and Rich in this issue of the Cleveland Clinic Journal of Medicine¹ covers an important topic—whether elderly patients with atrial fibrillation should receive anticoagulant therapy for it, or whether the risk of bleeding with this therapy outweighs the benefit of preventing stroke.

See related article

BETTER RISK PREDICTORS ARE NEEDED

Prediction tools are available for estimating the risk of stroke in patients with atrial fibrillation without anticoagulation^2,3 and to estimate bleeding risk from anticoagulation^4–7 (Table 1). Both tools have limitations, but as Hagerty and Rich point out, the stroke risk scales are likely better than the bleeding risk scales.

For example, Fang et al⁸ note that the risk of intracranial hemorrhage increases significantly after age 85. The bleeding risk scales use lower age cutoffs than this, perhaps increasing their sensitivity but decreasing their specificity.

Although HAS-BLED^5,6 includes antiplatelet drugs such as nonsteroidal anti-inflammatory drugs and aspirin as risk factors for bleeding, ATRIA⁴ and HEMORR₂HAGES⁷ do not.

Other drugs such as macrolides, quinolones, and high-dose corticosteroids raise the international normalized ratio (INR). These are typically used short-term, but can cause major fluctuations in the INR that may not be detected by monthly INR checks. Incorporating the short-term use of such drugs into bleeding risk scales would be difficult if not impossible a priori. Yet clinicians should be aware that these drugs can affect bleeding risk.

As Hagerty and Rich note,¹ the bleeding risk scores were developed for warfarin, and their applicability to patients treated with novel oral anticoagulants is uncertain.

All three of the available bleeding risk scales consider prior bleeding as a risk factor, but the severity of the prior bleeding varies. Although it is understandable to include major bleeding as a risk factor since it carries an increased risk of death, minor bleeding can affect morbidity and quality of life. Only the ATRIA score⁴ considers both major and minor bleeding, while HEMORR₂HAGES⁷ does not specify bleeding severity, and HAS-BLED^5,6 considers only major bleeding. Clearly, there is a need to update these existing bleeding risk scores so that they can apply to novel oral anticoagulants and consider both major and minor bleeding.

As the authors note, for predicting the risk of stroke, the CHA₂DS₂-VASc score³ provides more precision than the CHADS₂ score² at the lower end of the benefit spectrum. Unfortunately, there is no similar screening tool to predict bleeding risk from anticoagulation with greater precision in the middle to lower part of the risk spectrum.

THE PATIENT’S PREFERENCES MATTER

The patient’s life expectancy and personal preferences are important independent factors that affect the decision of whether to anticoagulate or not. It is the responsibility of clinicians who care for older adults to make sure that these two important considerations are included in any anticoagulation decision-making for this group of patients.

In this issue of the Journal, Ataya et al¹ provide a comprehensive review of thrombolysis in submassive pulmonary embolism, a subject of much debate. In massive pulmonary embolism, thrombolytic therapy is usually indicated²; in submassive pulmonary embolism, the decision is not so clear. Which patients with submassive embolism would benefit from thrombolysis, and which patients require only anticoagulant therapy? The answer lies in finding the balance between the potential benefit of thrombolytic therapy—preventing death or hemodynamic collapse—and the numerically low but potentially catastrophic risk of intracranial bleeding.

See related article

In general, submassive pulmonary embolism refers to an acute pulmonary embolus serious enough to cause evidence of right ventricular dysfunction or necrosis but not hemodynamic instability (ie, with systolic blood pressure > 90 mm Hg) on presentation.³ It accounts for about 25% of cases of pulmonary embolism,^4,5 and perhaps 0.5 to 1% of patients admitted to intensive care units across the country.⁶ The 30-day mortality rate can be as high as 30%, making it a condition that requires prompt identification and appropriate management.

But clinical trials have failed to demonstrate a substantial improvement in mortality rates with thrombolytic therapy in patients with submassive pulmonary embolism, and have shown improvement only in other clinical end points.⁷ Part of the problem is that this is a heterogeneous condition, posing a challenge for the optimal design and interpretation of studies.

WHO IS AT RISK OF DEATH OR DETERIORATION?

If clinicians could ascertain in each patient whether the risk-benefit ratio is favorable for thrombolytic therapy, it would be easier to provide optimal care. This is not a straightforward task, and it requires integration of clinical judgment, high index of suspicion for deterioration, and clinical tools.

One of the challenges is that it is difficult to identify normotensive patients at the highest risk of poor outcomes. Several factors are associated with a higher risk of death within 30 days (Table 1). While each of these has a negative predictive value of about 95% or even higher (meaning that it is very good at predicting who will not die), they all have very low positive predictive values (meaning that none of them, by itself, is very good at predicting who will die).

For this reason, a multimodal approach to risk stratification has emerged. For example, Jiménez et al⁸ showed that normotensive patients with acute pulmonary embolism and a combination of abnormal Simplified Pulmonary Embolism Severity Index, elevated B-type natriuretic peptide level, elevated troponin level, and lower-extremity deep vein thrombosis had a 26% rate of complications (death, hemodynamic collapse, or recurrent pulmonary embolism) within 30 days.

Bova et al⁹ showed that the combination of borderline low systolic blood pressure (90–100 mm Hg), tachycardia (heart rate ≥ 110 beats per minute), elevated troponin, and right ventricular dysfunction by echocardiography or computed tomography allowed for the separation of three groups with significantly different rates of poor outcomes.

WHO IS AT RISK OF BLEEDING?

Estimation of the risk of bleeding is currently less sophisticated, and we need a bleeding score to use in the setting of acute pulmonary embolism. A few studies have shed some light on this issue beyond the known absolute and relative contraindications to thrombolysis.

Ataya et al¹ note a meta-analysis¹⁰ showing that systemic thrombolytic therapy was not associated with an increased risk of major bleeding in patients age 65 or younger. Similarly, a large observational study showed a strong association between the risk of intracerebral hemorrhage and increasing age¹¹ and also identified comorbidities such as kidney disease as risk factors. While the frequently cited Pulmonary Embolism Thrombolysis trial¹² showed a significantly higher risk of stroke with tenecteplase, careful review of its data reveals that all 10 of the 506 patients in the tenecteplase group who sustained a hemorrhagic stroke were age 65 or older.¹²

A TEAM APPROACH

Thus, in patients with acute pulmonary embolism, clinicians face the difficult task of assessing the patient’s risk of death and clinical worsening and balancing that risk against the risk of bleeding, to identify those who may benefit from early reperfusion therapies, including systemic thrombolysis, catheter-directed thrombolysis, mechanical treatment, and surgical embolectomy.

Given the absence of high-quality evidence to guide these decisions, several institutions have developed multidisciplinary pulmonary embolism response teams to provide rapid evaluation and risk stratification and to recommend and implement advanced therapies, as appropriate. This is a novel concept that is still evolving but holds promise, as it integrates the experience and expertise of physicians in multiple specialties, such as pulmonary and critical care medicine, vascular medicine, interventional radiology, interventional cardiology, emergency medicine, and cardiothoracic surgery, who can then fill the currently existing knowledge gaps for clinical care and, possibly, research.¹³

Early published experience has documented the feasibility of this multidisciplinary approach.¹⁴ The first 95 patients treated at  Cleveland Clinic had a 30-day mortality rate of 3.2%, which was lower than the expected 9% rate predicted by the Pulmonary Embolism Severity Index score (unpublished observation).

Figure 1 shows the algorithm currently used by Cleveland Clinic’s pulmonary embolism response team, with the caveat that no algorithm can fully capture the extent of the complexities and discussions that each case triggers within the team.

TOWARD BETTER UNDERSTANDING

As Ataya et al point out,¹ the current state of the evidence does not allow a clear, simplistic, one-size-fits-all approach. A question that arises from this controversial topic is whether we should look for markers of right ventricular dysfunction in every patient admitted with a diagnosis of pulmonary embolism, or only in those with a significant anatomic burden of clot on imaging. Would testing everyone be an appropriate way to identify patients at risk of further deterioration early and therefore prevent adverse outcomes in a timely manner? Or would it not be cost-effective and translate into ordering more diagnostic testing, as well as an increase in downstream workup with higher healthcare costs?

Once we better understand this condition and the factors that predict a higher risk of deterioration, we should be able to design prospective studies that can help elucidate the most appropriate diagnostic and therapeutic approach for such challenging cases. In the meantime, it is important to appraise the evidence in a critical way, as Ataya et al have done in their review.

In this issue of the Journal, Ataya et al¹ provide a comprehensive review of thrombolysis in submassive pulmonary embolism, a subject of much debate. In massive pulmonary embolism, thrombolytic therapy is usually indicated²; in submassive pulmonary embolism, the decision is not so clear. Which patients with submassive embolism would benefit from thrombolysis, and which patients require only anticoagulant therapy? The answer lies in finding the balance between the potential benefit of thrombolytic therapy—preventing death or hemodynamic collapse—and the numerically low but potentially catastrophic risk of intracranial bleeding.

See related article

In general, submassive pulmonary embolism refers to an acute pulmonary embolus serious enough to cause evidence of right ventricular dysfunction or necrosis but not hemodynamic instability (ie, with systolic blood pressure > 90 mm Hg) on presentation.³ It accounts for about 25% of cases of pulmonary embolism,^4,5 and perhaps 0.5 to 1% of patients admitted to intensive care units across the country.⁶ The 30-day mortality rate can be as high as 30%, making it a condition that requires prompt identification and appropriate management.

But clinical trials have failed to demonstrate a substantial improvement in mortality rates with thrombolytic therapy in patients with submassive pulmonary embolism, and have shown improvement only in other clinical end points.⁷ Part of the problem is that this is a heterogeneous condition, posing a challenge for the optimal design and interpretation of studies.

WHO IS AT RISK OF DEATH OR DETERIORATION?

If clinicians could ascertain in each patient whether the risk-benefit ratio is favorable for thrombolytic therapy, it would be easier to provide optimal care. This is not a straightforward task, and it requires integration of clinical judgment, high index of suspicion for deterioration, and clinical tools.

One of the challenges is that it is difficult to identify normotensive patients at the highest risk of poor outcomes. Several factors are associated with a higher risk of death within 30 days (Table 1). While each of these has a negative predictive value of about 95% or even higher (meaning that it is very good at predicting who will not die), they all have very low positive predictive values (meaning that none of them, by itself, is very good at predicting who will die).

For this reason, a multimodal approach to risk stratification has emerged. For example, Jiménez et al⁸ showed that normotensive patients with acute pulmonary embolism and a combination of abnormal Simplified Pulmonary Embolism Severity Index, elevated B-type natriuretic peptide level, elevated troponin level, and lower-extremity deep vein thrombosis had a 26% rate of complications (death, hemodynamic collapse, or recurrent pulmonary embolism) within 30 days.

Bova et al⁹ showed that the combination of borderline low systolic blood pressure (90–100 mm Hg), tachycardia (heart rate ≥ 110 beats per minute), elevated troponin, and right ventricular dysfunction by echocardiography or computed tomography allowed for the separation of three groups with significantly different rates of poor outcomes.

WHO IS AT RISK OF BLEEDING?

Estimation of the risk of bleeding is currently less sophisticated, and we need a bleeding score to use in the setting of acute pulmonary embolism. A few studies have shed some light on this issue beyond the known absolute and relative contraindications to thrombolysis.

Ataya et al¹ note a meta-analysis¹⁰ showing that systemic thrombolytic therapy was not associated with an increased risk of major bleeding in patients age 65 or younger. Similarly, a large observational study showed a strong association between the risk of intracerebral hemorrhage and increasing age¹¹ and also identified comorbidities such as kidney disease as risk factors. While the frequently cited Pulmonary Embolism Thrombolysis trial¹² showed a significantly higher risk of stroke with tenecteplase, careful review of its data reveals that all 10 of the 506 patients in the tenecteplase group who sustained a hemorrhagic stroke were age 65 or older.¹²

A TEAM APPROACH

Thus, in patients with acute pulmonary embolism, clinicians face the difficult task of assessing the patient’s risk of death and clinical worsening and balancing that risk against the risk of bleeding, to identify those who may benefit from early reperfusion therapies, including systemic thrombolysis, catheter-directed thrombolysis, mechanical treatment, and surgical embolectomy.

Given the absence of high-quality evidence to guide these decisions, several institutions have developed multidisciplinary pulmonary embolism response teams to provide rapid evaluation and risk stratification and to recommend and implement advanced therapies, as appropriate. This is a novel concept that is still evolving but holds promise, as it integrates the experience and expertise of physicians in multiple specialties, such as pulmonary and critical care medicine, vascular medicine, interventional radiology, interventional cardiology, emergency medicine, and cardiothoracic surgery, who can then fill the currently existing knowledge gaps for clinical care and, possibly, research.¹³

Early published experience has documented the feasibility of this multidisciplinary approach.¹⁴ The first 95 patients treated at  Cleveland Clinic had a 30-day mortality rate of 3.2%, which was lower than the expected 9% rate predicted by the Pulmonary Embolism Severity Index score (unpublished observation).

Figure 1 shows the algorithm currently used by Cleveland Clinic’s pulmonary embolism response team, with the caveat that no algorithm can fully capture the extent of the complexities and discussions that each case triggers within the team.

TOWARD BETTER UNDERSTANDING

As Ataya et al point out,¹ the current state of the evidence does not allow a clear, simplistic, one-size-fits-all approach. A question that arises from this controversial topic is whether we should look for markers of right ventricular dysfunction in every patient admitted with a diagnosis of pulmonary embolism, or only in those with a significant anatomic burden of clot on imaging. Would testing everyone be an appropriate way to identify patients at risk of further deterioration early and therefore prevent adverse outcomes in a timely manner? Or would it not be cost-effective and translate into ordering more diagnostic testing, as well as an increase in downstream workup with higher healthcare costs?

Once we better understand this condition and the factors that predict a higher risk of deterioration, we should be able to design prospective studies that can help elucidate the most appropriate diagnostic and therapeutic approach for such challenging cases. In the meantime, it is important to appraise the evidence in a critical way, as Ataya et al have done in their review.

In this issue of the Journal, Ataya et al¹ provide a comprehensive review of thrombolysis in submassive pulmonary embolism, a subject of much debate. In massive pulmonary embolism, thrombolytic therapy is usually indicated²; in submassive pulmonary embolism, the decision is not so clear. Which patients with submassive embolism would benefit from thrombolysis, and which patients require only anticoagulant therapy? The answer lies in finding the balance between the potential benefit of thrombolytic therapy—preventing death or hemodynamic collapse—and the numerically low but potentially catastrophic risk of intracranial bleeding.

See related article

In general, submassive pulmonary embolism refers to an acute pulmonary embolus serious enough to cause evidence of right ventricular dysfunction or necrosis but not hemodynamic instability (ie, with systolic blood pressure > 90 mm Hg) on presentation.³ It accounts for about 25% of cases of pulmonary embolism,^4,5 and perhaps 0.5 to 1% of patients admitted to intensive care units across the country.⁶ The 30-day mortality rate can be as high as 30%, making it a condition that requires prompt identification and appropriate management.

But clinical trials have failed to demonstrate a substantial improvement in mortality rates with thrombolytic therapy in patients with submassive pulmonary embolism, and have shown improvement only in other clinical end points.⁷ Part of the problem is that this is a heterogeneous condition, posing a challenge for the optimal design and interpretation of studies.

WHO IS AT RISK OF DEATH OR DETERIORATION?

If clinicians could ascertain in each patient whether the risk-benefit ratio is favorable for thrombolytic therapy, it would be easier to provide optimal care. This is not a straightforward task, and it requires integration of clinical judgment, high index of suspicion for deterioration, and clinical tools.

One of the challenges is that it is difficult to identify normotensive patients at the highest risk of poor outcomes. Several factors are associated with a higher risk of death within 30 days (Table 1). While each of these has a negative predictive value of about 95% or even higher (meaning that it is very good at predicting who will not die), they all have very low positive predictive values (meaning that none of them, by itself, is very good at predicting who will die).

For this reason, a multimodal approach to risk stratification has emerged. For example, Jiménez et al⁸ showed that normotensive patients with acute pulmonary embolism and a combination of abnormal Simplified Pulmonary Embolism Severity Index, elevated B-type natriuretic peptide level, elevated troponin level, and lower-extremity deep vein thrombosis had a 26% rate of complications (death, hemodynamic collapse, or recurrent pulmonary embolism) within 30 days.

Bova et al⁹ showed that the combination of borderline low systolic blood pressure (90–100 mm Hg), tachycardia (heart rate ≥ 110 beats per minute), elevated troponin, and right ventricular dysfunction by echocardiography or computed tomography allowed for the separation of three groups with significantly different rates of poor outcomes.

WHO IS AT RISK OF BLEEDING?

Estimation of the risk of bleeding is currently less sophisticated, and we need a bleeding score to use in the setting of acute pulmonary embolism. A few studies have shed some light on this issue beyond the known absolute and relative contraindications to thrombolysis.

Ataya et al¹ note a meta-analysis¹⁰ showing that systemic thrombolytic therapy was not associated with an increased risk of major bleeding in patients age 65 or younger. Similarly, a large observational study showed a strong association between the risk of intracerebral hemorrhage and increasing age¹¹ and also identified comorbidities such as kidney disease as risk factors. While the frequently cited Pulmonary Embolism Thrombolysis trial¹² showed a significantly higher risk of stroke with tenecteplase, careful review of its data reveals that all 10 of the 506 patients in the tenecteplase group who sustained a hemorrhagic stroke were age 65 or older.¹²

A TEAM APPROACH

Thus, in patients with acute pulmonary embolism, clinicians face the difficult task of assessing the patient’s risk of death and clinical worsening and balancing that risk against the risk of bleeding, to identify those who may benefit from early reperfusion therapies, including systemic thrombolysis, catheter-directed thrombolysis, mechanical treatment, and surgical embolectomy.

Given the absence of high-quality evidence to guide these decisions, several institutions have developed multidisciplinary pulmonary embolism response teams to provide rapid evaluation and risk stratification and to recommend and implement advanced therapies, as appropriate. This is a novel concept that is still evolving but holds promise, as it integrates the experience and expertise of physicians in multiple specialties, such as pulmonary and critical care medicine, vascular medicine, interventional radiology, interventional cardiology, emergency medicine, and cardiothoracic surgery, who can then fill the currently existing knowledge gaps for clinical care and, possibly, research.¹³

Early published experience has documented the feasibility of this multidisciplinary approach.¹⁴ The first 95 patients treated at  Cleveland Clinic had a 30-day mortality rate of 3.2%, which was lower than the expected 9% rate predicted by the Pulmonary Embolism Severity Index score (unpublished observation).

Figure 1 shows the algorithm currently used by Cleveland Clinic’s pulmonary embolism response team, with the caveat that no algorithm can fully capture the extent of the complexities and discussions that each case triggers within the team.

TOWARD BETTER UNDERSTANDING

As Ataya et al point out,¹ the current state of the evidence does not allow a clear, simplistic, one-size-fits-all approach. A question that arises from this controversial topic is whether we should look for markers of right ventricular dysfunction in every patient admitted with a diagnosis of pulmonary embolism, or only in those with a significant anatomic burden of clot on imaging. Would testing everyone be an appropriate way to identify patients at risk of further deterioration early and therefore prevent adverse outcomes in a timely manner? Or would it not be cost-effective and translate into ordering more diagnostic testing, as well as an increase in downstream workup with higher healthcare costs?

Once we better understand this condition and the factors that predict a higher risk of deterioration, we should be able to design prospective studies that can help elucidate the most appropriate diagnostic and therapeutic approach for such challenging cases. In the meantime, it is important to appraise the evidence in a critical way, as Ataya et al have done in their review.

On an otherwise pleasant evening during the first week of July 2016, a businessman who was a citizen of the United Arab Emirates visiting Cleveland for medical treatment was falsely accused of links to a terror organization. Officers stormed his hotel with assault rifles and handcuffed and arrested him—all this, apparently, because the man was dressed in traditional Emirati clothing.

See related article

This case highlights a level of complexity in providing medical care to foreigners far beyond language interpreting services and outside the borders of the institution where medical care is provided. In the current issue of the Journal, Cawcutt and Wilson¹ review their experiences in the care of international patients and the unique challenges associated with it.

FROM THE TEMPLE OF AESCULAPIUS TO CLEVELAND CLINIC

In 2015, patients from more than 100 countries traveled to Cleveland seeking care at Cleveland Clinic. But medical travel was part of the practice of medicine long before major US hospitals became destinations for international patients, and it has been refined over the years.

Ancient cultures had a thriving tradition of patients traveling long distances for the best and most advanced medical treatment.^2–4 In ancient Greece, people from all around the Mediterranean came to the city of Epidaurus to be cured in its famous temple of Aesculapius, built as a medical center.

Similarly, early Islamic cultures established a healthcare system that catered to foreigners. A noted example is the Mansuri hospital in Cairo, built in 1248 ce and considered the most advanced hospital of its time. Accommodating nearly 8,000 patients, the Mansuri hospital became a healthcare destination for foreigners regardless of race or religion.^2–4

Europe also had a great tradition of providing medical care to foreign patients. Between the 15th and 17th centuries, belief in the healing power of mineral water led to the establishment of spas and the rise of spa towns, particularly in the south of France near mineral springs. The poor sanitary conditions of Europe at the time may have prompted the interest in the healing effect of mineral spas, but wealthy individuals from all over the world traveled to these destinations, creating local prosperity due to medical tourism.^2–4

The city of Bath, in England, is a great example. In the 1720s, Bath was a popular destination for those traveling for healthcare. It became the first city in England to build a covered sewage system, ahead of London by several years. It also had paved roads, lights, hotels, and restaurants in much greater numbers than other cities in England, a likely result of prosperity associated with medical tourism.

ALL PATIENTS WANT TO BE TREATED WITH RESPECT AND KINDNESS

While medical knowledge and health delivery models have changed over the years, caring for foreign patients is perhaps as old as medicine itself. The central focus of restoring health is certainly not unique to international patients, but understanding their unique needs is important in order to achieve the best outcomes, something that Cawcutt and Wilson highlight well.¹

A number of studies have addressed the question of what patients really want. Responses were surprisingly consistent: they want to be treated with respect and kindness.^5,6 In other words, they want empathy, and this is true of all patients regardless of ethnicity or background. Empathy is a tremendous therapeutic force and can narrow what may look like an unbridgeable gap between patient and physician.^7,8

EMPATHY REQUIRES EFFECTIVE COMMUNICATION

Empathy, though sometimes innate, requires effective communication and shared experiences. Neither of these two requirements is easily achievable in the care of foreign patients.

Communication is hampered by language barriers, although it can be enhanced significantly by language translating services and the work of certified medical interpreters. These often-invisible heroes should be recognized as essential members of the medical team. Their work requires cultural sensitivity and formal training to avoid miscommunication and medical errors. Codes of ethics for medical interpreters include confidentiality, accuracy in conveying the content and spirit of the message, freedom from personal biases, cultural training, and professional boundaries.⁹

TOWARD CULTURAL COMPETENCY

Lack of shared experiences between the foreign patient and care provider is an even greater obstacle to overcome in eliminating any empathy deficit. Shared experiences, whether cultural, religious, or social, help us to see the world through the eyes of the patient.

International patients may differ from us in background, ethnicity, religion, dress, expectations, and other areas. Cultural and religious backgrounds often dictate certain behaviors in the event of critical illness or death. Even in routine and less acute medical care, the background of a foreign patient may lead to logistical quandaries such as the need for same-sex caregivers or a private room.

A paradox currently exists in our efforts to meet patients’ need and desire for empathy. While culturally empathic care is necessary to achieve the best medical outcomes, this topic is not yet part of the curriculum for physicians or other healthcare providers in training. A culturally sensitive institution has many business advantages.¹⁰ Thorough and focused cultural training of medical staff is essential. Shared experiences can potentially be fashioned through a well-designed cultural competency training program to enhance empathy for foreign patients.

A SERVICE-ORIENTED APPROACH

Besides cultural competency and language training, a service-oriented approach to accommodate the needs of medical travelers and their family members is of paramount importance. Many of the complaints and burdens of medical visitors concern services that are not medical in nature, such as daily living necessities. Transportation, religious services, banking, extended-stay facilities, cell phone service, legal services, shopping, dining, and entertainment are among many other living needs for those receiving medical care abroad. These services are inconsistently provided throughout medical institutions in the United States, which provide care to thousands of international patients annually.

Unique challenges of providing medical care to international patients have direct effects on medical outcomes. A population-based cohort study of US-born and foreign-born adults with lung or colorectal cancer suggested disparities in quality and type of care.¹¹ Foreign-born patients reported lower-quality care and were less likely to receive complex cancer treatments recommended by clinical guidelines. The authors proposed that quality of care and outcomes may be improved with greater emphasis on coordination of care and improving communication. Similar findings were reported in foreign-born patients with breast cancer.¹²

‘WHAT WOULD YOU THINK TO BE USED THUS?’

Four hundred years ago, in the play Sir Thomas More (a collaboration between several Elizabethan playwrights),¹³ the title character confronts a mob of anti-immigrant rioters, and in a speech believed to have been written by William Shakespeare (Act 2, Scene 4), asks them to imagine themselves banished to a foreign country and subjected to hostility such as they were meting out:

Empathy for foreigners seeking medical care is not merely an act of kindness; rather, it is a central piece of healing. Medical institutions interested in providing healthcare to this unique group of patients should take these principles into account and carefully examine their ability to deliver compassionate care collectively to local and foreign-born patients alike.

On an otherwise pleasant evening during the first week of July 2016, a businessman who was a citizen of the United Arab Emirates visiting Cleveland for medical treatment was falsely accused of links to a terror organization. Officers stormed his hotel with assault rifles and handcuffed and arrested him—all this, apparently, because the man was dressed in traditional Emirati clothing.

See related article

This case highlights a level of complexity in providing medical care to foreigners far beyond language interpreting services and outside the borders of the institution where medical care is provided. In the current issue of the Journal, Cawcutt and Wilson¹ review their experiences in the care of international patients and the unique challenges associated with it.

FROM THE TEMPLE OF AESCULAPIUS TO CLEVELAND CLINIC

In 2015, patients from more than 100 countries traveled to Cleveland seeking care at Cleveland Clinic. But medical travel was part of the practice of medicine long before major US hospitals became destinations for international patients, and it has been refined over the years.

Ancient cultures had a thriving tradition of patients traveling long distances for the best and most advanced medical treatment.^2–4 In ancient Greece, people from all around the Mediterranean came to the city of Epidaurus to be cured in its famous temple of Aesculapius, built as a medical center.

Similarly, early Islamic cultures established a healthcare system that catered to foreigners. A noted example is the Mansuri hospital in Cairo, built in 1248 ce and considered the most advanced hospital of its time. Accommodating nearly 8,000 patients, the Mansuri hospital became a healthcare destination for foreigners regardless of race or religion.^2–4

Europe also had a great tradition of providing medical care to foreign patients. Between the 15th and 17th centuries, belief in the healing power of mineral water led to the establishment of spas and the rise of spa towns, particularly in the south of France near mineral springs. The poor sanitary conditions of Europe at the time may have prompted the interest in the healing effect of mineral spas, but wealthy individuals from all over the world traveled to these destinations, creating local prosperity due to medical tourism.^2–4

The city of Bath, in England, is a great example. In the 1720s, Bath was a popular destination for those traveling for healthcare. It became the first city in England to build a covered sewage system, ahead of London by several years. It also had paved roads, lights, hotels, and restaurants in much greater numbers than other cities in England, a likely result of prosperity associated with medical tourism.

ALL PATIENTS WANT TO BE TREATED WITH RESPECT AND KINDNESS

While medical knowledge and health delivery models have changed over the years, caring for foreign patients is perhaps as old as medicine itself. The central focus of restoring health is certainly not unique to international patients, but understanding their unique needs is important in order to achieve the best outcomes, something that Cawcutt and Wilson highlight well.¹

A number of studies have addressed the question of what patients really want. Responses were surprisingly consistent: they want to be treated with respect and kindness.^5,6 In other words, they want empathy, and this is true of all patients regardless of ethnicity or background. Empathy is a tremendous therapeutic force and can narrow what may look like an unbridgeable gap between patient and physician.^7,8

EMPATHY REQUIRES EFFECTIVE COMMUNICATION

Empathy, though sometimes innate, requires effective communication and shared experiences. Neither of these two requirements is easily achievable in the care of foreign patients.

Communication is hampered by language barriers, although it can be enhanced significantly by language translating services and the work of certified medical interpreters. These often-invisible heroes should be recognized as essential members of the medical team. Their work requires cultural sensitivity and formal training to avoid miscommunication and medical errors. Codes of ethics for medical interpreters include confidentiality, accuracy in conveying the content and spirit of the message, freedom from personal biases, cultural training, and professional boundaries.⁹

TOWARD CULTURAL COMPETENCY

Lack of shared experiences between the foreign patient and care provider is an even greater obstacle to overcome in eliminating any empathy deficit. Shared experiences, whether cultural, religious, or social, help us to see the world through the eyes of the patient.

International patients may differ from us in background, ethnicity, religion, dress, expectations, and other areas. Cultural and religious backgrounds often dictate certain behaviors in the event of critical illness or death. Even in routine and less acute medical care, the background of a foreign patient may lead to logistical quandaries such as the need for same-sex caregivers or a private room.

A paradox currently exists in our efforts to meet patients’ need and desire for empathy. While culturally empathic care is necessary to achieve the best medical outcomes, this topic is not yet part of the curriculum for physicians or other healthcare providers in training. A culturally sensitive institution has many business advantages.¹⁰ Thorough and focused cultural training of medical staff is essential. Shared experiences can potentially be fashioned through a well-designed cultural competency training program to enhance empathy for foreign patients.

A SERVICE-ORIENTED APPROACH

Besides cultural competency and language training, a service-oriented approach to accommodate the needs of medical travelers and their family members is of paramount importance. Many of the complaints and burdens of medical visitors concern services that are not medical in nature, such as daily living necessities. Transportation, religious services, banking, extended-stay facilities, cell phone service, legal services, shopping, dining, and entertainment are among many other living needs for those receiving medical care abroad. These services are inconsistently provided throughout medical institutions in the United States, which provide care to thousands of international patients annually.

Unique challenges of providing medical care to international patients have direct effects on medical outcomes. A population-based cohort study of US-born and foreign-born adults with lung or colorectal cancer suggested disparities in quality and type of care.¹¹ Foreign-born patients reported lower-quality care and were less likely to receive complex cancer treatments recommended by clinical guidelines. The authors proposed that quality of care and outcomes may be improved with greater emphasis on coordination of care and improving communication. Similar findings were reported in foreign-born patients with breast cancer.¹²

‘WHAT WOULD YOU THINK TO BE USED THUS?’

Four hundred years ago, in the play Sir Thomas More (a collaboration between several Elizabethan playwrights),¹³ the title character confronts a mob of anti-immigrant rioters, and in a speech believed to have been written by William Shakespeare (Act 2, Scene 4), asks them to imagine themselves banished to a foreign country and subjected to hostility such as they were meting out:

Empathy for foreigners seeking medical care is not merely an act of kindness; rather, it is a central piece of healing. Medical institutions interested in providing healthcare to this unique group of patients should take these principles into account and carefully examine their ability to deliver compassionate care collectively to local and foreign-born patients alike.

On an otherwise pleasant evening during the first week of July 2016, a businessman who was a citizen of the United Arab Emirates visiting Cleveland for medical treatment was falsely accused of links to a terror organization. Officers stormed his hotel with assault rifles and handcuffed and arrested him—all this, apparently, because the man was dressed in traditional Emirati clothing.

See related article

This case highlights a level of complexity in providing medical care to foreigners far beyond language interpreting services and outside the borders of the institution where medical care is provided. In the current issue of the Journal, Cawcutt and Wilson¹ review their experiences in the care of international patients and the unique challenges associated with it.

FROM THE TEMPLE OF AESCULAPIUS TO CLEVELAND CLINIC

In 2015, patients from more than 100 countries traveled to Cleveland seeking care at Cleveland Clinic. But medical travel was part of the practice of medicine long before major US hospitals became destinations for international patients, and it has been refined over the years.

Ancient cultures had a thriving tradition of patients traveling long distances for the best and most advanced medical treatment.^2–4 In ancient Greece, people from all around the Mediterranean came to the city of Epidaurus to be cured in its famous temple of Aesculapius, built as a medical center.

Similarly, early Islamic cultures established a healthcare system that catered to foreigners. A noted example is the Mansuri hospital in Cairo, built in 1248 ce and considered the most advanced hospital of its time. Accommodating nearly 8,000 patients, the Mansuri hospital became a healthcare destination for foreigners regardless of race or religion.^2–4

Europe also had a great tradition of providing medical care to foreign patients. Between the 15th and 17th centuries, belief in the healing power of mineral water led to the establishment of spas and the rise of spa towns, particularly in the south of France near mineral springs. The poor sanitary conditions of Europe at the time may have prompted the interest in the healing effect of mineral spas, but wealthy individuals from all over the world traveled to these destinations, creating local prosperity due to medical tourism.^2–4

The city of Bath, in England, is a great example. In the 1720s, Bath was a popular destination for those traveling for healthcare. It became the first city in England to build a covered sewage system, ahead of London by several years. It also had paved roads, lights, hotels, and restaurants in much greater numbers than other cities in England, a likely result of prosperity associated with medical tourism.

ALL PATIENTS WANT TO BE TREATED WITH RESPECT AND KINDNESS

While medical knowledge and health delivery models have changed over the years, caring for foreign patients is perhaps as old as medicine itself. The central focus of restoring health is certainly not unique to international patients, but understanding their unique needs is important in order to achieve the best outcomes, something that Cawcutt and Wilson highlight well.¹

A number of studies have addressed the question of what patients really want. Responses were surprisingly consistent: they want to be treated with respect and kindness.^5,6 In other words, they want empathy, and this is true of all patients regardless of ethnicity or background. Empathy is a tremendous therapeutic force and can narrow what may look like an unbridgeable gap between patient and physician.^7,8

EMPATHY REQUIRES EFFECTIVE COMMUNICATION

Empathy, though sometimes innate, requires effective communication and shared experiences. Neither of these two requirements is easily achievable in the care of foreign patients.

Communication is hampered by language barriers, although it can be enhanced significantly by language translating services and the work of certified medical interpreters. These often-invisible heroes should be recognized as essential members of the medical team. Their work requires cultural sensitivity and formal training to avoid miscommunication and medical errors. Codes of ethics for medical interpreters include confidentiality, accuracy in conveying the content and spirit of the message, freedom from personal biases, cultural training, and professional boundaries.⁹

TOWARD CULTURAL COMPETENCY

Lack of shared experiences between the foreign patient and care provider is an even greater obstacle to overcome in eliminating any empathy deficit. Shared experiences, whether cultural, religious, or social, help us to see the world through the eyes of the patient.

International patients may differ from us in background, ethnicity, religion, dress, expectations, and other areas. Cultural and religious backgrounds often dictate certain behaviors in the event of critical illness or death. Even in routine and less acute medical care, the background of a foreign patient may lead to logistical quandaries such as the need for same-sex caregivers or a private room.

A paradox currently exists in our efforts to meet patients’ need and desire for empathy. While culturally empathic care is necessary to achieve the best medical outcomes, this topic is not yet part of the curriculum for physicians or other healthcare providers in training. A culturally sensitive institution has many business advantages.¹⁰ Thorough and focused cultural training of medical staff is essential. Shared experiences can potentially be fashioned through a well-designed cultural competency training program to enhance empathy for foreign patients.

A SERVICE-ORIENTED APPROACH

Besides cultural competency and language training, a service-oriented approach to accommodate the needs of medical travelers and their family members is of paramount importance. Many of the complaints and burdens of medical visitors concern services that are not medical in nature, such as daily living necessities. Transportation, religious services, banking, extended-stay facilities, cell phone service, legal services, shopping, dining, and entertainment are among many other living needs for those receiving medical care abroad. These services are inconsistently provided throughout medical institutions in the United States, which provide care to thousands of international patients annually.

Unique challenges of providing medical care to international patients have direct effects on medical outcomes. A population-based cohort study of US-born and foreign-born adults with lung or colorectal cancer suggested disparities in quality and type of care.¹¹ Foreign-born patients reported lower-quality care and were less likely to receive complex cancer treatments recommended by clinical guidelines. The authors proposed that quality of care and outcomes may be improved with greater emphasis on coordination of care and improving communication. Similar findings were reported in foreign-born patients with breast cancer.¹²

‘WHAT WOULD YOU THINK TO BE USED THUS?’

Four hundred years ago, in the play Sir Thomas More (a collaboration between several Elizabethan playwrights),¹³ the title character confronts a mob of anti-immigrant rioters, and in a speech believed to have been written by William Shakespeare (Act 2, Scene 4), asks them to imagine themselves banished to a foreign country and subjected to hostility such as they were meting out:

Empathy for foreigners seeking medical care is not merely an act of kindness; rather, it is a central piece of healing. Medical institutions interested in providing healthcare to this unique group of patients should take these principles into account and carefully examine their ability to deliver compassionate care collectively to local and foreign-born patients alike.

The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.

—Robert Frost, “Stopping by Woods on a Snowy Evening”¹

Frost's words are simple yet elegant. They can be interpreted many ways. I see the allegory of life as a journey in this poem. The passage, like the woods, is beautiful, but there is a long, long way to go.

See related article

And so it is with the treatment of heart failure. There is beauty in our understanding of the syndrome’s physiologic complexities and natural history, and of effective treatments uncovered. Still, we’ve a monstrous climb ahead to get to the summit of this clinical challenge in order to start a real descent.

THE PAST, PRESENT, AND FUTURE OF HEART FAILURE THERAPY

Okwuosa et al,² in this issue of the Journal, have capably summarized the ABCs of treating heart failure with reduced ejection fraction (also called systolic heart failure), approaching the subject from a perspective on past, present, and future therapies. They summarize heart failure interventions with a guideline-based philosophy, pointing out that these care paths are supposed to be evidence-based. They observe that in the 1960s the standard of care was digitalis, diuretics (furosemide first became available in 1967), and rest. That was about all we had for this problem.

There are now many drugs, devices, and operations that help patients with heart failure. But they never really cure the disease or, more aptly, the syndrome—and therapies are supposed to cure. This limitation of present therapies is important, given the disturbing epidemiology of heart failure, its economic cost, and the suffering of patients. That burden is well detailed.

In addition to curing, the overarching goals of treatment generally are to ameliorate distressing symptoms and to prevent comorbidities. In heart failure with reduced ejection fraction, we want to prevent premature death, stroke, myocardial infarction, congestive states, hospitalization, renal insufficiency, renal failure, cachexia, inanition, feebleness, and respiratory distress, among others.

The ABC mnemonic of Okwuosa et al will help caregivers remember the basics. It is important, however, to put algorithms into proper perspective and to look toward the future.

PROBLEMS WITH EVIDENCE-BASED MEDICINE

Several problems with our current heart failure treatments are rooted in how we perform clinical trials, arguably the premier method of determining truth in clinical practice and the foundation of evidence-based medicine.^3,4

Do the trials represent real-world practice?

Were the clinical trials that led to regulatory approval and professional society endorsement of the therapies that we prescribe in our offices done in the same sorts of patients as those in our waiting rooms asking for help? Perhaps, for the most part, they have been. And thus, Okwuosa et al have crafted a work relevant to all of us and every patient.

But I believe there are major gaps in the types of participants enrolled in trials, eg, underrepresentation of certain racial and ethnic groups, not to mention the relative paucity of women. The very elderly (a rapidly growing population) have largely been ignored as well, and participants with significant renal insufficiency, anemia, and diabetes mellitus seem far fewer than what we deal with in a busy clinic.

In addition, Okwuosa et al focus only on patients with reduced left ventricular ejection fraction, a group that makes up only about half of the heart failure crowd.

What about quality of life and other important outcomes?

Clinical trials in heart failure with reduced ejection fraction have generally focused on major clinical end points (primarily, but not exclusively, mortality), to the exclusion of quality of life. Though sometimes included in trials, quality-of-life metrics generally get relegated to second-class seats or ‘tween-deck steerage. Perhaps that is because measuring quality of life can be time-consuming and difficult.

Yet, in the words of sociologist William Bruce Cameron, not everything that counts can be counted, and not everything that can be counted counts. That goes for quality of life.

Lies, damned lies, and P values

Quandaries in data management and analysis include what to do about trial dropouts, study power, precision of statistical analysis, intention-to-treat principles, and choice of the P value that defines significance (or not) for any end point observation. Of course, there are myriad sophisticated mathematical and statistical reasons to justify why we don’t simply count on-treatment participants or allow imputation of results when patients or results drop out, forcing us to worship at the altar of P < .05.

A review of the P value concept⁵ recently appeared with an accompanying editorial by Kyriacou⁶ that concluded that “the automatic application of dichotomized hypothesis testing based on prearranged levels of statistical significance should be substituted with a more complex process using effect estimates, confidence intervals, and even P values, thereby permitting scientists, statisticians, and clinicians to use their own inferential capabilities to assign scientific significance.”⁶

How many great treatments have we tossed out because of rigid reliance on old-fashioned approaches to determining therapeutic evidence? Many treatments studied have had great results in a minority of patients in clinical trials but did not have a major positive (or negative) impact on the overall cohort (with lack of primary end point statistical significance). And what to do when the primary end point is a neutral or negative one but secondary end points are positive? Why not focus more attention on those patients benefiting from an intervention despite the overall results of any trial?

Dilemmas of trials

Other issues are that clinical trials cost too much, and that recruitment and follow-up take too long. Intercurrent therapies (and guidelines) can emerge that jeopardize the trial itself or make observations untimely. The dilemma of stacking therapies one on top of another, often making patient compliance impossible, is another problem with clinical trials. Yet this is how we get to the ABCs.

A NEW WAY TO DO TRIALS

The information provided by Okwuosa et al is useful and encouraging, but too many gaps exist in our heart failure therapies to permit us to celebrate with exuberance. Too many patients still suffer, too many die too young, and the costs are still too great.

Perhaps the future of therapeutic development should embrace different and better ways to demonstrate real value (relying on the equation of value equals outcomes meaningful to patients, divided by cost) of therapies, including the old, the new, the trashed and the underdeveloped. More creative data analysis to reexamine the current tools on the shelf and the ones tried but discarded is essential.

A position paper from the Cardiovascular Round Table of the European Society of Cardiology concluded that “a coordinated effort involving academia, regulators, industry and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.”⁷

Lauer and D’Agostino,⁸ also in an editorial, argued for innovative methods of doing clinical trials and discovering truth about therapies that are applicable to the future of developing treatments for heart failure with reduced ejection fraction. They noted that “the randomized registry trial represents a disruptive technology” and wondered if it will be “given serious consideration as a way to resolve the recognized limitations of current clinical-trial design.”⁸

Indeed, conducting megatrials with existing megadatabases using a registry format could help. Registries emerging from early adaptive trial design efforts, particularly when Bayesian analysis theory is applied, might help inform clinical experience faster and more efficiently. Bayesian analysis is a statistical approach that attempts to estimate parameters of an underlying distribution of events in an ongoing fashion based on the observed distribution. A clinical trial of stem cell therapies could, at the end of the trial, be turned into a multicenter registry that would continue to inform us about the more real-world application of newer treatment approaches.

Though the therapeutic cupboard for heart failure is certainly not bare, as Okwuosa et al point out, it is wanting. Let’s look for new therapeutic ABCs differently. We should be attacking the real challenge—curing the disease processes that cause the syndrome. Yes, there are miles to go before we sleep.

The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.

—Robert Frost, “Stopping by Woods on a Snowy Evening”¹

Frost's words are simple yet elegant. They can be interpreted many ways. I see the allegory of life as a journey in this poem. The passage, like the woods, is beautiful, but there is a long, long way to go.

See related article

And so it is with the treatment of heart failure. There is beauty in our understanding of the syndrome’s physiologic complexities and natural history, and of effective treatments uncovered. Still, we’ve a monstrous climb ahead to get to the summit of this clinical challenge in order to start a real descent.

THE PAST, PRESENT, AND FUTURE OF HEART FAILURE THERAPY

Okwuosa et al,² in this issue of the Journal, have capably summarized the ABCs of treating heart failure with reduced ejection fraction (also called systolic heart failure), approaching the subject from a perspective on past, present, and future therapies. They summarize heart failure interventions with a guideline-based philosophy, pointing out that these care paths are supposed to be evidence-based. They observe that in the 1960s the standard of care was digitalis, diuretics (furosemide first became available in 1967), and rest. That was about all we had for this problem.

There are now many drugs, devices, and operations that help patients with heart failure. But they never really cure the disease or, more aptly, the syndrome—and therapies are supposed to cure. This limitation of present therapies is important, given the disturbing epidemiology of heart failure, its economic cost, and the suffering of patients. That burden is well detailed.

In addition to curing, the overarching goals of treatment generally are to ameliorate distressing symptoms and to prevent comorbidities. In heart failure with reduced ejection fraction, we want to prevent premature death, stroke, myocardial infarction, congestive states, hospitalization, renal insufficiency, renal failure, cachexia, inanition, feebleness, and respiratory distress, among others.

The ABC mnemonic of Okwuosa et al will help caregivers remember the basics. It is important, however, to put algorithms into proper perspective and to look toward the future.

PROBLEMS WITH EVIDENCE-BASED MEDICINE

Several problems with our current heart failure treatments are rooted in how we perform clinical trials, arguably the premier method of determining truth in clinical practice and the foundation of evidence-based medicine.^3,4

Do the trials represent real-world practice?

Were the clinical trials that led to regulatory approval and professional society endorsement of the therapies that we prescribe in our offices done in the same sorts of patients as those in our waiting rooms asking for help? Perhaps, for the most part, they have been. And thus, Okwuosa et al have crafted a work relevant to all of us and every patient.

But I believe there are major gaps in the types of participants enrolled in trials, eg, underrepresentation of certain racial and ethnic groups, not to mention the relative paucity of women. The very elderly (a rapidly growing population) have largely been ignored as well, and participants with significant renal insufficiency, anemia, and diabetes mellitus seem far fewer than what we deal with in a busy clinic.

In addition, Okwuosa et al focus only on patients with reduced left ventricular ejection fraction, a group that makes up only about half of the heart failure crowd.

What about quality of life and other important outcomes?

Clinical trials in heart failure with reduced ejection fraction have generally focused on major clinical end points (primarily, but not exclusively, mortality), to the exclusion of quality of life. Though sometimes included in trials, quality-of-life metrics generally get relegated to second-class seats or ‘tween-deck steerage. Perhaps that is because measuring quality of life can be time-consuming and difficult.

Yet, in the words of sociologist William Bruce Cameron, not everything that counts can be counted, and not everything that can be counted counts. That goes for quality of life.

Lies, damned lies, and P values

Quandaries in data management and analysis include what to do about trial dropouts, study power, precision of statistical analysis, intention-to-treat principles, and choice of the P value that defines significance (or not) for any end point observation. Of course, there are myriad sophisticated mathematical and statistical reasons to justify why we don’t simply count on-treatment participants or allow imputation of results when patients or results drop out, forcing us to worship at the altar of P < .05.

A review of the P value concept⁵ recently appeared with an accompanying editorial by Kyriacou⁶ that concluded that “the automatic application of dichotomized hypothesis testing based on prearranged levels of statistical significance should be substituted with a more complex process using effect estimates, confidence intervals, and even P values, thereby permitting scientists, statisticians, and clinicians to use their own inferential capabilities to assign scientific significance.”⁶

How many great treatments have we tossed out because of rigid reliance on old-fashioned approaches to determining therapeutic evidence? Many treatments studied have had great results in a minority of patients in clinical trials but did not have a major positive (or negative) impact on the overall cohort (with lack of primary end point statistical significance). And what to do when the primary end point is a neutral or negative one but secondary end points are positive? Why not focus more attention on those patients benefiting from an intervention despite the overall results of any trial?

Dilemmas of trials

Other issues are that clinical trials cost too much, and that recruitment and follow-up take too long. Intercurrent therapies (and guidelines) can emerge that jeopardize the trial itself or make observations untimely. The dilemma of stacking therapies one on top of another, often making patient compliance impossible, is another problem with clinical trials. Yet this is how we get to the ABCs.

A NEW WAY TO DO TRIALS

The information provided by Okwuosa et al is useful and encouraging, but too many gaps exist in our heart failure therapies to permit us to celebrate with exuberance. Too many patients still suffer, too many die too young, and the costs are still too great.

Perhaps the future of therapeutic development should embrace different and better ways to demonstrate real value (relying on the equation of value equals outcomes meaningful to patients, divided by cost) of therapies, including the old, the new, the trashed and the underdeveloped. More creative data analysis to reexamine the current tools on the shelf and the ones tried but discarded is essential.

A position paper from the Cardiovascular Round Table of the European Society of Cardiology concluded that “a coordinated effort involving academia, regulators, industry and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.”⁷

Lauer and D’Agostino,⁸ also in an editorial, argued for innovative methods of doing clinical trials and discovering truth about therapies that are applicable to the future of developing treatments for heart failure with reduced ejection fraction. They noted that “the randomized registry trial represents a disruptive technology” and wondered if it will be “given serious consideration as a way to resolve the recognized limitations of current clinical-trial design.”⁸

Indeed, conducting megatrials with existing megadatabases using a registry format could help. Registries emerging from early adaptive trial design efforts, particularly when Bayesian analysis theory is applied, might help inform clinical experience faster and more efficiently. Bayesian analysis is a statistical approach that attempts to estimate parameters of an underlying distribution of events in an ongoing fashion based on the observed distribution. A clinical trial of stem cell therapies could, at the end of the trial, be turned into a multicenter registry that would continue to inform us about the more real-world application of newer treatment approaches.

Though the therapeutic cupboard for heart failure is certainly not bare, as Okwuosa et al point out, it is wanting. Let’s look for new therapeutic ABCs differently. We should be attacking the real challenge—curing the disease processes that cause the syndrome. Yes, there are miles to go before we sleep.

The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.

—Robert Frost, “Stopping by Woods on a Snowy Evening”¹

Frost's words are simple yet elegant. They can be interpreted many ways. I see the allegory of life as a journey in this poem. The passage, like the woods, is beautiful, but there is a long, long way to go.

See related article

And so it is with the treatment of heart failure. There is beauty in our understanding of the syndrome’s physiologic complexities and natural history, and of effective treatments uncovered. Still, we’ve a monstrous climb ahead to get to the summit of this clinical challenge in order to start a real descent.

THE PAST, PRESENT, AND FUTURE OF HEART FAILURE THERAPY

Okwuosa et al,² in this issue of the Journal, have capably summarized the ABCs of treating heart failure with reduced ejection fraction (also called systolic heart failure), approaching the subject from a perspective on past, present, and future therapies. They summarize heart failure interventions with a guideline-based philosophy, pointing out that these care paths are supposed to be evidence-based. They observe that in the 1960s the standard of care was digitalis, diuretics (furosemide first became available in 1967), and rest. That was about all we had for this problem.

There are now many drugs, devices, and operations that help patients with heart failure. But they never really cure the disease or, more aptly, the syndrome—and therapies are supposed to cure. This limitation of present therapies is important, given the disturbing epidemiology of heart failure, its economic cost, and the suffering of patients. That burden is well detailed.

In addition to curing, the overarching goals of treatment generally are to ameliorate distressing symptoms and to prevent comorbidities. In heart failure with reduced ejection fraction, we want to prevent premature death, stroke, myocardial infarction, congestive states, hospitalization, renal insufficiency, renal failure, cachexia, inanition, feebleness, and respiratory distress, among others.

The ABC mnemonic of Okwuosa et al will help caregivers remember the basics. It is important, however, to put algorithms into proper perspective and to look toward the future.

PROBLEMS WITH EVIDENCE-BASED MEDICINE

Several problems with our current heart failure treatments are rooted in how we perform clinical trials, arguably the premier method of determining truth in clinical practice and the foundation of evidence-based medicine.^3,4

Do the trials represent real-world practice?

Were the clinical trials that led to regulatory approval and professional society endorsement of the therapies that we prescribe in our offices done in the same sorts of patients as those in our waiting rooms asking for help? Perhaps, for the most part, they have been. And thus, Okwuosa et al have crafted a work relevant to all of us and every patient.

But I believe there are major gaps in the types of participants enrolled in trials, eg, underrepresentation of certain racial and ethnic groups, not to mention the relative paucity of women. The very elderly (a rapidly growing population) have largely been ignored as well, and participants with significant renal insufficiency, anemia, and diabetes mellitus seem far fewer than what we deal with in a busy clinic.

In addition, Okwuosa et al focus only on patients with reduced left ventricular ejection fraction, a group that makes up only about half of the heart failure crowd.

What about quality of life and other important outcomes?

Clinical trials in heart failure with reduced ejection fraction have generally focused on major clinical end points (primarily, but not exclusively, mortality), to the exclusion of quality of life. Though sometimes included in trials, quality-of-life metrics generally get relegated to second-class seats or ‘tween-deck steerage. Perhaps that is because measuring quality of life can be time-consuming and difficult.

Yet, in the words of sociologist William Bruce Cameron, not everything that counts can be counted, and not everything that can be counted counts. That goes for quality of life.

Lies, damned lies, and P values

Quandaries in data management and analysis include what to do about trial dropouts, study power, precision of statistical analysis, intention-to-treat principles, and choice of the P value that defines significance (or not) for any end point observation. Of course, there are myriad sophisticated mathematical and statistical reasons to justify why we don’t simply count on-treatment participants or allow imputation of results when patients or results drop out, forcing us to worship at the altar of P < .05.

A review of the P value concept⁵ recently appeared with an accompanying editorial by Kyriacou⁶ that concluded that “the automatic application of dichotomized hypothesis testing based on prearranged levels of statistical significance should be substituted with a more complex process using effect estimates, confidence intervals, and even P values, thereby permitting scientists, statisticians, and clinicians to use their own inferential capabilities to assign scientific significance.”⁶

How many great treatments have we tossed out because of rigid reliance on old-fashioned approaches to determining therapeutic evidence? Many treatments studied have had great results in a minority of patients in clinical trials but did not have a major positive (or negative) impact on the overall cohort (with lack of primary end point statistical significance). And what to do when the primary end point is a neutral or negative one but secondary end points are positive? Why not focus more attention on those patients benefiting from an intervention despite the overall results of any trial?

Dilemmas of trials

Other issues are that clinical trials cost too much, and that recruitment and follow-up take too long. Intercurrent therapies (and guidelines) can emerge that jeopardize the trial itself or make observations untimely. The dilemma of stacking therapies one on top of another, often making patient compliance impossible, is another problem with clinical trials. Yet this is how we get to the ABCs.

A NEW WAY TO DO TRIALS

The information provided by Okwuosa et al is useful and encouraging, but too many gaps exist in our heart failure therapies to permit us to celebrate with exuberance. Too many patients still suffer, too many die too young, and the costs are still too great.

Perhaps the future of therapeutic development should embrace different and better ways to demonstrate real value (relying on the equation of value equals outcomes meaningful to patients, divided by cost) of therapies, including the old, the new, the trashed and the underdeveloped. More creative data analysis to reexamine the current tools on the shelf and the ones tried but discarded is essential.

A position paper from the Cardiovascular Round Table of the European Society of Cardiology concluded that “a coordinated effort involving academia, regulators, industry and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.”⁷

Lauer and D’Agostino,⁸ also in an editorial, argued for innovative methods of doing clinical trials and discovering truth about therapies that are applicable to the future of developing treatments for heart failure with reduced ejection fraction. They noted that “the randomized registry trial represents a disruptive technology” and wondered if it will be “given serious consideration as a way to resolve the recognized limitations of current clinical-trial design.”⁸

Indeed, conducting megatrials with existing megadatabases using a registry format could help. Registries emerging from early adaptive trial design efforts, particularly when Bayesian analysis theory is applied, might help inform clinical experience faster and more efficiently. Bayesian analysis is a statistical approach that attempts to estimate parameters of an underlying distribution of events in an ongoing fashion based on the observed distribution. A clinical trial of stem cell therapies could, at the end of the trial, be turned into a multicenter registry that would continue to inform us about the more real-world application of newer treatment approaches.

Though the therapeutic cupboard for heart failure is certainly not bare, as Okwuosa et al point out, it is wanting. Let’s look for new therapeutic ABCs differently. We should be attacking the real challenge—curing the disease processes that cause the syndrome. Yes, there are miles to go before we sleep.