Sidney Goldstein, MD

 

Nearly 2 years ago I speculated in this column that health planners or health economists would attempt to manipulate the patterns of patient care to influence the cost and/or quality of clinical care. At that time I suggested that, in that event, the intervention should be managed as we have with drug or device trials to ensure the authenticity and accuracy and most of all assuring the safety of the patient. Furthermore, the design should be incorporated in the intervention, that equipoise be present in the arms of the trial and that a safety monitoring board be in place to alert investigators when and if patient safety is threatened. Patient consent should also be obtained.

Little did I know that an example was in play at the time of publication. A study presented at the Heart Failure Society of America meeting indicates that the Centers for Medicare & Medicaid Services, as part of the Affordable Care Act, was carrying out such an experiment in the attempt to lower cost and improve the quality of the care of heart failure patients by decreasing the occurrence of readmissions. On the surface, that appears to be a laudable goal and one that we can all support. In an attempt to decrease the readmissions, CMS had incentivized the process by financially rewarding hospitals if they decreased repeat admissions after discharge. Much to the surprise of the health planners, the intervention reported that, although 30-day readmission decreased as the result of the financial incentives, 30-day mortality increased. This was particularly surprising since in numerous drug trials, notably MERIT-HF (Lancet. 1999 Jun 12;353:2001-7), readmission usually tracked closely with mortality.

Beginning in 2012, CMS, using claims data from 2008 to 2012, penalized hospitals if they did not achieve acceptable readmission rates. At the same time, the agency established the Hospital Admission Reduction Program to monitor 30-day mortality and standardize readmission data. The recent data indicate that the incentives did achieve some decrease in rehospitalization but this was associated with a 16.5% relative increase in 30-day mortality. It was of particular concern that in the previous decade there had been a progressive decrease in 30-day mortality (Circulation 2014;130:966-75). The increase in 30-day mortality observed in the 4-year observational period appears to have interrupted the progressive decrease in 30-day mortality, which would have decreased to 30% if not impacted by the plan.

My previous concerns with this type of social experimentation and manipulation of health care was carried out, and as far as I can tell, continues without any oversight and little insight into the possible risks of this process. A better designed study would have provided better understanding of these results and might have mitigated the adverse effects and mortality events. It is suggested that some hospitals actually gamed the system to their economic advantage. In addition, no oversight board was or is in place as we have with drug trials to allow monitors to become aware of adverse events before there any further loss of life occurs.

I would agree that a randomized trial in this environment would be difficult to achieve. Obtaining consent from thousands of patients would also be difficult. Nevertheless, health care planners should not have free rein to modify accepted processes without taking into consideration the potential risks of their intervention.
 

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

 

Nearly 2 years ago I speculated in this column that health planners or health economists would attempt to manipulate the patterns of patient care to influence the cost and/or quality of clinical care. At that time I suggested that, in that event, the intervention should be managed as we have with drug or device trials to ensure the authenticity and accuracy and most of all assuring the safety of the patient. Furthermore, the design should be incorporated in the intervention, that equipoise be present in the arms of the trial and that a safety monitoring board be in place to alert investigators when and if patient safety is threatened. Patient consent should also be obtained.

Little did I know that an example was in play at the time of publication. A study presented at the Heart Failure Society of America meeting indicates that the Centers for Medicare & Medicaid Services, as part of the Affordable Care Act, was carrying out such an experiment in the attempt to lower cost and improve the quality of the care of heart failure patients by decreasing the occurrence of readmissions. On the surface, that appears to be a laudable goal and one that we can all support. In an attempt to decrease the readmissions, CMS had incentivized the process by financially rewarding hospitals if they decreased repeat admissions after discharge. Much to the surprise of the health planners, the intervention reported that, although 30-day readmission decreased as the result of the financial incentives, 30-day mortality increased. This was particularly surprising since in numerous drug trials, notably MERIT-HF (Lancet. 1999 Jun 12;353:2001-7), readmission usually tracked closely with mortality.

Beginning in 2012, CMS, using claims data from 2008 to 2012, penalized hospitals if they did not achieve acceptable readmission rates. At the same time, the agency established the Hospital Admission Reduction Program to monitor 30-day mortality and standardize readmission data. The recent data indicate that the incentives did achieve some decrease in rehospitalization but this was associated with a 16.5% relative increase in 30-day mortality. It was of particular concern that in the previous decade there had been a progressive decrease in 30-day mortality (Circulation 2014;130:966-75). The increase in 30-day mortality observed in the 4-year observational period appears to have interrupted the progressive decrease in 30-day mortality, which would have decreased to 30% if not impacted by the plan.

My previous concerns with this type of social experimentation and manipulation of health care was carried out, and as far as I can tell, continues without any oversight and little insight into the possible risks of this process. A better designed study would have provided better understanding of these results and might have mitigated the adverse effects and mortality events. It is suggested that some hospitals actually gamed the system to their economic advantage. In addition, no oversight board was or is in place as we have with drug trials to allow monitors to become aware of adverse events before there any further loss of life occurs.

I would agree that a randomized trial in this environment would be difficult to achieve. Obtaining consent from thousands of patients would also be difficult. Nevertheless, health care planners should not have free rein to modify accepted processes without taking into consideration the potential risks of their intervention.
 

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

 

Nearly 2 years ago I speculated in this column that health planners or health economists would attempt to manipulate the patterns of patient care to influence the cost and/or quality of clinical care. At that time I suggested that, in that event, the intervention should be managed as we have with drug or device trials to ensure the authenticity and accuracy and most of all assuring the safety of the patient. Furthermore, the design should be incorporated in the intervention, that equipoise be present in the arms of the trial and that a safety monitoring board be in place to alert investigators when and if patient safety is threatened. Patient consent should also be obtained.

Little did I know that an example was in play at the time of publication. A study presented at the Heart Failure Society of America meeting indicates that the Centers for Medicare & Medicaid Services, as part of the Affordable Care Act, was carrying out such an experiment in the attempt to lower cost and improve the quality of the care of heart failure patients by decreasing the occurrence of readmissions. On the surface, that appears to be a laudable goal and one that we can all support. In an attempt to decrease the readmissions, CMS had incentivized the process by financially rewarding hospitals if they decreased repeat admissions after discharge. Much to the surprise of the health planners, the intervention reported that, although 30-day readmission decreased as the result of the financial incentives, 30-day mortality increased. This was particularly surprising since in numerous drug trials, notably MERIT-HF (Lancet. 1999 Jun 12;353:2001-7), readmission usually tracked closely with mortality.

Beginning in 2012, CMS, using claims data from 2008 to 2012, penalized hospitals if they did not achieve acceptable readmission rates. At the same time, the agency established the Hospital Admission Reduction Program to monitor 30-day mortality and standardize readmission data. The recent data indicate that the incentives did achieve some decrease in rehospitalization but this was associated with a 16.5% relative increase in 30-day mortality. It was of particular concern that in the previous decade there had been a progressive decrease in 30-day mortality (Circulation 2014;130:966-75). The increase in 30-day mortality observed in the 4-year observational period appears to have interrupted the progressive decrease in 30-day mortality, which would have decreased to 30% if not impacted by the plan.

My previous concerns with this type of social experimentation and manipulation of health care was carried out, and as far as I can tell, continues without any oversight and little insight into the possible risks of this process. A better designed study would have provided better understanding of these results and might have mitigated the adverse effects and mortality events. It is suggested that some hospitals actually gamed the system to their economic advantage. In addition, no oversight board was or is in place as we have with drug trials to allow monitors to become aware of adverse events before there any further loss of life occurs.

I would agree that a randomized trial in this environment would be difficult to achieve. Obtaining consent from thousands of patients would also be difficult. Nevertheless, health care planners should not have free rein to modify accepted processes without taking into consideration the potential risks of their intervention.
 

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

 

The recent report from the SYNTAX trials should give pause to our interventionalist colleagues embarking on multiple angioplasty and stenting procedures in patients with complex coronary anatomy.

SYNTAX randomized 1,800 patients with left main or triple-vessel coronary artery disease to either percutaneous coronary intervention (PCI) with the TAXUS drug-eluting stent or coronary artery bypass grafting (CABG) after being judged by a heart team as being in equipoise in regard to the appropriateness of either procedure (Eur Heart J. 2011;32;2125-34). The findings of several previous analyses have trended toward benefit for CABG, but none as clearly as SYNTAX. The original study was reported 6 years ago (Lancet 2013 Feb;381:629-38) and indicated that CABG was superior to PCI in patients with complex lesions. The most recent 5-year data of that study (J Am Coll Cardiol. 2016 Jan:67;42-55) indicates that cardiac mortality in the CABG patients is superior to that in the PCI group (5.3% vs. 9.6%, respectively), and the follow-up data provide more in-depth analysis in addition to the mechanism of death. Most importantly, the recent 5-year data clarify the reasons PCI fails to measure up to the results of CABG in patients with complex coronary artery disease.

Although randomized data in regard to the benefit of CABG, compared with medical therapy in this high-risk population, are now available from the STICH 5-year follow-up (N Engl J Med. 2016 Apr 21;374:1511-20), information about the long-term benefit of PCI, compared with medical therapy, does not exist. SYNTAX provides us at least a reference point in regard to the relative benefit of these two interventions. The recent analysis assists the interventional cardiologist and surgeon in making the choice between these two procedures based on anatomy. The joint decision making that has evolved in the last few years in regard to valvular surgery appears to have had an impact on the decision-making process in other cardiosurgical procedures, and particularly coronary artery interventions.

One of the overriding predictors of increased mortality with PCI is the increased complexity of anatomy. The higher SYNTAX score was related to incomplete revascularization using PCI, compared with CABG. The presence of concomitant peripheral and carotid vascular disease, in addition to a left ventricular ejection fraction of less than 30%, favored the CABG group. Multiple stents and stent thrombosis were also issues leading to the increased mortality in the PCI group. The main cause of death was recurrent myocardial infarction, which occurred more frequently in the PCI patients and was associated with incomplete revascularization.

The data in the SYNTAX follow-up is not new, but do reinforce what has been reported in previous meta-analyses. This study does, however, emphasize the importance of recurrent infarction as a cause of death in these patients with complex anatomy. It is possible that new stent technology and coronary flow assessment at the time of intervention could have improved the outcome of this comparison and improved the long-term patency of the stented vessels. PCI is an evolving technology heavily affected by the experience of the operator. CABG surgery has also changed, and its associated mortality and morbidity have also changed and improved. It is clear that this population raises important questions in which the operators need to individualize their decision based on trials like SYNTAX.

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

 

The recent report from the SYNTAX trials should give pause to our interventionalist colleagues embarking on multiple angioplasty and stenting procedures in patients with complex coronary anatomy.

SYNTAX randomized 1,800 patients with left main or triple-vessel coronary artery disease to either percutaneous coronary intervention (PCI) with the TAXUS drug-eluting stent or coronary artery bypass grafting (CABG) after being judged by a heart team as being in equipoise in regard to the appropriateness of either procedure (Eur Heart J. 2011;32;2125-34). The findings of several previous analyses have trended toward benefit for CABG, but none as clearly as SYNTAX. The original study was reported 6 years ago (Lancet 2013 Feb;381:629-38) and indicated that CABG was superior to PCI in patients with complex lesions. The most recent 5-year data of that study (J Am Coll Cardiol. 2016 Jan:67;42-55) indicates that cardiac mortality in the CABG patients is superior to that in the PCI group (5.3% vs. 9.6%, respectively), and the follow-up data provide more in-depth analysis in addition to the mechanism of death. Most importantly, the recent 5-year data clarify the reasons PCI fails to measure up to the results of CABG in patients with complex coronary artery disease.

Although randomized data in regard to the benefit of CABG, compared with medical therapy in this high-risk population, are now available from the STICH 5-year follow-up (N Engl J Med. 2016 Apr 21;374:1511-20), information about the long-term benefit of PCI, compared with medical therapy, does not exist. SYNTAX provides us at least a reference point in regard to the relative benefit of these two interventions. The recent analysis assists the interventional cardiologist and surgeon in making the choice between these two procedures based on anatomy. The joint decision making that has evolved in the last few years in regard to valvular surgery appears to have had an impact on the decision-making process in other cardiosurgical procedures, and particularly coronary artery interventions.

One of the overriding predictors of increased mortality with PCI is the increased complexity of anatomy. The higher SYNTAX score was related to incomplete revascularization using PCI, compared with CABG. The presence of concomitant peripheral and carotid vascular disease, in addition to a left ventricular ejection fraction of less than 30%, favored the CABG group. Multiple stents and stent thrombosis were also issues leading to the increased mortality in the PCI group. The main cause of death was recurrent myocardial infarction, which occurred more frequently in the PCI patients and was associated with incomplete revascularization.

The data in the SYNTAX follow-up is not new, but do reinforce what has been reported in previous meta-analyses. This study does, however, emphasize the importance of recurrent infarction as a cause of death in these patients with complex anatomy. It is possible that new stent technology and coronary flow assessment at the time of intervention could have improved the outcome of this comparison and improved the long-term patency of the stented vessels. PCI is an evolving technology heavily affected by the experience of the operator. CABG surgery has also changed, and its associated mortality and morbidity have also changed and improved. It is clear that this population raises important questions in which the operators need to individualize their decision based on trials like SYNTAX.

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

 

The recent report from the SYNTAX trials should give pause to our interventionalist colleagues embarking on multiple angioplasty and stenting procedures in patients with complex coronary anatomy.

SYNTAX randomized 1,800 patients with left main or triple-vessel coronary artery disease to either percutaneous coronary intervention (PCI) with the TAXUS drug-eluting stent or coronary artery bypass grafting (CABG) after being judged by a heart team as being in equipoise in regard to the appropriateness of either procedure (Eur Heart J. 2011;32;2125-34). The findings of several previous analyses have trended toward benefit for CABG, but none as clearly as SYNTAX. The original study was reported 6 years ago (Lancet 2013 Feb;381:629-38) and indicated that CABG was superior to PCI in patients with complex lesions. The most recent 5-year data of that study (J Am Coll Cardiol. 2016 Jan:67;42-55) indicates that cardiac mortality in the CABG patients is superior to that in the PCI group (5.3% vs. 9.6%, respectively), and the follow-up data provide more in-depth analysis in addition to the mechanism of death. Most importantly, the recent 5-year data clarify the reasons PCI fails to measure up to the results of CABG in patients with complex coronary artery disease.

Although randomized data in regard to the benefit of CABG, compared with medical therapy in this high-risk population, are now available from the STICH 5-year follow-up (N Engl J Med. 2016 Apr 21;374:1511-20), information about the long-term benefit of PCI, compared with medical therapy, does not exist. SYNTAX provides us at least a reference point in regard to the relative benefit of these two interventions. The recent analysis assists the interventional cardiologist and surgeon in making the choice between these two procedures based on anatomy. The joint decision making that has evolved in the last few years in regard to valvular surgery appears to have had an impact on the decision-making process in other cardiosurgical procedures, and particularly coronary artery interventions.

One of the overriding predictors of increased mortality with PCI is the increased complexity of anatomy. The higher SYNTAX score was related to incomplete revascularization using PCI, compared with CABG. The presence of concomitant peripheral and carotid vascular disease, in addition to a left ventricular ejection fraction of less than 30%, favored the CABG group. Multiple stents and stent thrombosis were also issues leading to the increased mortality in the PCI group. The main cause of death was recurrent myocardial infarction, which occurred more frequently in the PCI patients and was associated with incomplete revascularization.

The data in the SYNTAX follow-up is not new, but do reinforce what has been reported in previous meta-analyses. This study does, however, emphasize the importance of recurrent infarction as a cause of death in these patients with complex anatomy. It is possible that new stent technology and coronary flow assessment at the time of intervention could have improved the outcome of this comparison and improved the long-term patency of the stented vessels. PCI is an evolving technology heavily affected by the experience of the operator. CABG surgery has also changed, and its associated mortality and morbidity have also changed and improved. It is clear that this population raises important questions in which the operators need to individualize their decision based on trials like SYNTAX.

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

 

Shakespeare, in Romeo and Juliet, refers to the proverb, “A cat has nine lives. For three he plays, for three he strays, and for the last he stays.”

TOPCAT is back again, having randomized its first patient with heart failure with preserved ejection fraction (HFpEF) almost 10 years ago for its treatment with spironolactone (SPIRO), a mineralocorticoid receptor antagonist.

HFpEF is a poorly described clinical entity as well as an elusive therapeutic topic. Clinically, it encompasses individuals who develop clinical heart failure with normal ejection fraction but with a number of associated precipitating events, including hypertension, arrhythmia, and often underlying pulmonary disease. A number of drugs, including beta-blockers and renin angiotensin-converting enzyme inhibitors, have been studied with variable and unconvincing results. Guideline committees have wrestled with advice for the treatment of HFpEF issue for a number of years. SPIRO, which has been shown to be effective in heart failure with reduced ejection fraction, seemed to be a likely candidate for its treatment. Many of the heart failure gurus had great expectation that TOPCAT would prove its benefit.

The first report of the results of TOPCAT in 2014 indicated that there was no benefit associate with SPIRO therapy tested in the 3,445 patients randomized in 244 sites around the world (N Engl J Med. 2014 Apr 10;370[15]:1383-92). A subsequent analysis of data carried out in 2015 reported a striking regional difference in the outcome of patients randomized in the 1,767 patients in the Americas, compared with the 1,678 randomized in Russia and Georgia (Circulation. 2015 Jan 6;131[1]:34-42). In the Americas, there was an 18% decrease in the primary event of death and heart failure rehospitalization (3.6% in the SPIRO vs. 4.9% in the placebo; hazard ratio, 0.82; P = .026). There was essentially no difference in the groups randomized in Russia and Georgia, which had a 1.6% placebo event rate.

And now in 2016, at the recent meeting of the Heart Failure Society of America, we were informed that there was no detectable level of blood canrenone, a metabolite of SPIRO, in 30% of the 66 randomized patients in Russia and Georgia, compared with 3% of the patients randomized in the Americas (Cardiology News. Oct 2016. p 8). These data tend to confirm that the patients randomized in Russia and Georgia were either undertreated or not treated. In fact, after examination of the baseline characteristics of the two groups it is possible that many of the patients may not have had heart failure at all.

So what are we left with? One thing that is clear is that the management of TOPCAT was flawed and constitutes an example of how not to run an international clinical trial. Can we make any conclusion about the benefit of SPIRO? TOPCAT initially was powered for over 3,515 patients and 630 events in order to achieve a 85% benefit. The current analysis has now narrowed the population down to 1,787 patients with 522 events with an 18% decrease (P = .02) in the primary end point. During the mean follow-up of 3.3 years there was a placebo mortality of 4.9%, which is impressive in the setting of concomitant beta-blocker and renin angiotensin-converting enzyme inhibitor therapy. The only significant adverse observation was a threefold occurrence in hyperkalemia (potassium greater than 5.5 mmols/L) in the 25.2% in the Americas group treated with SPIRO, compared with the Russian-Georgian patients

Unfortunately the answer is not entirely clear. We all know who HFpEF patients are when they walk into the clinic but identifying them for a clinical trial has been difficult if not impossible. As for me, I will choose to treat their hypertension aggressively (not an easy task) and prevent or suppress their arrhythmias. In that project I will use beta-blockers and SPIRO to prevent their next heart failure episode and hope for the best.
 

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

 

Shakespeare, in Romeo and Juliet, refers to the proverb, “A cat has nine lives. For three he plays, for three he strays, and for the last he stays.”

TOPCAT is back again, having randomized its first patient with heart failure with preserved ejection fraction (HFpEF) almost 10 years ago for its treatment with spironolactone (SPIRO), a mineralocorticoid receptor antagonist.

HFpEF is a poorly described clinical entity as well as an elusive therapeutic topic. Clinically, it encompasses individuals who develop clinical heart failure with normal ejection fraction but with a number of associated precipitating events, including hypertension, arrhythmia, and often underlying pulmonary disease. A number of drugs, including beta-blockers and renin angiotensin-converting enzyme inhibitors, have been studied with variable and unconvincing results. Guideline committees have wrestled with advice for the treatment of HFpEF issue for a number of years. SPIRO, which has been shown to be effective in heart failure with reduced ejection fraction, seemed to be a likely candidate for its treatment. Many of the heart failure gurus had great expectation that TOPCAT would prove its benefit.

The first report of the results of TOPCAT in 2014 indicated that there was no benefit associate with SPIRO therapy tested in the 3,445 patients randomized in 244 sites around the world (N Engl J Med. 2014 Apr 10;370[15]:1383-92). A subsequent analysis of data carried out in 2015 reported a striking regional difference in the outcome of patients randomized in the 1,767 patients in the Americas, compared with the 1,678 randomized in Russia and Georgia (Circulation. 2015 Jan 6;131[1]:34-42). In the Americas, there was an 18% decrease in the primary event of death and heart failure rehospitalization (3.6% in the SPIRO vs. 4.9% in the placebo; hazard ratio, 0.82; P = .026). There was essentially no difference in the groups randomized in Russia and Georgia, which had a 1.6% placebo event rate.

And now in 2016, at the recent meeting of the Heart Failure Society of America, we were informed that there was no detectable level of blood canrenone, a metabolite of SPIRO, in 30% of the 66 randomized patients in Russia and Georgia, compared with 3% of the patients randomized in the Americas (Cardiology News. Oct 2016. p 8). These data tend to confirm that the patients randomized in Russia and Georgia were either undertreated or not treated. In fact, after examination of the baseline characteristics of the two groups it is possible that many of the patients may not have had heart failure at all.

So what are we left with? One thing that is clear is that the management of TOPCAT was flawed and constitutes an example of how not to run an international clinical trial. Can we make any conclusion about the benefit of SPIRO? TOPCAT initially was powered for over 3,515 patients and 630 events in order to achieve a 85% benefit. The current analysis has now narrowed the population down to 1,787 patients with 522 events with an 18% decrease (P = .02) in the primary end point. During the mean follow-up of 3.3 years there was a placebo mortality of 4.9%, which is impressive in the setting of concomitant beta-blocker and renin angiotensin-converting enzyme inhibitor therapy. The only significant adverse observation was a threefold occurrence in hyperkalemia (potassium greater than 5.5 mmols/L) in the 25.2% in the Americas group treated with SPIRO, compared with the Russian-Georgian patients

Unfortunately the answer is not entirely clear. We all know who HFpEF patients are when they walk into the clinic but identifying them for a clinical trial has been difficult if not impossible. As for me, I will choose to treat their hypertension aggressively (not an easy task) and prevent or suppress their arrhythmias. In that project I will use beta-blockers and SPIRO to prevent their next heart failure episode and hope for the best.
 

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

 

Shakespeare, in Romeo and Juliet, refers to the proverb, “A cat has nine lives. For three he plays, for three he strays, and for the last he stays.”

TOPCAT is back again, having randomized its first patient with heart failure with preserved ejection fraction (HFpEF) almost 10 years ago for its treatment with spironolactone (SPIRO), a mineralocorticoid receptor antagonist.

HFpEF is a poorly described clinical entity as well as an elusive therapeutic topic. Clinically, it encompasses individuals who develop clinical heart failure with normal ejection fraction but with a number of associated precipitating events, including hypertension, arrhythmia, and often underlying pulmonary disease. A number of drugs, including beta-blockers and renin angiotensin-converting enzyme inhibitors, have been studied with variable and unconvincing results. Guideline committees have wrestled with advice for the treatment of HFpEF issue for a number of years. SPIRO, which has been shown to be effective in heart failure with reduced ejection fraction, seemed to be a likely candidate for its treatment. Many of the heart failure gurus had great expectation that TOPCAT would prove its benefit.

The first report of the results of TOPCAT in 2014 indicated that there was no benefit associate with SPIRO therapy tested in the 3,445 patients randomized in 244 sites around the world (N Engl J Med. 2014 Apr 10;370[15]:1383-92). A subsequent analysis of data carried out in 2015 reported a striking regional difference in the outcome of patients randomized in the 1,767 patients in the Americas, compared with the 1,678 randomized in Russia and Georgia (Circulation. 2015 Jan 6;131[1]:34-42). In the Americas, there was an 18% decrease in the primary event of death and heart failure rehospitalization (3.6% in the SPIRO vs. 4.9% in the placebo; hazard ratio, 0.82; P = .026). There was essentially no difference in the groups randomized in Russia and Georgia, which had a 1.6% placebo event rate.

And now in 2016, at the recent meeting of the Heart Failure Society of America, we were informed that there was no detectable level of blood canrenone, a metabolite of SPIRO, in 30% of the 66 randomized patients in Russia and Georgia, compared with 3% of the patients randomized in the Americas (Cardiology News. Oct 2016. p 8). These data tend to confirm that the patients randomized in Russia and Georgia were either undertreated or not treated. In fact, after examination of the baseline characteristics of the two groups it is possible that many of the patients may not have had heart failure at all.

So what are we left with? One thing that is clear is that the management of TOPCAT was flawed and constitutes an example of how not to run an international clinical trial. Can we make any conclusion about the benefit of SPIRO? TOPCAT initially was powered for over 3,515 patients and 630 events in order to achieve a 85% benefit. The current analysis has now narrowed the population down to 1,787 patients with 522 events with an 18% decrease (P = .02) in the primary end point. During the mean follow-up of 3.3 years there was a placebo mortality of 4.9%, which is impressive in the setting of concomitant beta-blocker and renin angiotensin-converting enzyme inhibitor therapy. The only significant adverse observation was a threefold occurrence in hyperkalemia (potassium greater than 5.5 mmols/L) in the 25.2% in the Americas group treated with SPIRO, compared with the Russian-Georgian patients

Unfortunately the answer is not entirely clear. We all know who HFpEF patients are when they walk into the clinic but identifying them for a clinical trial has been difficult if not impossible. As for me, I will choose to treat their hypertension aggressively (not an easy task) and prevent or suppress their arrhythmias. In that project I will use beta-blockers and SPIRO to prevent their next heart failure episode and hope for the best.
 

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

A good way to survive an acute myocardial infarction is to go to the best hospital.

Some patients seem to have found out where those are. For those of us who want to know where to go and what to look for, a recent analysis of 800,000 Medicare patients admitted with acute myocardial infarction (AMI) and heart failure in 10,000 hospitals between 2008 and 2009 provides some reassuring news (National Bureau of Economic Research Working Paper 21603). Its findings indicated that in an era when health care choice is seemingly influenced by testimonial TV ads and the creation of hospitals that look like hotels, technical medical quality outranks all the glitz and bricks. Quality was measured by hospital mortality, 30-day readmissions, adherence to well-established guidelines, and patient satisfaction questionnaires. The investigators measured the effect that medical quality and the “comfort quotient” had on the growth of hospital patient volume through the emergency departments and interhospital referrals.

Hospital admissions increased in hospitals with the highest-quality performance. Over the 2-year period, the hospitals with the highest-quality performance had increases in hospital volume. Hospitals with a 1% improvement in the adjusted AMI mortality had a 17% increase in market share and a 1.5 % growth rate.

The authors estimated that patients with an AMI (or their family) were willing to travel an additional 1.8 miles for an ED admission to a hospital with a higher survival rate, and 34 miles further for a transfer to a hospital with a higher survival rate. When patients had the option to choose a hospital to be transferred to for further care, quality of care measures had an even greater impact on choice. Postdischarge evaluation of patient satisfaction had little or no effect on growth.

Patients admitted through the ED have the least chance for hospital choice, but even in these patients knowledge about quality influenced the choice of the hospital and the long-term hospital growth rate. Considering the fact that there is scant information available either to patients or even doctors about quality measures, there appears to be a choice process either by patient family, doctor, or ambulance driver to direct patients to the hospital with the best survival rate.

How they made those decisions is not clear. Comparative hospital survival data are rarely transmitted to staff physicians and are not widely available to the public. I have never seen any data like these in the multitude of hospital TV ads, yet somehow those numbers, real or perceived, affected admission and transfer. Maybe it’s just reputation; we all know about that. If you are really interested, you can find hospital medical quality and patient experience data at Medicare’s Hospital Compare site.

All this is good. Medical quality wins. Other studies, however, suggest that usually the “comfort quotient” and measures of medical quality are more closely linked. It has also been suggested that volume is the driving force for the improvement in both quality measures by providing the resources and logistics for better care. Whatever the mechanism, it seems that high-quality medical care is not a bad way to choose which neighborhood hospital to go to in order to survive an AMI.

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

A good way to survive an acute myocardial infarction is to go to the best hospital.

Some patients seem to have found out where those are. For those of us who want to know where to go and what to look for, a recent analysis of 800,000 Medicare patients admitted with acute myocardial infarction (AMI) and heart failure in 10,000 hospitals between 2008 and 2009 provides some reassuring news (National Bureau of Economic Research Working Paper 21603). Its findings indicated that in an era when health care choice is seemingly influenced by testimonial TV ads and the creation of hospitals that look like hotels, technical medical quality outranks all the glitz and bricks. Quality was measured by hospital mortality, 30-day readmissions, adherence to well-established guidelines, and patient satisfaction questionnaires. The investigators measured the effect that medical quality and the “comfort quotient” had on the growth of hospital patient volume through the emergency departments and interhospital referrals.

Hospital admissions increased in hospitals with the highest-quality performance. Over the 2-year period, the hospitals with the highest-quality performance had increases in hospital volume. Hospitals with a 1% improvement in the adjusted AMI mortality had a 17% increase in market share and a 1.5 % growth rate.

The authors estimated that patients with an AMI (or their family) were willing to travel an additional 1.8 miles for an ED admission to a hospital with a higher survival rate, and 34 miles further for a transfer to a hospital with a higher survival rate. When patients had the option to choose a hospital to be transferred to for further care, quality of care measures had an even greater impact on choice. Postdischarge evaluation of patient satisfaction had little or no effect on growth.

Patients admitted through the ED have the least chance for hospital choice, but even in these patients knowledge about quality influenced the choice of the hospital and the long-term hospital growth rate. Considering the fact that there is scant information available either to patients or even doctors about quality measures, there appears to be a choice process either by patient family, doctor, or ambulance driver to direct patients to the hospital with the best survival rate.

How they made those decisions is not clear. Comparative hospital survival data are rarely transmitted to staff physicians and are not widely available to the public. I have never seen any data like these in the multitude of hospital TV ads, yet somehow those numbers, real or perceived, affected admission and transfer. Maybe it’s just reputation; we all know about that. If you are really interested, you can find hospital medical quality and patient experience data at Medicare’s Hospital Compare site.

All this is good. Medical quality wins. Other studies, however, suggest that usually the “comfort quotient” and measures of medical quality are more closely linked. It has also been suggested that volume is the driving force for the improvement in both quality measures by providing the resources and logistics for better care. Whatever the mechanism, it seems that high-quality medical care is not a bad way to choose which neighborhood hospital to go to in order to survive an AMI.

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

A good way to survive an acute myocardial infarction is to go to the best hospital.

Some patients seem to have found out where those are. For those of us who want to know where to go and what to look for, a recent analysis of 800,000 Medicare patients admitted with acute myocardial infarction (AMI) and heart failure in 10,000 hospitals between 2008 and 2009 provides some reassuring news (National Bureau of Economic Research Working Paper 21603). Its findings indicated that in an era when health care choice is seemingly influenced by testimonial TV ads and the creation of hospitals that look like hotels, technical medical quality outranks all the glitz and bricks. Quality was measured by hospital mortality, 30-day readmissions, adherence to well-established guidelines, and patient satisfaction questionnaires. The investigators measured the effect that medical quality and the “comfort quotient” had on the growth of hospital patient volume through the emergency departments and interhospital referrals.

Hospital admissions increased in hospitals with the highest-quality performance. Over the 2-year period, the hospitals with the highest-quality performance had increases in hospital volume. Hospitals with a 1% improvement in the adjusted AMI mortality had a 17% increase in market share and a 1.5 % growth rate.

The authors estimated that patients with an AMI (or their family) were willing to travel an additional 1.8 miles for an ED admission to a hospital with a higher survival rate, and 34 miles further for a transfer to a hospital with a higher survival rate. When patients had the option to choose a hospital to be transferred to for further care, quality of care measures had an even greater impact on choice. Postdischarge evaluation of patient satisfaction had little or no effect on growth.

Patients admitted through the ED have the least chance for hospital choice, but even in these patients knowledge about quality influenced the choice of the hospital and the long-term hospital growth rate. Considering the fact that there is scant information available either to patients or even doctors about quality measures, there appears to be a choice process either by patient family, doctor, or ambulance driver to direct patients to the hospital with the best survival rate.

How they made those decisions is not clear. Comparative hospital survival data are rarely transmitted to staff physicians and are not widely available to the public. I have never seen any data like these in the multitude of hospital TV ads, yet somehow those numbers, real or perceived, affected admission and transfer. Maybe it’s just reputation; we all know about that. If you are really interested, you can find hospital medical quality and patient experience data at Medicare’s Hospital Compare site.

All this is good. Medical quality wins. Other studies, however, suggest that usually the “comfort quotient” and measures of medical quality are more closely linked. It has also been suggested that volume is the driving force for the improvement in both quality measures by providing the resources and logistics for better care. Whatever the mechanism, it seems that high-quality medical care is not a bad way to choose which neighborhood hospital to go to in order to survive an AMI.

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

Walking around the Cardiac Intensive Care Unit (CICU) with one of my heart failure colleagues, I was struck by the relative absence of patients with acute myocardial infarctions. Over the past 50 years, they have been replaced by patients with advanced heart failure, many of whom had been implanted with left ventricular assist devices or connected to a variety of extracorporeal support devices.

Although some of the patients were new New York Heart Association class IV patients, many had been treated for years with beta-blockers and renal ACE inhibitors or aldosterone antagonists. Their disease had now recurred and progressed despite what I had presumed to be curative drug therapy. They were experiencing the relentless progression of heart failure despite treatment that was developed almost 20 years ago and which has not advanced much since then. Many cardiologists of my generation presumed that heart failure was no longer a problem even though we knew that annual mortality rates of heart failure remained in the 10% range and that its incidence was increasing.

It has become clear to many of us that there has been little advance in the treatment of heart failure since the introduction of those 20th century drugs, notwithstanding the importance of the development of end stage cardiac support devices.

It seems our success in treating patients with ischemic heart disease had only delayed the expression and progression of cardiac dysfunction. Even with our success in treating patients with nonischemic heart failure, whatever that is, after reaching a brief plateau with drug therapy, they often experienced recurrence. It is true that many patients had improved as a result of drug therapy and that progression had been arrested and in some patients heart failure had actually been reversed. But many, like the patients I saw in our CICU, had progressed to advanced heart failure with little to be offered other than end-stage device therapy or heart transplantation. Both of these outcomes, although lifesaving, represent therapeutic failures.

It is time that we refocus our efforts on the treatment and eradication of heart failure. Although a number of contemporary treatment strategies have been developed, for the most part they have only resulted in modest additive benefit. We need to reconsider the protection of the heart during and after an ischemic event and prevent the insidious progression of ischemia in those patients with chronic coronary heart disease. In addition we need to direct our research to understand the pathophysiology of the “heart” in heart failure and to unlock the mysticism associated with the many etiologies of idiopathic nonischemic heart failure. Our knowledge in this disease or diseases is embarrassingly poor.

It is time to move on from the 20th century drug foundation of therapy based on neurohumoral control, to a 21st century understanding of the cellular and molecular targets affecting cardiac function. Recent investigations of collagen synthesis and degradation, cardiac energetics, and mitochondrial function have provided provocative information but represent only forays into the vast unknown mechanism of heart failure. The solution to worldwide heart failure is not in device therapy for everyone but in a deeper understanding of the mechanisms of heart failure and its application to therapy.

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

Walking around the Cardiac Intensive Care Unit (CICU) with one of my heart failure colleagues, I was struck by the relative absence of patients with acute myocardial infarctions. Over the past 50 years, they have been replaced by patients with advanced heart failure, many of whom had been implanted with left ventricular assist devices or connected to a variety of extracorporeal support devices.

Although some of the patients were new New York Heart Association class IV patients, many had been treated for years with beta-blockers and renal ACE inhibitors or aldosterone antagonists. Their disease had now recurred and progressed despite what I had presumed to be curative drug therapy. They were experiencing the relentless progression of heart failure despite treatment that was developed almost 20 years ago and which has not advanced much since then. Many cardiologists of my generation presumed that heart failure was no longer a problem even though we knew that annual mortality rates of heart failure remained in the 10% range and that its incidence was increasing.

It has become clear to many of us that there has been little advance in the treatment of heart failure since the introduction of those 20th century drugs, notwithstanding the importance of the development of end stage cardiac support devices.

It seems our success in treating patients with ischemic heart disease had only delayed the expression and progression of cardiac dysfunction. Even with our success in treating patients with nonischemic heart failure, whatever that is, after reaching a brief plateau with drug therapy, they often experienced recurrence. It is true that many patients had improved as a result of drug therapy and that progression had been arrested and in some patients heart failure had actually been reversed. But many, like the patients I saw in our CICU, had progressed to advanced heart failure with little to be offered other than end-stage device therapy or heart transplantation. Both of these outcomes, although lifesaving, represent therapeutic failures.

It is time that we refocus our efforts on the treatment and eradication of heart failure. Although a number of contemporary treatment strategies have been developed, for the most part they have only resulted in modest additive benefit. We need to reconsider the protection of the heart during and after an ischemic event and prevent the insidious progression of ischemia in those patients with chronic coronary heart disease. In addition we need to direct our research to understand the pathophysiology of the “heart” in heart failure and to unlock the mysticism associated with the many etiologies of idiopathic nonischemic heart failure. Our knowledge in this disease or diseases is embarrassingly poor.

It is time to move on from the 20th century drug foundation of therapy based on neurohumoral control, to a 21st century understanding of the cellular and molecular targets affecting cardiac function. Recent investigations of collagen synthesis and degradation, cardiac energetics, and mitochondrial function have provided provocative information but represent only forays into the vast unknown mechanism of heart failure. The solution to worldwide heart failure is not in device therapy for everyone but in a deeper understanding of the mechanisms of heart failure and its application to therapy.

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

Walking around the Cardiac Intensive Care Unit (CICU) with one of my heart failure colleagues, I was struck by the relative absence of patients with acute myocardial infarctions. Over the past 50 years, they have been replaced by patients with advanced heart failure, many of whom had been implanted with left ventricular assist devices or connected to a variety of extracorporeal support devices.

Although some of the patients were new New York Heart Association class IV patients, many had been treated for years with beta-blockers and renal ACE inhibitors or aldosterone antagonists. Their disease had now recurred and progressed despite what I had presumed to be curative drug therapy. They were experiencing the relentless progression of heart failure despite treatment that was developed almost 20 years ago and which has not advanced much since then. Many cardiologists of my generation presumed that heart failure was no longer a problem even though we knew that annual mortality rates of heart failure remained in the 10% range and that its incidence was increasing.

It has become clear to many of us that there has been little advance in the treatment of heart failure since the introduction of those 20th century drugs, notwithstanding the importance of the development of end stage cardiac support devices.

It seems our success in treating patients with ischemic heart disease had only delayed the expression and progression of cardiac dysfunction. Even with our success in treating patients with nonischemic heart failure, whatever that is, after reaching a brief plateau with drug therapy, they often experienced recurrence. It is true that many patients had improved as a result of drug therapy and that progression had been arrested and in some patients heart failure had actually been reversed. But many, like the patients I saw in our CICU, had progressed to advanced heart failure with little to be offered other than end-stage device therapy or heart transplantation. Both of these outcomes, although lifesaving, represent therapeutic failures.

It is time that we refocus our efforts on the treatment and eradication of heart failure. Although a number of contemporary treatment strategies have been developed, for the most part they have only resulted in modest additive benefit. We need to reconsider the protection of the heart during and after an ischemic event and prevent the insidious progression of ischemia in those patients with chronic coronary heart disease. In addition we need to direct our research to understand the pathophysiology of the “heart” in heart failure and to unlock the mysticism associated with the many etiologies of idiopathic nonischemic heart failure. Our knowledge in this disease or diseases is embarrassingly poor.

It is time to move on from the 20th century drug foundation of therapy based on neurohumoral control, to a 21st century understanding of the cellular and molecular targets affecting cardiac function. Recent investigations of collagen synthesis and degradation, cardiac energetics, and mitochondrial function have provided provocative information but represent only forays into the vast unknown mechanism of heart failure. The solution to worldwide heart failure is not in device therapy for everyone but in a deeper understanding of the mechanisms of heart failure and its application to therapy.

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

At a time when therapeutics is emphasizing personalized therapy, it is reassuring that someone is interested in the big picture. Treating a single patient with drugs that cost $500 a pill seems in conflict with the needs of millions of individuals who might have the expression of cardiovascular disease delayed with a pill that might cost pennies.

Dr. Saleem Yusuf originated the concept of the polypill more than 10 years ago by proposing to make one simple pill to mitigate the effect of aging on cardiovascular mortality, particularly in the underdeveloped and rapidly aging countries of the world. Working at the Population Health Research Institute at the McMaster University in Canada, he has moved through a number of iterations of the original Polypill, the most recent reported from the Heart Outcomes Evaluation (HOPE-3) trial (N Engl J Med. 2016 May; 374:2021-31). HOPE-3 distilled the initial polypill array of five drugs (three antihypertensives, a statin, and an aspirin) down to a combination of three drugs; two hypertensives and a statin. One hypertension drug was discarded in the face of concerns of the potential of symptomatic hypotension, and aspirin because of its bleeding potential.

HOPE-3 included 12,705 patients in 21 countries around the world with 50% coming from Asia and China, 80% of whom were nonwhite. Patients aged at least 55 (men) and 65 (women) years with only one cardiovascular risk factor and with systolic pressure less than 160 mm Hg, were followed for 5.6 years. Patients were randomized to a combination of hypertension medications (candesartan, 16 mg, and hydrochlorothiazide, 12.5 mg), a statin (rosuvastatin, 10 mg) or both, or to placebo. The hypertension drug combination was successful in lowering the systolic pressure at randomization of 138/81 by 10 mm Hg but had no effect on cardiovascular mortality or morbidity. In contrast, the rosuvastatin arm successfully lowered the mean LDL cholesterol of 127.8 mg/dL by 26.5% at the conclusion of the trial. This was associated with a 24% decrease in the combined cardiovascular morbidity and mortality endpoint and a decrease in myocardial infarction and stroke of 35% and 30% respectively. The addition of the hypertension drugs to rosuvastatin added little to the morbidity and mortality benefit observed with rosuvastatin alone.

The initial concept of the polypill was greeted with considerable skepticism by the medical community, which has viewed attacking cardiovascular mortality as a one-on-one experience between patient and doctor. This, despite the benefit of a broad array of prevention efforts, including lifestyle and hypertension therapy that has occurred over the last half-century.

The concept of a polypill with five different medications appears to have failed, but its outcome refined to just to one statin is a message of great importance. In a universe of indigent and undertreated humans, the need for some form of intervention seems to be a crying one. The results of HOPE-3 are consistent with JUPITER and other statin lipid-lowering trials and indicates that just treating cholesterol alone in this low-risk population achieved significant benefit of itself. Application of such an intervention in the Third World could have an important benefit. The cost of such an intervention is minimal, compared with the recent additions to the cardiovascular pharmacopeia in both heart failure and lipid therapy.

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

At a time when therapeutics is emphasizing personalized therapy, it is reassuring that someone is interested in the big picture. Treating a single patient with drugs that cost $500 a pill seems in conflict with the needs of millions of individuals who might have the expression of cardiovascular disease delayed with a pill that might cost pennies.

Dr. Saleem Yusuf originated the concept of the polypill more than 10 years ago by proposing to make one simple pill to mitigate the effect of aging on cardiovascular mortality, particularly in the underdeveloped and rapidly aging countries of the world. Working at the Population Health Research Institute at the McMaster University in Canada, he has moved through a number of iterations of the original Polypill, the most recent reported from the Heart Outcomes Evaluation (HOPE-3) trial (N Engl J Med. 2016 May; 374:2021-31). HOPE-3 distilled the initial polypill array of five drugs (three antihypertensives, a statin, and an aspirin) down to a combination of three drugs; two hypertensives and a statin. One hypertension drug was discarded in the face of concerns of the potential of symptomatic hypotension, and aspirin because of its bleeding potential.

HOPE-3 included 12,705 patients in 21 countries around the world with 50% coming from Asia and China, 80% of whom were nonwhite. Patients aged at least 55 (men) and 65 (women) years with only one cardiovascular risk factor and with systolic pressure less than 160 mm Hg, were followed for 5.6 years. Patients were randomized to a combination of hypertension medications (candesartan, 16 mg, and hydrochlorothiazide, 12.5 mg), a statin (rosuvastatin, 10 mg) or both, or to placebo. The hypertension drug combination was successful in lowering the systolic pressure at randomization of 138/81 by 10 mm Hg but had no effect on cardiovascular mortality or morbidity. In contrast, the rosuvastatin arm successfully lowered the mean LDL cholesterol of 127.8 mg/dL by 26.5% at the conclusion of the trial. This was associated with a 24% decrease in the combined cardiovascular morbidity and mortality endpoint and a decrease in myocardial infarction and stroke of 35% and 30% respectively. The addition of the hypertension drugs to rosuvastatin added little to the morbidity and mortality benefit observed with rosuvastatin alone.

The initial concept of the polypill was greeted with considerable skepticism by the medical community, which has viewed attacking cardiovascular mortality as a one-on-one experience between patient and doctor. This, despite the benefit of a broad array of prevention efforts, including lifestyle and hypertension therapy that has occurred over the last half-century.

The concept of a polypill with five different medications appears to have failed, but its outcome refined to just to one statin is a message of great importance. In a universe of indigent and undertreated humans, the need for some form of intervention seems to be a crying one. The results of HOPE-3 are consistent with JUPITER and other statin lipid-lowering trials and indicates that just treating cholesterol alone in this low-risk population achieved significant benefit of itself. Application of such an intervention in the Third World could have an important benefit. The cost of such an intervention is minimal, compared with the recent additions to the cardiovascular pharmacopeia in both heart failure and lipid therapy.

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

At a time when therapeutics is emphasizing personalized therapy, it is reassuring that someone is interested in the big picture. Treating a single patient with drugs that cost $500 a pill seems in conflict with the needs of millions of individuals who might have the expression of cardiovascular disease delayed with a pill that might cost pennies.

Dr. Saleem Yusuf originated the concept of the polypill more than 10 years ago by proposing to make one simple pill to mitigate the effect of aging on cardiovascular mortality, particularly in the underdeveloped and rapidly aging countries of the world. Working at the Population Health Research Institute at the McMaster University in Canada, he has moved through a number of iterations of the original Polypill, the most recent reported from the Heart Outcomes Evaluation (HOPE-3) trial (N Engl J Med. 2016 May; 374:2021-31). HOPE-3 distilled the initial polypill array of five drugs (three antihypertensives, a statin, and an aspirin) down to a combination of three drugs; two hypertensives and a statin. One hypertension drug was discarded in the face of concerns of the potential of symptomatic hypotension, and aspirin because of its bleeding potential.

HOPE-3 included 12,705 patients in 21 countries around the world with 50% coming from Asia and China, 80% of whom were nonwhite. Patients aged at least 55 (men) and 65 (women) years with only one cardiovascular risk factor and with systolic pressure less than 160 mm Hg, were followed for 5.6 years. Patients were randomized to a combination of hypertension medications (candesartan, 16 mg, and hydrochlorothiazide, 12.5 mg), a statin (rosuvastatin, 10 mg) or both, or to placebo. The hypertension drug combination was successful in lowering the systolic pressure at randomization of 138/81 by 10 mm Hg but had no effect on cardiovascular mortality or morbidity. In contrast, the rosuvastatin arm successfully lowered the mean LDL cholesterol of 127.8 mg/dL by 26.5% at the conclusion of the trial. This was associated with a 24% decrease in the combined cardiovascular morbidity and mortality endpoint and a decrease in myocardial infarction and stroke of 35% and 30% respectively. The addition of the hypertension drugs to rosuvastatin added little to the morbidity and mortality benefit observed with rosuvastatin alone.

The initial concept of the polypill was greeted with considerable skepticism by the medical community, which has viewed attacking cardiovascular mortality as a one-on-one experience between patient and doctor. This, despite the benefit of a broad array of prevention efforts, including lifestyle and hypertension therapy that has occurred over the last half-century.

The concept of a polypill with five different medications appears to have failed, but its outcome refined to just to one statin is a message of great importance. In a universe of indigent and undertreated humans, the need for some form of intervention seems to be a crying one. The results of HOPE-3 are consistent with JUPITER and other statin lipid-lowering trials and indicates that just treating cholesterol alone in this low-risk population achieved significant benefit of itself. Application of such an intervention in the Third World could have an important benefit. The cost of such an intervention is minimal, compared with the recent additions to the cardiovascular pharmacopeia in both heart failure and lipid therapy.

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

Recently published guidelines for the pharmacologic management of heart failure in patients with reduced ejection fraction (HFrEF) focus on two drugs – both of which have been approved by the Food and Drug Administration – that have shown promise in managing heart failure patients.

The guideline committee has deemed that the combination drug sacubitril-valsartan (Entresto, Novartis) and ivabradine (Corlanor, Amgen) as “milestone” achievements. In this reader’s mind, compared with the mortality and morbidity effect of beta-blockers and ACE inhibitors, they really don’t make it to that status. They do, however, reach the threshold of important adjuncts to the care for heart failure treatment.

Ivabradine was shown to improve the combination of rehospitalization and mortality when added to conventional therapy, including beta-blockers, by decreasing heart rate. Unfortunately, many of the patients in the trial were not adequately treated with beta-blockers. Sacubitril-valsartan, a drug we have commented about in previous columns, is interesting and adds an additional effect on mortality and morbidity when compared with enalapril alone. In the PARADIGM-HF trial, it showed a significant 20% decrease in rehospitalization and total mortality. A strong case can be made that it should be used instead of an ACE inhibitor, although it is associated with some increased hypotension and angioneurotic edema.

Sacubitril-valsartan poses a significant social issue in regard to its pricing. Most of the drugs we use for the treatment of heart failure cost less than a dollar a day when introduced, and pennies now, and they are immensely effective. Sacubitril-valsartan on average moves the mortality needle a bit, but at a cost of 20 times its competitor, enalapril. It doesn’t do it in all patients, so that it might be reasonable to use it just in those patients who are failing with an ACE inhibitor alone. This is the first time heart failure doctors have had to grapple with the problem of drug pricing, whereas the oncologist and the lipid specialists have been facing this issue for some time. Is it worth $500 a month, compared to $25 a month, to possibly move the mortality index, which has already been modified with the previous ACE inhibitors, down a bit? I suppose that the decision is up to all of us to make.

Reading the guidelines, however, provided me with some insight that I have missed in the past. Of the 17 members of the guideline writing team representing the American College of Cardiology, American Heart Association, and the Heart Failure Society of America, eight had “significant relationships” with the two pharmaceutical companies in question. Committee members were advised not to vote if they had a relevant relationship with industry. How they functioned in the committee proceeding it’s impossible to tell, but the potential for bias is there. I would imagine that eight other heart failure specialists who did not have a conflict could have been found to serve on the writing committee. As guidelines have become such a major part of the construct of the pharmacopoeia, potential bias like this should and easily can be avoided.

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

Recently published guidelines for the pharmacologic management of heart failure in patients with reduced ejection fraction (HFrEF) focus on two drugs – both of which have been approved by the Food and Drug Administration – that have shown promise in managing heart failure patients.

The guideline committee has deemed that the combination drug sacubitril-valsartan (Entresto, Novartis) and ivabradine (Corlanor, Amgen) as “milestone” achievements. In this reader’s mind, compared with the mortality and morbidity effect of beta-blockers and ACE inhibitors, they really don’t make it to that status. They do, however, reach the threshold of important adjuncts to the care for heart failure treatment.

Ivabradine was shown to improve the combination of rehospitalization and mortality when added to conventional therapy, including beta-blockers, by decreasing heart rate. Unfortunately, many of the patients in the trial were not adequately treated with beta-blockers. Sacubitril-valsartan, a drug we have commented about in previous columns, is interesting and adds an additional effect on mortality and morbidity when compared with enalapril alone. In the PARADIGM-HF trial, it showed a significant 20% decrease in rehospitalization and total mortality. A strong case can be made that it should be used instead of an ACE inhibitor, although it is associated with some increased hypotension and angioneurotic edema.

Sacubitril-valsartan poses a significant social issue in regard to its pricing. Most of the drugs we use for the treatment of heart failure cost less than a dollar a day when introduced, and pennies now, and they are immensely effective. Sacubitril-valsartan on average moves the mortality needle a bit, but at a cost of 20 times its competitor, enalapril. It doesn’t do it in all patients, so that it might be reasonable to use it just in those patients who are failing with an ACE inhibitor alone. This is the first time heart failure doctors have had to grapple with the problem of drug pricing, whereas the oncologist and the lipid specialists have been facing this issue for some time. Is it worth $500 a month, compared to $25 a month, to possibly move the mortality index, which has already been modified with the previous ACE inhibitors, down a bit? I suppose that the decision is up to all of us to make.

Reading the guidelines, however, provided me with some insight that I have missed in the past. Of the 17 members of the guideline writing team representing the American College of Cardiology, American Heart Association, and the Heart Failure Society of America, eight had “significant relationships” with the two pharmaceutical companies in question. Committee members were advised not to vote if they had a relevant relationship with industry. How they functioned in the committee proceeding it’s impossible to tell, but the potential for bias is there. I would imagine that eight other heart failure specialists who did not have a conflict could have been found to serve on the writing committee. As guidelines have become such a major part of the construct of the pharmacopoeia, potential bias like this should and easily can be avoided.

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

Recently published guidelines for the pharmacologic management of heart failure in patients with reduced ejection fraction (HFrEF) focus on two drugs – both of which have been approved by the Food and Drug Administration – that have shown promise in managing heart failure patients.

The guideline committee has deemed that the combination drug sacubitril-valsartan (Entresto, Novartis) and ivabradine (Corlanor, Amgen) as “milestone” achievements. In this reader’s mind, compared with the mortality and morbidity effect of beta-blockers and ACE inhibitors, they really don’t make it to that status. They do, however, reach the threshold of important adjuncts to the care for heart failure treatment.

Ivabradine was shown to improve the combination of rehospitalization and mortality when added to conventional therapy, including beta-blockers, by decreasing heart rate. Unfortunately, many of the patients in the trial were not adequately treated with beta-blockers. Sacubitril-valsartan, a drug we have commented about in previous columns, is interesting and adds an additional effect on mortality and morbidity when compared with enalapril alone. In the PARADIGM-HF trial, it showed a significant 20% decrease in rehospitalization and total mortality. A strong case can be made that it should be used instead of an ACE inhibitor, although it is associated with some increased hypotension and angioneurotic edema.

Sacubitril-valsartan poses a significant social issue in regard to its pricing. Most of the drugs we use for the treatment of heart failure cost less than a dollar a day when introduced, and pennies now, and they are immensely effective. Sacubitril-valsartan on average moves the mortality needle a bit, but at a cost of 20 times its competitor, enalapril. It doesn’t do it in all patients, so that it might be reasonable to use it just in those patients who are failing with an ACE inhibitor alone. This is the first time heart failure doctors have had to grapple with the problem of drug pricing, whereas the oncologist and the lipid specialists have been facing this issue for some time. Is it worth $500 a month, compared to $25 a month, to possibly move the mortality index, which has already been modified with the previous ACE inhibitors, down a bit? I suppose that the decision is up to all of us to make.

Reading the guidelines, however, provided me with some insight that I have missed in the past. Of the 17 members of the guideline writing team representing the American College of Cardiology, American Heart Association, and the Heart Failure Society of America, eight had “significant relationships” with the two pharmaceutical companies in question. Committee members were advised not to vote if they had a relevant relationship with industry. How they functioned in the committee proceeding it’s impossible to tell, but the potential for bias is there. I would imagine that eight other heart failure specialists who did not have a conflict could have been found to serve on the writing committee. As guidelines have become such a major part of the construct of the pharmacopoeia, potential bias like this should and easily can be avoided.

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

The randomized clinical trial (RCT) has been the bulwark of the development of effective and safe medical and surgical therapy. Developed over the last half-century, they have proved the benefit and safety of new drugs and procedures and provided guidance to physicians in choosing therapeutic choices for their patients. They have replaced intuitive care that had largely directed medical care for centuries with a degree of science in making therapeutic decisions.

Although less than perfect, the RCT has been the reason for the remarkable success that we have achieved in decreasing the mortality of heart disease. This success has been driven largely by scientific altruism modified to some degree by the financial benefits of both the medical profession and the pharmaceutical industry.

As corporate hospital and third-party payers expand their role in the pattern of health care, there is the potential to make changes in how care is rendered beyond the choice of medical or surgical therapy. The expansion of care regionally and nationally provides tempting targets to modify the quality and efficacy on a large scale. It also provides potential cost-saving targets and generates corporate profits. Decisions at the corporate or administrative area in the past have been initiated on the basis of competitive costs and on intuitive decision making. The size of the market, however, provides an opportunity to test a variety of administrative plans that can lead to cost saving. These initiatives, well-meaning in their genesis, may result in patient participation in “studies” in which the patient may have a limited knowledge and benefit and uncertain risks.

RCTs demand informed consent by patients and unbiased temporal oversight by safety boards when searching for answers to questions based on contemporary knowledge. At present, there is no specific role for the patient’s voluntary and informed participation should a corporate representative initiate a “study” to answer a corporate question. Before we embark on “research” in patient care, it is imperative that we consider the principles established by RCTs. I propose two scenarios that may provide illustrative insight:

1. A nurse administrator wishes to explore the question of the cost savings achieved on a general medical ward by changing the current nurse staffing of eight professional nurses to a staffing with two professional nurses and six nursing assistants. The administrator will use personnel costs as the endpoint of the study and consider a variety of secondary issues such as the duration of time to respond to a call, sacral erythema, and wrong-dose administration, or other quality measurements.

2. The administrator of the catheterization laboratory decides to compare two catheters in the laboratory driven again by the costs of the catheters. The primary endpoint of the study will be cost savings. Secondary measurements will be time in the catheterization laboratory and postprocedure bleeding.

In both cases, the patient may or not have been informed about the research project in which they have been enrolled. In addition, there is no temporal assessment of the occurrence of adverse events that could occur during the progress of the “study” to ensure its safety. Many of the safeguards that have been developed around the RCT need to be incorporated into the design of these investigations.

This, of course, is all hypothetical, but on the other hand, it is not beyond the realm of possibility; as we move from “local care” to a system driven by anonymous personnel, it is important to obtain the consent of the patient and to establish procedures to ensure their safety.

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

The randomized clinical trial (RCT) has been the bulwark of the development of effective and safe medical and surgical therapy. Developed over the last half-century, they have proved the benefit and safety of new drugs and procedures and provided guidance to physicians in choosing therapeutic choices for their patients. They have replaced intuitive care that had largely directed medical care for centuries with a degree of science in making therapeutic decisions.

Although less than perfect, the RCT has been the reason for the remarkable success that we have achieved in decreasing the mortality of heart disease. This success has been driven largely by scientific altruism modified to some degree by the financial benefits of both the medical profession and the pharmaceutical industry.

As corporate hospital and third-party payers expand their role in the pattern of health care, there is the potential to make changes in how care is rendered beyond the choice of medical or surgical therapy. The expansion of care regionally and nationally provides tempting targets to modify the quality and efficacy on a large scale. It also provides potential cost-saving targets and generates corporate profits. Decisions at the corporate or administrative area in the past have been initiated on the basis of competitive costs and on intuitive decision making. The size of the market, however, provides an opportunity to test a variety of administrative plans that can lead to cost saving. These initiatives, well-meaning in their genesis, may result in patient participation in “studies” in which the patient may have a limited knowledge and benefit and uncertain risks.

RCTs demand informed consent by patients and unbiased temporal oversight by safety boards when searching for answers to questions based on contemporary knowledge. At present, there is no specific role for the patient’s voluntary and informed participation should a corporate representative initiate a “study” to answer a corporate question. Before we embark on “research” in patient care, it is imperative that we consider the principles established by RCTs. I propose two scenarios that may provide illustrative insight:

1. A nurse administrator wishes to explore the question of the cost savings achieved on a general medical ward by changing the current nurse staffing of eight professional nurses to a staffing with two professional nurses and six nursing assistants. The administrator will use personnel costs as the endpoint of the study and consider a variety of secondary issues such as the duration of time to respond to a call, sacral erythema, and wrong-dose administration, or other quality measurements.

2. The administrator of the catheterization laboratory decides to compare two catheters in the laboratory driven again by the costs of the catheters. The primary endpoint of the study will be cost savings. Secondary measurements will be time in the catheterization laboratory and postprocedure bleeding.

In both cases, the patient may or not have been informed about the research project in which they have been enrolled. In addition, there is no temporal assessment of the occurrence of adverse events that could occur during the progress of the “study” to ensure its safety. Many of the safeguards that have been developed around the RCT need to be incorporated into the design of these investigations.

This, of course, is all hypothetical, but on the other hand, it is not beyond the realm of possibility; as we move from “local care” to a system driven by anonymous personnel, it is important to obtain the consent of the patient and to establish procedures to ensure their safety.

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

The randomized clinical trial (RCT) has been the bulwark of the development of effective and safe medical and surgical therapy. Developed over the last half-century, they have proved the benefit and safety of new drugs and procedures and provided guidance to physicians in choosing therapeutic choices for their patients. They have replaced intuitive care that had largely directed medical care for centuries with a degree of science in making therapeutic decisions.

Although less than perfect, the RCT has been the reason for the remarkable success that we have achieved in decreasing the mortality of heart disease. This success has been driven largely by scientific altruism modified to some degree by the financial benefits of both the medical profession and the pharmaceutical industry.

As corporate hospital and third-party payers expand their role in the pattern of health care, there is the potential to make changes in how care is rendered beyond the choice of medical or surgical therapy. The expansion of care regionally and nationally provides tempting targets to modify the quality and efficacy on a large scale. It also provides potential cost-saving targets and generates corporate profits. Decisions at the corporate or administrative area in the past have been initiated on the basis of competitive costs and on intuitive decision making. The size of the market, however, provides an opportunity to test a variety of administrative plans that can lead to cost saving. These initiatives, well-meaning in their genesis, may result in patient participation in “studies” in which the patient may have a limited knowledge and benefit and uncertain risks.

RCTs demand informed consent by patients and unbiased temporal oversight by safety boards when searching for answers to questions based on contemporary knowledge. At present, there is no specific role for the patient’s voluntary and informed participation should a corporate representative initiate a “study” to answer a corporate question. Before we embark on “research” in patient care, it is imperative that we consider the principles established by RCTs. I propose two scenarios that may provide illustrative insight:

1. A nurse administrator wishes to explore the question of the cost savings achieved on a general medical ward by changing the current nurse staffing of eight professional nurses to a staffing with two professional nurses and six nursing assistants. The administrator will use personnel costs as the endpoint of the study and consider a variety of secondary issues such as the duration of time to respond to a call, sacral erythema, and wrong-dose administration, or other quality measurements.

2. The administrator of the catheterization laboratory decides to compare two catheters in the laboratory driven again by the costs of the catheters. The primary endpoint of the study will be cost savings. Secondary measurements will be time in the catheterization laboratory and postprocedure bleeding.

In both cases, the patient may or not have been informed about the research project in which they have been enrolled. In addition, there is no temporal assessment of the occurrence of adverse events that could occur during the progress of the “study” to ensure its safety. Many of the safeguards that have been developed around the RCT need to be incorporated into the design of these investigations.

This, of course, is all hypothetical, but on the other hand, it is not beyond the realm of possibility; as we move from “local care” to a system driven by anonymous personnel, it is important to obtain the consent of the patient and to establish procedures to ensure their safety.

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

Two new drugs have arrived to challenge our prescription pad or electronic record, depending on which you use. Empagliflozin (Jardiance), a drug used to modify glucose metabolism in type 2 diabetes in patients with preexisting cardiovascular disease, demonstrated a decrease in cardiovascular mortality. The other drug, Entresto, appears to provide an added benefit in heart failure therapy and was compared with a standard ACE inhibitor.

The results of EMPA-REG OUTCOME, reported at the European Association for the Study of Diabetes meeting in Stockholm, showed empagliflozin to be the first drug to decrease the mortality and morbidity of cardiovascular disease in diabetes. It is one of a group of new sodium-glucose cotransporter 2 (SGLT-2) blockers being tested in type 2 diabetes with established cardiovascular disease. Patients were randomized to placebo or empagliflozin while receiving standard medical and cardiovascular medications. After 3 years of follow-up, patients receiving the drug experienced a lower cardiovascular mortality rate, compared with placebo patients (3.7% vs. 5.9%, a 38% reduction) in addition to a decrease in hospitalization for heart failure and death from any cause. No effect was observed on the incidence of myocardial infarction or stroke. In addition, the drug also lowered blood glucose and blood pressure and led to some significant weight loss. The drug also was shown to decrease vascular resistance and albuminuria (N Engl J Med. 2015. 373:2117-2).

Furthermore, an analysis of EMPA-REG OUTCOME presented in November at the American Society of Nephrology meeting in San Diego, showed a profound benefit on the new onset and progression of chronic renal disease in diabetes patients. The importance of these results needs emphasis. Up until recently, the Food and Drug Administration has given a pass to diabetes drugs in regard to cardiovascular endpoints; approval has been based on their primary effect on lowering blood glucose. Some drugs in the past, such as rosiglitazone, actually have shown an increase in mortality in some diabetes patients. At long last, FDA approval for diabetes drugs hinges on acceptable outcomes in cardiovascular endpoints. The addition of a drug that can actually affect cardiovascular mortality and morbidity, the major risk factor of diabetes, provides an important addition to therapy.

The other drug that provides a choice of drugs for the treatment of heart failure is Entresto, a combination of sacubitril, a neprilysin inhibitor, and the angiotensin receptor inhibitor valsartan, approved in July 2015. In PARADIGM-HF, the compound was compared to enalapril in the treatment of patients with class II, III, and IV heart failure who were also receiving beta-blockers. Entresto-treated patients reported a 21.8% incidence of the primary outcome measure, cardiovascular death and hospitalization for heart failure, compared with the enalapril alone incidence of 26.5% (P less than .001) (N Engl J Med. 2014;371:993-1004). Investigators initially excluded 11.4% of the recruited patients from the study who could not tolerate Entresto or enalapril therapy. The drugs were well tolerated without any adverse reactions during therapy. Entresto was more effective than enalapril in regards to the occurrence of heart failure and death from any cause over a 27-month average follow-up.

The observations in this study emphasize how much the mortality of heart failure has decreased over the last decade. Cardiovascular deaths have decreased to roughly 7% per year and rehospitalization occurs in about 8% in the first year. Both drugs provide an important incremental benefit in heart failure patients.

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

Two new drugs have arrived to challenge our prescription pad or electronic record, depending on which you use. Empagliflozin (Jardiance), a drug used to modify glucose metabolism in type 2 diabetes in patients with preexisting cardiovascular disease, demonstrated a decrease in cardiovascular mortality. The other drug, Entresto, appears to provide an added benefit in heart failure therapy and was compared with a standard ACE inhibitor.

The results of EMPA-REG OUTCOME, reported at the European Association for the Study of Diabetes meeting in Stockholm, showed empagliflozin to be the first drug to decrease the mortality and morbidity of cardiovascular disease in diabetes. It is one of a group of new sodium-glucose cotransporter 2 (SGLT-2) blockers being tested in type 2 diabetes with established cardiovascular disease. Patients were randomized to placebo or empagliflozin while receiving standard medical and cardiovascular medications. After 3 years of follow-up, patients receiving the drug experienced a lower cardiovascular mortality rate, compared with placebo patients (3.7% vs. 5.9%, a 38% reduction) in addition to a decrease in hospitalization for heart failure and death from any cause. No effect was observed on the incidence of myocardial infarction or stroke. In addition, the drug also lowered blood glucose and blood pressure and led to some significant weight loss. The drug also was shown to decrease vascular resistance and albuminuria (N Engl J Med. 2015. 373:2117-2).

Furthermore, an analysis of EMPA-REG OUTCOME presented in November at the American Society of Nephrology meeting in San Diego, showed a profound benefit on the new onset and progression of chronic renal disease in diabetes patients. The importance of these results needs emphasis. Up until recently, the Food and Drug Administration has given a pass to diabetes drugs in regard to cardiovascular endpoints; approval has been based on their primary effect on lowering blood glucose. Some drugs in the past, such as rosiglitazone, actually have shown an increase in mortality in some diabetes patients. At long last, FDA approval for diabetes drugs hinges on acceptable outcomes in cardiovascular endpoints. The addition of a drug that can actually affect cardiovascular mortality and morbidity, the major risk factor of diabetes, provides an important addition to therapy.

The other drug that provides a choice of drugs for the treatment of heart failure is Entresto, a combination of sacubitril, a neprilysin inhibitor, and the angiotensin receptor inhibitor valsartan, approved in July 2015. In PARADIGM-HF, the compound was compared to enalapril in the treatment of patients with class II, III, and IV heart failure who were also receiving beta-blockers. Entresto-treated patients reported a 21.8% incidence of the primary outcome measure, cardiovascular death and hospitalization for heart failure, compared with the enalapril alone incidence of 26.5% (P less than .001) (N Engl J Med. 2014;371:993-1004). Investigators initially excluded 11.4% of the recruited patients from the study who could not tolerate Entresto or enalapril therapy. The drugs were well tolerated without any adverse reactions during therapy. Entresto was more effective than enalapril in regards to the occurrence of heart failure and death from any cause over a 27-month average follow-up.

The observations in this study emphasize how much the mortality of heart failure has decreased over the last decade. Cardiovascular deaths have decreased to roughly 7% per year and rehospitalization occurs in about 8% in the first year. Both drugs provide an important incremental benefit in heart failure patients.

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

Two new drugs have arrived to challenge our prescription pad or electronic record, depending on which you use. Empagliflozin (Jardiance), a drug used to modify glucose metabolism in type 2 diabetes in patients with preexisting cardiovascular disease, demonstrated a decrease in cardiovascular mortality. The other drug, Entresto, appears to provide an added benefit in heart failure therapy and was compared with a standard ACE inhibitor.

The results of EMPA-REG OUTCOME, reported at the European Association for the Study of Diabetes meeting in Stockholm, showed empagliflozin to be the first drug to decrease the mortality and morbidity of cardiovascular disease in diabetes. It is one of a group of new sodium-glucose cotransporter 2 (SGLT-2) blockers being tested in type 2 diabetes with established cardiovascular disease. Patients were randomized to placebo or empagliflozin while receiving standard medical and cardiovascular medications. After 3 years of follow-up, patients receiving the drug experienced a lower cardiovascular mortality rate, compared with placebo patients (3.7% vs. 5.9%, a 38% reduction) in addition to a decrease in hospitalization for heart failure and death from any cause. No effect was observed on the incidence of myocardial infarction or stroke. In addition, the drug also lowered blood glucose and blood pressure and led to some significant weight loss. The drug also was shown to decrease vascular resistance and albuminuria (N Engl J Med. 2015. 373:2117-2).

Furthermore, an analysis of EMPA-REG OUTCOME presented in November at the American Society of Nephrology meeting in San Diego, showed a profound benefit on the new onset and progression of chronic renal disease in diabetes patients. The importance of these results needs emphasis. Up until recently, the Food and Drug Administration has given a pass to diabetes drugs in regard to cardiovascular endpoints; approval has been based on their primary effect on lowering blood glucose. Some drugs in the past, such as rosiglitazone, actually have shown an increase in mortality in some diabetes patients. At long last, FDA approval for diabetes drugs hinges on acceptable outcomes in cardiovascular endpoints. The addition of a drug that can actually affect cardiovascular mortality and morbidity, the major risk factor of diabetes, provides an important addition to therapy.

The other drug that provides a choice of drugs for the treatment of heart failure is Entresto, a combination of sacubitril, a neprilysin inhibitor, and the angiotensin receptor inhibitor valsartan, approved in July 2015. In PARADIGM-HF, the compound was compared to enalapril in the treatment of patients with class II, III, and IV heart failure who were also receiving beta-blockers. Entresto-treated patients reported a 21.8% incidence of the primary outcome measure, cardiovascular death and hospitalization for heart failure, compared with the enalapril alone incidence of 26.5% (P less than .001) (N Engl J Med. 2014;371:993-1004). Investigators initially excluded 11.4% of the recruited patients from the study who could not tolerate Entresto or enalapril therapy. The drugs were well tolerated without any adverse reactions during therapy. Entresto was more effective than enalapril in regards to the occurrence of heart failure and death from any cause over a 27-month average follow-up.

The observations in this study emphasize how much the mortality of heart failure has decreased over the last decade. Cardiovascular deaths have decreased to roughly 7% per year and rehospitalization occurs in about 8% in the first year. Both drugs provide an important incremental benefit in heart failure patients.

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

The possibility that we can define the specific and unique treatment for an individual’s specific disease is the holy grail of therapeutics. Our current therapy is largely defined by randomized clinical trials (RCTs), which provide an average response of therapy in a given disease tested in hundreds or thousands of patients.

RCTs identify the statistical benefit of a particular treatment when compared with a placebo in heterogeneous patients who, at best, are demographically similar but do not truly represent the general population.

Dr. Sidney Goldstein

Although an RCT shows an average statistical benefit, some individuals may have a profound benefit; others in the trial may not benefit at all, and some may do worse than placebo. The reason for the differential response is poorly understood. Therefore, treatment programs based on RCT data by definition are crude and imprecise by design for a variety of conditions, including cancer and cardiovascular diseases.

There has been a call for more personalization and precision in defining and developing predictably successful therapy. It is proposed that precision medicine will lead to optimal targeted individualized treatment based on patients’ genetic profile. This has led oncologists to use genetic profiling of therapy based on cells derived from patient’s tumor. Cancer therapy is in the forefront of genomic analysis of tumor tissue in order to guide specific tumor therapy. Unique DNA gene mutations are now being identified that may explain the genesis, spread, and growth of a tumor. It also provides a potential link between the genetic characteristics of the tumor to specific therapy. As a result, a number of laboratories have developed genetic probes that can mitigate gene expression or overexpression and thereby modify progression of disease.

To some degree, the field of cardiology has found some precision in defining individual therapy for the treatment of a variety of expressions of cardiovascular disease. We have drugs that are aimed at the treatment of hypertension, hypercholesterolemia, heart failure, and vascular thrombogenesis, to name some of the major targets. Just as the oncologists are searching for specific treatments of individual tumors, cardiology is searching for specific targets based on our understanding of the pathophysiologic mechanism leading to the expression and progression of disease. We have been fortunate in a large part to be able to measure pathophysiology and therapy at the bedside.

For some time, investigators have been examining the genetic variants in human tissue in order to understand drug responsiveness in several cardiovascular environments. Single nucleotide polymorphisms (SNP) have been discovered in beta-receptors that may define risk factors for disease and function as modifiers of disease once it has occurred. These factors also have the potential to modify beta-receptor response to adrenergic agonists and antagonists. The understanding of the SNP expression is anticipated to lead to the individualization of drug therapy and define or predict an individual’s response to particular drug therapy. As a result, they may explain the spectrum of clinical response observed in RCTs. Similar observations have been observed with the genetic polymorphism, of renin-angiotensin-aldosterone system and sympathetic systems. The understanding of genetic polymorphism may also provide insight into the expression of disease in particular demographic groups.

So far, the cost of these drugs is huge when applied to just a few individuals who are potential beneficiaries of the therapy. Consequently, patient and society and your insurance company are asked to pay the cost of the drugs to treat just a few patients. Over time, it is possible that these unique genomic characteristics can be applied to larger populations and may spread the costs over a larger number of patients. So far, the potential for this to happen is limited.

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

The possibility that we can define the specific and unique treatment for an individual’s specific disease is the holy grail of therapeutics. Our current therapy is largely defined by randomized clinical trials (RCTs), which provide an average response of therapy in a given disease tested in hundreds or thousands of patients.

RCTs identify the statistical benefit of a particular treatment when compared with a placebo in heterogeneous patients who, at best, are demographically similar but do not truly represent the general population.

Dr. Sidney Goldstein

Although an RCT shows an average statistical benefit, some individuals may have a profound benefit; others in the trial may not benefit at all, and some may do worse than placebo. The reason for the differential response is poorly understood. Therefore, treatment programs based on RCT data by definition are crude and imprecise by design for a variety of conditions, including cancer and cardiovascular diseases.

There has been a call for more personalization and precision in defining and developing predictably successful therapy. It is proposed that precision medicine will lead to optimal targeted individualized treatment based on patients’ genetic profile. This has led oncologists to use genetic profiling of therapy based on cells derived from patient’s tumor. Cancer therapy is in the forefront of genomic analysis of tumor tissue in order to guide specific tumor therapy. Unique DNA gene mutations are now being identified that may explain the genesis, spread, and growth of a tumor. It also provides a potential link between the genetic characteristics of the tumor to specific therapy. As a result, a number of laboratories have developed genetic probes that can mitigate gene expression or overexpression and thereby modify progression of disease.

To some degree, the field of cardiology has found some precision in defining individual therapy for the treatment of a variety of expressions of cardiovascular disease. We have drugs that are aimed at the treatment of hypertension, hypercholesterolemia, heart failure, and vascular thrombogenesis, to name some of the major targets. Just as the oncologists are searching for specific treatments of individual tumors, cardiology is searching for specific targets based on our understanding of the pathophysiologic mechanism leading to the expression and progression of disease. We have been fortunate in a large part to be able to measure pathophysiology and therapy at the bedside.

For some time, investigators have been examining the genetic variants in human tissue in order to understand drug responsiveness in several cardiovascular environments. Single nucleotide polymorphisms (SNP) have been discovered in beta-receptors that may define risk factors for disease and function as modifiers of disease once it has occurred. These factors also have the potential to modify beta-receptor response to adrenergic agonists and antagonists. The understanding of the SNP expression is anticipated to lead to the individualization of drug therapy and define or predict an individual’s response to particular drug therapy. As a result, they may explain the spectrum of clinical response observed in RCTs. Similar observations have been observed with the genetic polymorphism, of renin-angiotensin-aldosterone system and sympathetic systems. The understanding of genetic polymorphism may also provide insight into the expression of disease in particular demographic groups.

So far, the cost of these drugs is huge when applied to just a few individuals who are potential beneficiaries of the therapy. Consequently, patient and society and your insurance company are asked to pay the cost of the drugs to treat just a few patients. Over time, it is possible that these unique genomic characteristics can be applied to larger populations and may spread the costs over a larger number of patients. So far, the potential for this to happen is limited.

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

The possibility that we can define the specific and unique treatment for an individual’s specific disease is the holy grail of therapeutics. Our current therapy is largely defined by randomized clinical trials (RCTs), which provide an average response of therapy in a given disease tested in hundreds or thousands of patients.

RCTs identify the statistical benefit of a particular treatment when compared with a placebo in heterogeneous patients who, at best, are demographically similar but do not truly represent the general population.

Dr. Sidney Goldstein

Although an RCT shows an average statistical benefit, some individuals may have a profound benefit; others in the trial may not benefit at all, and some may do worse than placebo. The reason for the differential response is poorly understood. Therefore, treatment programs based on RCT data by definition are crude and imprecise by design for a variety of conditions, including cancer and cardiovascular diseases.

There has been a call for more personalization and precision in defining and developing predictably successful therapy. It is proposed that precision medicine will lead to optimal targeted individualized treatment based on patients’ genetic profile. This has led oncologists to use genetic profiling of therapy based on cells derived from patient’s tumor. Cancer therapy is in the forefront of genomic analysis of tumor tissue in order to guide specific tumor therapy. Unique DNA gene mutations are now being identified that may explain the genesis, spread, and growth of a tumor. It also provides a potential link between the genetic characteristics of the tumor to specific therapy. As a result, a number of laboratories have developed genetic probes that can mitigate gene expression or overexpression and thereby modify progression of disease.

To some degree, the field of cardiology has found some precision in defining individual therapy for the treatment of a variety of expressions of cardiovascular disease. We have drugs that are aimed at the treatment of hypertension, hypercholesterolemia, heart failure, and vascular thrombogenesis, to name some of the major targets. Just as the oncologists are searching for specific treatments of individual tumors, cardiology is searching for specific targets based on our understanding of the pathophysiologic mechanism leading to the expression and progression of disease. We have been fortunate in a large part to be able to measure pathophysiology and therapy at the bedside.

For some time, investigators have been examining the genetic variants in human tissue in order to understand drug responsiveness in several cardiovascular environments. Single nucleotide polymorphisms (SNP) have been discovered in beta-receptors that may define risk factors for disease and function as modifiers of disease once it has occurred. These factors also have the potential to modify beta-receptor response to adrenergic agonists and antagonists. The understanding of the SNP expression is anticipated to lead to the individualization of drug therapy and define or predict an individual’s response to particular drug therapy. As a result, they may explain the spectrum of clinical response observed in RCTs. Similar observations have been observed with the genetic polymorphism, of renin-angiotensin-aldosterone system and sympathetic systems. The understanding of genetic polymorphism may also provide insight into the expression of disease in particular demographic groups.

So far, the cost of these drugs is huge when applied to just a few individuals who are potential beneficiaries of the therapy. Consequently, patient and society and your insurance company are asked to pay the cost of the drugs to treat just a few patients. Over time, it is possible that these unique genomic characteristics can be applied to larger populations and may spread the costs over a larger number of patients. So far, the potential for this to happen is limited.

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