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Take Your Statins, for Heaven’s Sake
It’s an extremely common scenario. A patient’s screening tests return, showing a significant elevation of the calculated low-density lipoprotein cholesterol (LDL-C), known to the lay public as bad cholesterol. To a physician like myself, someone who prides himself on a modest bit of expertise in lipids, it’s an absolute no-brainer. The patient should be placed on statin therapy pronto to reduce the major risks of heart attack, stroke, and other vascular misfortunes that are clearly associated with an elevated LDL-C level.
The tremendous ability of statins to reduce cardiovascular risk is among the best-demonstrated therapeutic effects of any class of medication in any branch of medical practice. The first major trial to show definitive benefits with the use of statins was the Scandinavian Simvastatin Survival Study, which came out in 1994 and showed a 30% relative reduction in cardiovascular events in a high-risk secondary prevention population, meaning that the subjects already had documented vascular disease before entering the trial.
Related: Did Niacin Get a Bum Rap?
Similar results were reported soon after in primary prevention populations in the WOSCOPS study in the United Kingdom (UK), and from the AFCAPS/TexCAPS studies in the U.S. Then the large UK-based Heart Protection Study showed that statins reduce cardiovascular risk regardless of the initial LDL-C level. Some experts suspected that many of the protective effects of statins were due not only to the LDL-C reduction per se, but also the so-called pleiotropic benefits, which included vasodilation, antithrombotic effects, and improved function of the endothelial cells that line the walls of blood vessels.
A number of additional studies have since markedly expanded the role of statins. The CARDS study showed that patients with diabetes had fewer events on statins. The ASCOT study suggested that statins reduce risk in patients with hypertension. And the SPARCL study revealed fewer recurrent events in patients on statins who had experienced a stroke or transient ischemic attack. Perhaps an even greater advance came with the JUPITER study, which showed that patients with elevated C-reactive protein levels—a marker of systemic inflammation—had fewer cardiovascular events when treated with statins than with placebo.
As you can imagine, there are plenty of times when I reach for my prescription pad (actually, my mouse) with the intention of ordering a statin to reduce a patient’s cardiovascular risk. But unfortunately, many times the patient catches me up short by objecting to such a plan. I can’t tell you how many times a patient responds by asking rather pointedly about the adverse effects (AEs) of statins. Now, I’ll readily admit that a small number of patients ask about AEs with any medication, but I would submit that the question comes up far more commonly with statins than it does with almost any other class of medication. Why?
I firmly believe that a huge driver of my patients’ irrational suspicions of statins is the drivel that is found on countless unreliable and unscientific websites. Antistatin nonsense is readily available, and many patients have thoroughly marinated themselves in a toxic slurry of misinformation and medical fantasy. Most of these sites emphasize known statin AEs, such as myalgias and myopathies, liver damage, and rhabdomyolysis, but then grossly exaggerate the severity and frequency. Other sites hammer on the modest number of patients who are nudged from prediabetes to full-fledged diabetes by the statins or rant about medically unsubstantiated AEs of statins, such as worsened mentation and depression.
Related: Are Statins Safe to Use in Pregnancy? (Clinical Edge)
That’s all bad enough, but what’s even worse is when patients attack the very medical foundation for prescribing statins, claiming that their online “research” causes them to doubt the reported association between LDL-C levels and cardiovascular risk. They also hint darkly at a vast medical-industrial conspiracy to inflate the true importance of LDL-C, thus allowing for more sales of the highly questionable statins and increased drug company profits. No patient has directly accused me of personally benefitting financially by overprescribing statins, but some have certainly hinted at it.
Another large group of patients declines to take the proffered statins by insisting that they would much rather pursue diet and exercise to bring down their high levels of LDL-C. They are invariably surprised when I tell them that even the most aggressive approaches are unlikely to reduce LDL-C by more than a negligible amount. I suspect that they think that their tired old doctor has bought into a reflexive pills-cure-all mentality and does not appreciate the wondrous benefits of a holistic approach.
The most annoying patients tell me they will instead take red yeast rice to bring down their LDL-C, because they prefer a “natural” remedy to some monstrous artificial chemical produced in a pharmaceutical company laboratory. When I try to tell them that red yeast rice contains a varying but unknown amount of a natural inhibitor of hMG-coA reductase, the same enzyme targeted with precisely dosed statins, they gape at me with unhidden disgust for completely missing the point: The naturally occurring remedy is inherently superior, precisely because it is naturally occurring!
Of course, I have to remind myself that a good number of patients simply do not want to take statins because it is a reminder of their vulnerability, status as a cardiac patient, or as a potential future victim of a heart attack or stroke. Some patients find that concept so upsetting that they would rather ignore it altogether.
Reluctantly, I admit that statins are not perfect drugs. But I would still submit that they’re the closest things we have to wonder drugs today. Yes, a fair number of patients do develop myalgias, but these are often mild and transient and can be managed. Very infrequently, patients may manifest some degree of hepatotoxicity, and very rarely rhabdomyolysis can rear its ugly head. Statins can sometimes nudge prediabetes into diabetes, just as thiazide diuretics and beta-blockers will sometimes do. However, on balance, the risk-benefit analysis of taking statins in both primary and secondary prevention settings is very much in favor of taking the drugs.
So my message to my patients (and to your patients as well) is a very simple one. Take advantage of the phenomenal life-saving benefits of these near-wonder drugs, ignore the unscientific online nonsense authored by individuals practicing medicine without a license, and do what your tired but well-meaning doctor urges: take your statins, for Heaven’s sake!
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
It’s an extremely common scenario. A patient’s screening tests return, showing a significant elevation of the calculated low-density lipoprotein cholesterol (LDL-C), known to the lay public as bad cholesterol. To a physician like myself, someone who prides himself on a modest bit of expertise in lipids, it’s an absolute no-brainer. The patient should be placed on statin therapy pronto to reduce the major risks of heart attack, stroke, and other vascular misfortunes that are clearly associated with an elevated LDL-C level.
The tremendous ability of statins to reduce cardiovascular risk is among the best-demonstrated therapeutic effects of any class of medication in any branch of medical practice. The first major trial to show definitive benefits with the use of statins was the Scandinavian Simvastatin Survival Study, which came out in 1994 and showed a 30% relative reduction in cardiovascular events in a high-risk secondary prevention population, meaning that the subjects already had documented vascular disease before entering the trial.
Related: Did Niacin Get a Bum Rap?
Similar results were reported soon after in primary prevention populations in the WOSCOPS study in the United Kingdom (UK), and from the AFCAPS/TexCAPS studies in the U.S. Then the large UK-based Heart Protection Study showed that statins reduce cardiovascular risk regardless of the initial LDL-C level. Some experts suspected that many of the protective effects of statins were due not only to the LDL-C reduction per se, but also the so-called pleiotropic benefits, which included vasodilation, antithrombotic effects, and improved function of the endothelial cells that line the walls of blood vessels.
A number of additional studies have since markedly expanded the role of statins. The CARDS study showed that patients with diabetes had fewer events on statins. The ASCOT study suggested that statins reduce risk in patients with hypertension. And the SPARCL study revealed fewer recurrent events in patients on statins who had experienced a stroke or transient ischemic attack. Perhaps an even greater advance came with the JUPITER study, which showed that patients with elevated C-reactive protein levels—a marker of systemic inflammation—had fewer cardiovascular events when treated with statins than with placebo.
As you can imagine, there are plenty of times when I reach for my prescription pad (actually, my mouse) with the intention of ordering a statin to reduce a patient’s cardiovascular risk. But unfortunately, many times the patient catches me up short by objecting to such a plan. I can’t tell you how many times a patient responds by asking rather pointedly about the adverse effects (AEs) of statins. Now, I’ll readily admit that a small number of patients ask about AEs with any medication, but I would submit that the question comes up far more commonly with statins than it does with almost any other class of medication. Why?
I firmly believe that a huge driver of my patients’ irrational suspicions of statins is the drivel that is found on countless unreliable and unscientific websites. Antistatin nonsense is readily available, and many patients have thoroughly marinated themselves in a toxic slurry of misinformation and medical fantasy. Most of these sites emphasize known statin AEs, such as myalgias and myopathies, liver damage, and rhabdomyolysis, but then grossly exaggerate the severity and frequency. Other sites hammer on the modest number of patients who are nudged from prediabetes to full-fledged diabetes by the statins or rant about medically unsubstantiated AEs of statins, such as worsened mentation and depression.
Related: Are Statins Safe to Use in Pregnancy? (Clinical Edge)
That’s all bad enough, but what’s even worse is when patients attack the very medical foundation for prescribing statins, claiming that their online “research” causes them to doubt the reported association between LDL-C levels and cardiovascular risk. They also hint darkly at a vast medical-industrial conspiracy to inflate the true importance of LDL-C, thus allowing for more sales of the highly questionable statins and increased drug company profits. No patient has directly accused me of personally benefitting financially by overprescribing statins, but some have certainly hinted at it.
Another large group of patients declines to take the proffered statins by insisting that they would much rather pursue diet and exercise to bring down their high levels of LDL-C. They are invariably surprised when I tell them that even the most aggressive approaches are unlikely to reduce LDL-C by more than a negligible amount. I suspect that they think that their tired old doctor has bought into a reflexive pills-cure-all mentality and does not appreciate the wondrous benefits of a holistic approach.
The most annoying patients tell me they will instead take red yeast rice to bring down their LDL-C, because they prefer a “natural” remedy to some monstrous artificial chemical produced in a pharmaceutical company laboratory. When I try to tell them that red yeast rice contains a varying but unknown amount of a natural inhibitor of hMG-coA reductase, the same enzyme targeted with precisely dosed statins, they gape at me with unhidden disgust for completely missing the point: The naturally occurring remedy is inherently superior, precisely because it is naturally occurring!
Of course, I have to remind myself that a good number of patients simply do not want to take statins because it is a reminder of their vulnerability, status as a cardiac patient, or as a potential future victim of a heart attack or stroke. Some patients find that concept so upsetting that they would rather ignore it altogether.
Reluctantly, I admit that statins are not perfect drugs. But I would still submit that they’re the closest things we have to wonder drugs today. Yes, a fair number of patients do develop myalgias, but these are often mild and transient and can be managed. Very infrequently, patients may manifest some degree of hepatotoxicity, and very rarely rhabdomyolysis can rear its ugly head. Statins can sometimes nudge prediabetes into diabetes, just as thiazide diuretics and beta-blockers will sometimes do. However, on balance, the risk-benefit analysis of taking statins in both primary and secondary prevention settings is very much in favor of taking the drugs.
So my message to my patients (and to your patients as well) is a very simple one. Take advantage of the phenomenal life-saving benefits of these near-wonder drugs, ignore the unscientific online nonsense authored by individuals practicing medicine without a license, and do what your tired but well-meaning doctor urges: take your statins, for Heaven’s sake!
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
It’s an extremely common scenario. A patient’s screening tests return, showing a significant elevation of the calculated low-density lipoprotein cholesterol (LDL-C), known to the lay public as bad cholesterol. To a physician like myself, someone who prides himself on a modest bit of expertise in lipids, it’s an absolute no-brainer. The patient should be placed on statin therapy pronto to reduce the major risks of heart attack, stroke, and other vascular misfortunes that are clearly associated with an elevated LDL-C level.
The tremendous ability of statins to reduce cardiovascular risk is among the best-demonstrated therapeutic effects of any class of medication in any branch of medical practice. The first major trial to show definitive benefits with the use of statins was the Scandinavian Simvastatin Survival Study, which came out in 1994 and showed a 30% relative reduction in cardiovascular events in a high-risk secondary prevention population, meaning that the subjects already had documented vascular disease before entering the trial.
Related: Did Niacin Get a Bum Rap?
Similar results were reported soon after in primary prevention populations in the WOSCOPS study in the United Kingdom (UK), and from the AFCAPS/TexCAPS studies in the U.S. Then the large UK-based Heart Protection Study showed that statins reduce cardiovascular risk regardless of the initial LDL-C level. Some experts suspected that many of the protective effects of statins were due not only to the LDL-C reduction per se, but also the so-called pleiotropic benefits, which included vasodilation, antithrombotic effects, and improved function of the endothelial cells that line the walls of blood vessels.
A number of additional studies have since markedly expanded the role of statins. The CARDS study showed that patients with diabetes had fewer events on statins. The ASCOT study suggested that statins reduce risk in patients with hypertension. And the SPARCL study revealed fewer recurrent events in patients on statins who had experienced a stroke or transient ischemic attack. Perhaps an even greater advance came with the JUPITER study, which showed that patients with elevated C-reactive protein levels—a marker of systemic inflammation—had fewer cardiovascular events when treated with statins than with placebo.
As you can imagine, there are plenty of times when I reach for my prescription pad (actually, my mouse) with the intention of ordering a statin to reduce a patient’s cardiovascular risk. But unfortunately, many times the patient catches me up short by objecting to such a plan. I can’t tell you how many times a patient responds by asking rather pointedly about the adverse effects (AEs) of statins. Now, I’ll readily admit that a small number of patients ask about AEs with any medication, but I would submit that the question comes up far more commonly with statins than it does with almost any other class of medication. Why?
I firmly believe that a huge driver of my patients’ irrational suspicions of statins is the drivel that is found on countless unreliable and unscientific websites. Antistatin nonsense is readily available, and many patients have thoroughly marinated themselves in a toxic slurry of misinformation and medical fantasy. Most of these sites emphasize known statin AEs, such as myalgias and myopathies, liver damage, and rhabdomyolysis, but then grossly exaggerate the severity and frequency. Other sites hammer on the modest number of patients who are nudged from prediabetes to full-fledged diabetes by the statins or rant about medically unsubstantiated AEs of statins, such as worsened mentation and depression.
Related: Are Statins Safe to Use in Pregnancy? (Clinical Edge)
That’s all bad enough, but what’s even worse is when patients attack the very medical foundation for prescribing statins, claiming that their online “research” causes them to doubt the reported association between LDL-C levels and cardiovascular risk. They also hint darkly at a vast medical-industrial conspiracy to inflate the true importance of LDL-C, thus allowing for more sales of the highly questionable statins and increased drug company profits. No patient has directly accused me of personally benefitting financially by overprescribing statins, but some have certainly hinted at it.
Another large group of patients declines to take the proffered statins by insisting that they would much rather pursue diet and exercise to bring down their high levels of LDL-C. They are invariably surprised when I tell them that even the most aggressive approaches are unlikely to reduce LDL-C by more than a negligible amount. I suspect that they think that their tired old doctor has bought into a reflexive pills-cure-all mentality and does not appreciate the wondrous benefits of a holistic approach.
The most annoying patients tell me they will instead take red yeast rice to bring down their LDL-C, because they prefer a “natural” remedy to some monstrous artificial chemical produced in a pharmaceutical company laboratory. When I try to tell them that red yeast rice contains a varying but unknown amount of a natural inhibitor of hMG-coA reductase, the same enzyme targeted with precisely dosed statins, they gape at me with unhidden disgust for completely missing the point: The naturally occurring remedy is inherently superior, precisely because it is naturally occurring!
Of course, I have to remind myself that a good number of patients simply do not want to take statins because it is a reminder of their vulnerability, status as a cardiac patient, or as a potential future victim of a heart attack or stroke. Some patients find that concept so upsetting that they would rather ignore it altogether.
Reluctantly, I admit that statins are not perfect drugs. But I would still submit that they’re the closest things we have to wonder drugs today. Yes, a fair number of patients do develop myalgias, but these are often mild and transient and can be managed. Very infrequently, patients may manifest some degree of hepatotoxicity, and very rarely rhabdomyolysis can rear its ugly head. Statins can sometimes nudge prediabetes into diabetes, just as thiazide diuretics and beta-blockers will sometimes do. However, on balance, the risk-benefit analysis of taking statins in both primary and secondary prevention settings is very much in favor of taking the drugs.
So my message to my patients (and to your patients as well) is a very simple one. Take advantage of the phenomenal life-saving benefits of these near-wonder drugs, ignore the unscientific online nonsense authored by individuals practicing medicine without a license, and do what your tired but well-meaning doctor urges: take your statins, for Heaven’s sake!
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Did Niacin Get a Bum Rap?
I had thought that my long-standing romance with niacin was finally over. Although it was a very early love of mine, reluctantly I had gone along with the mainstream consensus. It seemed that niacin had been sent into near-permanent pharmaceutical exile by the devastating one-two punches of the AIM HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) and the HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) studies. I had even stopped taking my own self- prescribed niacin 2,500 mg twice a day, which I had been religiously consuming for over 2 decades. But before long, I found that I had real difficulty divorcing myself completely from the charms of this lipid-lowering Lorelei. Now, after agonizing over the issue for some time, I’m here to tell you that niacin almost certainly did get a bum rap and should be restored as an important tool in your therapeutic armamentarium.
Related: Niacin: Not Dead Yet, but on Life Support
A recent report that niacin seems to function partially as an inhibitor of the PCSK-9 enzyme accelerated my reconsideration. The inhibition of PCSK-9, an enzyme that removes low-density lipoprotein cholesterol (LDL-C) receptors from hepatocytes, is the hot new way of dropping LDL-C levels. And I mean really dropping LDL-C levels. Studies conducted with investigational compounds developed by Amgen and Pfizer have shown truly dramatic drops in LDL-C levels by as much as 80%—often down to ridiculously low levels (around 25 mg/dL).
Of course, we are still waiting for outcome trials, which will answer the critical question: Are these dramatic falls in LDL-C levels actually associated with meaningful reductions in the occurrence rates for cardiovascular events such as myocardial infarction and stroke? For now, inhibiting PCSK-9 seems to be a good way to change the lipid profile dramatically. Even if niacin is not nearly as potent an inhibitor of the PCSK-9 enzymes as some newer compounds, the fact that it has measurable inhibiting activity seems enough to earn it a second look.
The concerns over niacin derive almost entirely from the results of the AIM HIGH study and the HPS2-THRIVE trials. Thus, any effort to rehabilitate niacin will require a reckoning with each of these major trials.
Related: The Niacin Debate Continues: Higher Doses, Please
I was one of the original AIM HIGH investigators, but our study site at the Phoenix VA eventually was removed from the trial because of poor enrollment. Nonetheless, I had a front-row seat to observe the conduct of the trial, and it seemed less than optimal. The relatively infrequent monitor visits for this study probably contributed to the finding that the lipid differences between the 2 study groups were considerably smaller than they could have been. It was my impression that study sites did not have their feet held to the fire when niacin compliance became problematic for subjects randomized to the larger dose of niacin.
The study design also contributed to blunting the difference between the 2 study groups. Subjects in the control group actually received 200 mg of immediate-release niacin to help blind the study by ensuring that all subjects experienced a niacin flush. The statin dose wound up being higher in the control group, and the use of the add-on lipid-lowering agent ezetimibe was also greater (22% vs 10%) in the control group. All these factors would tend to blunt the differences between the 2 groups, and indeed lipid levels did improve significantly in both groups.
To add insult to injury, the trial was stopped after just 3 years. A number of other lipid trials that were ultimately positive had not yet reached a statistically significant separation between the control and the experimental groups after that relatively brief study interval. Although these study flaws are hardly fatal, when taken together, they suggest the need to maintain an open mind. If niacin is like Brylcreem and “a little dab’ll do ya,” then the small dusting received by the control subjects might have been cardioprotective enough to blunt any differences in event rates between the 2 groups, especially over the truncated period of the actual trial.
What about the much larger HPS2-THRIVE study; surely there can’t be similar flaws in that study as well? Well, a critical review identifies a number of significant shortcomings. Although conducted by British academics through the Medical Research Council, the trial was funded and largely designed by Merck, which had hoped it would demonstrate the clinical utility of its new combination of extended-release niacin and an antiflushing agent called laropiprant, a prostaglandin-inhibiting compound. One has only to remember the fiasco with the cyclo-oxygenase-2 inhibitor celecoxib to recognize the potential increase in cardiovascular events of any agent that blocks prostaglandins. Any failure of the niacin/laropiprant arm to show a reduced cardiovascular event rate on top of baseline statin therapy might have been because the laropiprant was increasing events enough to cancel any reductions the niacin might have produced.
Related: You'll Have a Dickens of a Time
A fair trial of the potential effectiveness of a niacin preparation on top of statin therapy should test niacin in a clinical setting in which it is typically prescribed. I’m not going far out on a limb by asserting that the majority of niacin prescriptions are written for patients who have low levels of high-density lipoprotein cholesterol (HDL-C), typically < 40 mg/dL but often much lower than that. Yet the mean HDL-C in the HPS2-THRIVE study was a robust 44 mg/dL, and the mean LDL-C level was a well-controlled 63 mg/dL. The subjects who were randomized to receive either placebo or niacin/laropiprant on top of their preexisting statin therapy were simply not the typical patients who would normally be started on niacin.
The supposedly airtight case against niacin isn’t really so strong after all. Where does this leave us? Let’s not forget that there is a sizable population of individuals who cannot or will not take statins. Surely these individuals would be better off on niacin therapy than on no therapy, particularly if they have a combination of low HDL-C levels, elevated triglyceride levels, and elevated LDL-C levels.
I currently prescribe this combination in patients who have persistently elevated triglyceride levels even after their statins have been maxed out, because I believe that lowering triglycerides in such patients may well translate into lower cardiovascular risk. Some recent evidence suggests that the epidemiologic association of low HDL-C levels with cardiovascular events may not be due so much to the low HDL-C levels per se, but rather to the very frequent association of elevated triglyceride levels—the true culprit, with low HDL-C levels. So if you have a need to lower either triglyceride levels or LDL-C levels in a patient already taking as much statin as they can tolerate, niacin would be a very reasonable drug to consider. My romance with niacin has been rekindled, and perhaps you’ll want to give it a second look as well.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
I had thought that my long-standing romance with niacin was finally over. Although it was a very early love of mine, reluctantly I had gone along with the mainstream consensus. It seemed that niacin had been sent into near-permanent pharmaceutical exile by the devastating one-two punches of the AIM HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) and the HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) studies. I had even stopped taking my own self- prescribed niacin 2,500 mg twice a day, which I had been religiously consuming for over 2 decades. But before long, I found that I had real difficulty divorcing myself completely from the charms of this lipid-lowering Lorelei. Now, after agonizing over the issue for some time, I’m here to tell you that niacin almost certainly did get a bum rap and should be restored as an important tool in your therapeutic armamentarium.
Related: Niacin: Not Dead Yet, but on Life Support
A recent report that niacin seems to function partially as an inhibitor of the PCSK-9 enzyme accelerated my reconsideration. The inhibition of PCSK-9, an enzyme that removes low-density lipoprotein cholesterol (LDL-C) receptors from hepatocytes, is the hot new way of dropping LDL-C levels. And I mean really dropping LDL-C levels. Studies conducted with investigational compounds developed by Amgen and Pfizer have shown truly dramatic drops in LDL-C levels by as much as 80%—often down to ridiculously low levels (around 25 mg/dL).
Of course, we are still waiting for outcome trials, which will answer the critical question: Are these dramatic falls in LDL-C levels actually associated with meaningful reductions in the occurrence rates for cardiovascular events such as myocardial infarction and stroke? For now, inhibiting PCSK-9 seems to be a good way to change the lipid profile dramatically. Even if niacin is not nearly as potent an inhibitor of the PCSK-9 enzymes as some newer compounds, the fact that it has measurable inhibiting activity seems enough to earn it a second look.
The concerns over niacin derive almost entirely from the results of the AIM HIGH study and the HPS2-THRIVE trials. Thus, any effort to rehabilitate niacin will require a reckoning with each of these major trials.
Related: The Niacin Debate Continues: Higher Doses, Please
I was one of the original AIM HIGH investigators, but our study site at the Phoenix VA eventually was removed from the trial because of poor enrollment. Nonetheless, I had a front-row seat to observe the conduct of the trial, and it seemed less than optimal. The relatively infrequent monitor visits for this study probably contributed to the finding that the lipid differences between the 2 study groups were considerably smaller than they could have been. It was my impression that study sites did not have their feet held to the fire when niacin compliance became problematic for subjects randomized to the larger dose of niacin.
The study design also contributed to blunting the difference between the 2 study groups. Subjects in the control group actually received 200 mg of immediate-release niacin to help blind the study by ensuring that all subjects experienced a niacin flush. The statin dose wound up being higher in the control group, and the use of the add-on lipid-lowering agent ezetimibe was also greater (22% vs 10%) in the control group. All these factors would tend to blunt the differences between the 2 groups, and indeed lipid levels did improve significantly in both groups.
To add insult to injury, the trial was stopped after just 3 years. A number of other lipid trials that were ultimately positive had not yet reached a statistically significant separation between the control and the experimental groups after that relatively brief study interval. Although these study flaws are hardly fatal, when taken together, they suggest the need to maintain an open mind. If niacin is like Brylcreem and “a little dab’ll do ya,” then the small dusting received by the control subjects might have been cardioprotective enough to blunt any differences in event rates between the 2 groups, especially over the truncated period of the actual trial.
What about the much larger HPS2-THRIVE study; surely there can’t be similar flaws in that study as well? Well, a critical review identifies a number of significant shortcomings. Although conducted by British academics through the Medical Research Council, the trial was funded and largely designed by Merck, which had hoped it would demonstrate the clinical utility of its new combination of extended-release niacin and an antiflushing agent called laropiprant, a prostaglandin-inhibiting compound. One has only to remember the fiasco with the cyclo-oxygenase-2 inhibitor celecoxib to recognize the potential increase in cardiovascular events of any agent that blocks prostaglandins. Any failure of the niacin/laropiprant arm to show a reduced cardiovascular event rate on top of baseline statin therapy might have been because the laropiprant was increasing events enough to cancel any reductions the niacin might have produced.
Related: You'll Have a Dickens of a Time
A fair trial of the potential effectiveness of a niacin preparation on top of statin therapy should test niacin in a clinical setting in which it is typically prescribed. I’m not going far out on a limb by asserting that the majority of niacin prescriptions are written for patients who have low levels of high-density lipoprotein cholesterol (HDL-C), typically < 40 mg/dL but often much lower than that. Yet the mean HDL-C in the HPS2-THRIVE study was a robust 44 mg/dL, and the mean LDL-C level was a well-controlled 63 mg/dL. The subjects who were randomized to receive either placebo or niacin/laropiprant on top of their preexisting statin therapy were simply not the typical patients who would normally be started on niacin.
The supposedly airtight case against niacin isn’t really so strong after all. Where does this leave us? Let’s not forget that there is a sizable population of individuals who cannot or will not take statins. Surely these individuals would be better off on niacin therapy than on no therapy, particularly if they have a combination of low HDL-C levels, elevated triglyceride levels, and elevated LDL-C levels.
I currently prescribe this combination in patients who have persistently elevated triglyceride levels even after their statins have been maxed out, because I believe that lowering triglycerides in such patients may well translate into lower cardiovascular risk. Some recent evidence suggests that the epidemiologic association of low HDL-C levels with cardiovascular events may not be due so much to the low HDL-C levels per se, but rather to the very frequent association of elevated triglyceride levels—the true culprit, with low HDL-C levels. So if you have a need to lower either triglyceride levels or LDL-C levels in a patient already taking as much statin as they can tolerate, niacin would be a very reasonable drug to consider. My romance with niacin has been rekindled, and perhaps you’ll want to give it a second look as well.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
I had thought that my long-standing romance with niacin was finally over. Although it was a very early love of mine, reluctantly I had gone along with the mainstream consensus. It seemed that niacin had been sent into near-permanent pharmaceutical exile by the devastating one-two punches of the AIM HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) and the HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) studies. I had even stopped taking my own self- prescribed niacin 2,500 mg twice a day, which I had been religiously consuming for over 2 decades. But before long, I found that I had real difficulty divorcing myself completely from the charms of this lipid-lowering Lorelei. Now, after agonizing over the issue for some time, I’m here to tell you that niacin almost certainly did get a bum rap and should be restored as an important tool in your therapeutic armamentarium.
Related: Niacin: Not Dead Yet, but on Life Support
A recent report that niacin seems to function partially as an inhibitor of the PCSK-9 enzyme accelerated my reconsideration. The inhibition of PCSK-9, an enzyme that removes low-density lipoprotein cholesterol (LDL-C) receptors from hepatocytes, is the hot new way of dropping LDL-C levels. And I mean really dropping LDL-C levels. Studies conducted with investigational compounds developed by Amgen and Pfizer have shown truly dramatic drops in LDL-C levels by as much as 80%—often down to ridiculously low levels (around 25 mg/dL).
Of course, we are still waiting for outcome trials, which will answer the critical question: Are these dramatic falls in LDL-C levels actually associated with meaningful reductions in the occurrence rates for cardiovascular events such as myocardial infarction and stroke? For now, inhibiting PCSK-9 seems to be a good way to change the lipid profile dramatically. Even if niacin is not nearly as potent an inhibitor of the PCSK-9 enzymes as some newer compounds, the fact that it has measurable inhibiting activity seems enough to earn it a second look.
The concerns over niacin derive almost entirely from the results of the AIM HIGH study and the HPS2-THRIVE trials. Thus, any effort to rehabilitate niacin will require a reckoning with each of these major trials.
Related: The Niacin Debate Continues: Higher Doses, Please
I was one of the original AIM HIGH investigators, but our study site at the Phoenix VA eventually was removed from the trial because of poor enrollment. Nonetheless, I had a front-row seat to observe the conduct of the trial, and it seemed less than optimal. The relatively infrequent monitor visits for this study probably contributed to the finding that the lipid differences between the 2 study groups were considerably smaller than they could have been. It was my impression that study sites did not have their feet held to the fire when niacin compliance became problematic for subjects randomized to the larger dose of niacin.
The study design also contributed to blunting the difference between the 2 study groups. Subjects in the control group actually received 200 mg of immediate-release niacin to help blind the study by ensuring that all subjects experienced a niacin flush. The statin dose wound up being higher in the control group, and the use of the add-on lipid-lowering agent ezetimibe was also greater (22% vs 10%) in the control group. All these factors would tend to blunt the differences between the 2 groups, and indeed lipid levels did improve significantly in both groups.
To add insult to injury, the trial was stopped after just 3 years. A number of other lipid trials that were ultimately positive had not yet reached a statistically significant separation between the control and the experimental groups after that relatively brief study interval. Although these study flaws are hardly fatal, when taken together, they suggest the need to maintain an open mind. If niacin is like Brylcreem and “a little dab’ll do ya,” then the small dusting received by the control subjects might have been cardioprotective enough to blunt any differences in event rates between the 2 groups, especially over the truncated period of the actual trial.
What about the much larger HPS2-THRIVE study; surely there can’t be similar flaws in that study as well? Well, a critical review identifies a number of significant shortcomings. Although conducted by British academics through the Medical Research Council, the trial was funded and largely designed by Merck, which had hoped it would demonstrate the clinical utility of its new combination of extended-release niacin and an antiflushing agent called laropiprant, a prostaglandin-inhibiting compound. One has only to remember the fiasco with the cyclo-oxygenase-2 inhibitor celecoxib to recognize the potential increase in cardiovascular events of any agent that blocks prostaglandins. Any failure of the niacin/laropiprant arm to show a reduced cardiovascular event rate on top of baseline statin therapy might have been because the laropiprant was increasing events enough to cancel any reductions the niacin might have produced.
Related: You'll Have a Dickens of a Time
A fair trial of the potential effectiveness of a niacin preparation on top of statin therapy should test niacin in a clinical setting in which it is typically prescribed. I’m not going far out on a limb by asserting that the majority of niacin prescriptions are written for patients who have low levels of high-density lipoprotein cholesterol (HDL-C), typically < 40 mg/dL but often much lower than that. Yet the mean HDL-C in the HPS2-THRIVE study was a robust 44 mg/dL, and the mean LDL-C level was a well-controlled 63 mg/dL. The subjects who were randomized to receive either placebo or niacin/laropiprant on top of their preexisting statin therapy were simply not the typical patients who would normally be started on niacin.
The supposedly airtight case against niacin isn’t really so strong after all. Where does this leave us? Let’s not forget that there is a sizable population of individuals who cannot or will not take statins. Surely these individuals would be better off on niacin therapy than on no therapy, particularly if they have a combination of low HDL-C levels, elevated triglyceride levels, and elevated LDL-C levels.
I currently prescribe this combination in patients who have persistently elevated triglyceride levels even after their statins have been maxed out, because I believe that lowering triglycerides in such patients may well translate into lower cardiovascular risk. Some recent evidence suggests that the epidemiologic association of low HDL-C levels with cardiovascular events may not be due so much to the low HDL-C levels per se, but rather to the very frequent association of elevated triglyceride levels—the true culprit, with low HDL-C levels. So if you have a need to lower either triglyceride levels or LDL-C levels in a patient already taking as much statin as they can tolerate, niacin would be a very reasonable drug to consider. My romance with niacin has been rekindled, and perhaps you’ll want to give it a second look as well.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
A Medical Tower of Babel
I see a multitude of veterans with assorted endocrine problems in my current position at the VA outpatient clinic in Oxnard, California. I have discovered a great many satisfactions and frustrations that go hand in hand in assuming such a frontline position. Please indulge me as I rant about one of my biggest frustrations that is inextricably associated with providing direct patient care.
I’m referring to the extreme difficulty that frontline providers have in communicating effectively with one another in today’s mixed-up medical world. The problem is magnified, because a large number of patients visit more than one medical provider for the same basic medical problems—at least those patients who come to VA medical clinics.
Related: The Use of Secure Messaging in Medical Specialty Care
I recognize that my patients all served their time faithfully in the U.S. military and that they are therefore entitled to as much or as little medical care as they may choose to receive through the VA. However, the desired involvement with the VA for many patients is limited to receiving medications, particularly if they are for service-connected health problems and do not have copays (usually $9 for 30 days’ medication). Most of the time the medications prescribed by non-VA providers are the standard antidiabetic drugs or antihypertensive and lipid-lowering agents that all of our shared patients with diabetes also take.
There will be the occasional patient who wants to have his hydrazine prescription refilled, even though he admits to feeling sluggish and lightheaded much of the time. I’m then left wondering to myself whether the private provider dislikes this particular patient or whether he is losing the battle to keep up with new guidelines and recommendations.
My frustration is that I have no easy way to communicate with the private providers with whom I am sharing patient care responsibilities—especially if I disagree with their medical decisions. It is difficult, if not impossible, to review non-VA medical records to understand their reasoning. Only occasionally will patients bring along dribs and drabs of their private medical records.
Related: Mutual Alignment Trumps Merger for Joint VA/DoD Health Care Programs
For patients who have seen other VA providers, I can access the sophisticated and beloved CPRS (Computerized Patient Record System) and view all the records of their medical visits at any of the nearly 1,000 VA sites. The records of patient care delivered by the myriad of providers outside of the VA system are inaccessible, even though most of these providers are also using an electronic medical record (EMR) system.
As most of you know, these EMR systems do not communicate with one another. As a result, I usually get fragmentary medical information, if any, from the other providers with whom I am comanaging patients.
Some of these patients are critically ill, leaving a small margin for error. Let’s say that one of my diabetic patients develops ketoacidosis and is admitted to a private hospital. There’s no way that I can directly access the EMRs from that hospitalization when the patient comes to see me for postdischarge, follow-up diabetes management a week later. Even if I were to take the time to try to track down the treating hospitalist, many times the patient cannot recall the doctor’s name, and I am thwarted by byzantine HIPAA rules if I try to call the facility. I’m usually left to hope that the patient brought a concise discharge summary, which rarely happens.
There are glimmers of hope on the horizon. According to The Wall Street Journal, significant progress is being made in improving sharing between EMR systems. Carequality, an information technology collaborative, was formed last year to create common standards to handle both the technology and legal issues involved. Also last year, CommonWell Health Alliance, which now has 17 members, formed to share EMRs. Although CPRS is not part of either initiative, these groups represent important steps forward. Still, as far as I and my long-suffering patients are concerned, it can’t happen soon enough.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
I see a multitude of veterans with assorted endocrine problems in my current position at the VA outpatient clinic in Oxnard, California. I have discovered a great many satisfactions and frustrations that go hand in hand in assuming such a frontline position. Please indulge me as I rant about one of my biggest frustrations that is inextricably associated with providing direct patient care.
I’m referring to the extreme difficulty that frontline providers have in communicating effectively with one another in today’s mixed-up medical world. The problem is magnified, because a large number of patients visit more than one medical provider for the same basic medical problems—at least those patients who come to VA medical clinics.
Related: The Use of Secure Messaging in Medical Specialty Care
I recognize that my patients all served their time faithfully in the U.S. military and that they are therefore entitled to as much or as little medical care as they may choose to receive through the VA. However, the desired involvement with the VA for many patients is limited to receiving medications, particularly if they are for service-connected health problems and do not have copays (usually $9 for 30 days’ medication). Most of the time the medications prescribed by non-VA providers are the standard antidiabetic drugs or antihypertensive and lipid-lowering agents that all of our shared patients with diabetes also take.
There will be the occasional patient who wants to have his hydrazine prescription refilled, even though he admits to feeling sluggish and lightheaded much of the time. I’m then left wondering to myself whether the private provider dislikes this particular patient or whether he is losing the battle to keep up with new guidelines and recommendations.
My frustration is that I have no easy way to communicate with the private providers with whom I am sharing patient care responsibilities—especially if I disagree with their medical decisions. It is difficult, if not impossible, to review non-VA medical records to understand their reasoning. Only occasionally will patients bring along dribs and drabs of their private medical records.
Related: Mutual Alignment Trumps Merger for Joint VA/DoD Health Care Programs
For patients who have seen other VA providers, I can access the sophisticated and beloved CPRS (Computerized Patient Record System) and view all the records of their medical visits at any of the nearly 1,000 VA sites. The records of patient care delivered by the myriad of providers outside of the VA system are inaccessible, even though most of these providers are also using an electronic medical record (EMR) system.
As most of you know, these EMR systems do not communicate with one another. As a result, I usually get fragmentary medical information, if any, from the other providers with whom I am comanaging patients.
Some of these patients are critically ill, leaving a small margin for error. Let’s say that one of my diabetic patients develops ketoacidosis and is admitted to a private hospital. There’s no way that I can directly access the EMRs from that hospitalization when the patient comes to see me for postdischarge, follow-up diabetes management a week later. Even if I were to take the time to try to track down the treating hospitalist, many times the patient cannot recall the doctor’s name, and I am thwarted by byzantine HIPAA rules if I try to call the facility. I’m usually left to hope that the patient brought a concise discharge summary, which rarely happens.
There are glimmers of hope on the horizon. According to The Wall Street Journal, significant progress is being made in improving sharing between EMR systems. Carequality, an information technology collaborative, was formed last year to create common standards to handle both the technology and legal issues involved. Also last year, CommonWell Health Alliance, which now has 17 members, formed to share EMRs. Although CPRS is not part of either initiative, these groups represent important steps forward. Still, as far as I and my long-suffering patients are concerned, it can’t happen soon enough.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
I see a multitude of veterans with assorted endocrine problems in my current position at the VA outpatient clinic in Oxnard, California. I have discovered a great many satisfactions and frustrations that go hand in hand in assuming such a frontline position. Please indulge me as I rant about one of my biggest frustrations that is inextricably associated with providing direct patient care.
I’m referring to the extreme difficulty that frontline providers have in communicating effectively with one another in today’s mixed-up medical world. The problem is magnified, because a large number of patients visit more than one medical provider for the same basic medical problems—at least those patients who come to VA medical clinics.
Related: The Use of Secure Messaging in Medical Specialty Care
I recognize that my patients all served their time faithfully in the U.S. military and that they are therefore entitled to as much or as little medical care as they may choose to receive through the VA. However, the desired involvement with the VA for many patients is limited to receiving medications, particularly if they are for service-connected health problems and do not have copays (usually $9 for 30 days’ medication). Most of the time the medications prescribed by non-VA providers are the standard antidiabetic drugs or antihypertensive and lipid-lowering agents that all of our shared patients with diabetes also take.
There will be the occasional patient who wants to have his hydrazine prescription refilled, even though he admits to feeling sluggish and lightheaded much of the time. I’m then left wondering to myself whether the private provider dislikes this particular patient or whether he is losing the battle to keep up with new guidelines and recommendations.
My frustration is that I have no easy way to communicate with the private providers with whom I am sharing patient care responsibilities—especially if I disagree with their medical decisions. It is difficult, if not impossible, to review non-VA medical records to understand their reasoning. Only occasionally will patients bring along dribs and drabs of their private medical records.
Related: Mutual Alignment Trumps Merger for Joint VA/DoD Health Care Programs
For patients who have seen other VA providers, I can access the sophisticated and beloved CPRS (Computerized Patient Record System) and view all the records of their medical visits at any of the nearly 1,000 VA sites. The records of patient care delivered by the myriad of providers outside of the VA system are inaccessible, even though most of these providers are also using an electronic medical record (EMR) system.
As most of you know, these EMR systems do not communicate with one another. As a result, I usually get fragmentary medical information, if any, from the other providers with whom I am comanaging patients.
Some of these patients are critically ill, leaving a small margin for error. Let’s say that one of my diabetic patients develops ketoacidosis and is admitted to a private hospital. There’s no way that I can directly access the EMRs from that hospitalization when the patient comes to see me for postdischarge, follow-up diabetes management a week later. Even if I were to take the time to try to track down the treating hospitalist, many times the patient cannot recall the doctor’s name, and I am thwarted by byzantine HIPAA rules if I try to call the facility. I’m usually left to hope that the patient brought a concise discharge summary, which rarely happens.
There are glimmers of hope on the horizon. According to The Wall Street Journal, significant progress is being made in improving sharing between EMR systems. Carequality, an information technology collaborative, was formed last year to create common standards to handle both the technology and legal issues involved. Also last year, CommonWell Health Alliance, which now has 17 members, formed to share EMRs. Although CPRS is not part of either initiative, these groups represent important steps forward. Still, as far as I and my long-suffering patients are concerned, it can’t happen soon enough.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Retire, Who Me?
Okay, so I didn’t last long as a VA retiree. My original plan was to hang it up entirely when I stepped down from my longstanding (27 years!) position as chief of medicine at the Phoenix VA Health Care System (VAHCS) at the end of June 2014. As some longtime readers may recall, my wife, Susan, has had a severe case of Sjögren’s syndrome for many years, and her symptoms have worsened progressively recently.
Our vacation home seemed a logical place to retire to, since it is in a more humid and oceanside California climate, and my wife could have some hope of breathing easier. As long as our youngest son was in high school in Phoenix, I had an excuse to stay in Arizona, but he graduated at the end of June.
Related: What's Wrong With My Wife?
Thus, all the stars aligned and I made my formal e-mail announcement to my troops in the Department of Medicine on February 14. The access scandal whose epicenter was the Phoenix VAHCS hit a couple of months later in April, and the horrendous press that ensued seemed to confirm that I should retire.
I mention these dates to counter the suspicion that I got out of Dodge because things got rough. Nothing could be further from the truth: I had to be practically dragged kicking and screaming from my office when the time arrived. I was not an enthusiastic retiree.
By early May I was already worrying about the idleness and boredom I assumed would be the hallmarks of true retirement. So I began to search frantically online for employment opportunities near our home. As it turned out, the best employment opportunity in the area was at a VA contract clinic in Oxnard. The clinic is a fully integrated part of the Greater Los Angeles VAHCS operated by Humana Government Services, not the VA.
I surprised myself by jumping at the opportunity to continue to work in a medical setting, especially one with a strong VA flavor. But I became increasingly apprehensive as the planned start date of August 4 approached. After all, for years I had had a vast array of hardworking medical helpers standing between me and the patients, including medical students, interns, residents, endocrine fellows, nurse practitioners, and physician assistants who would do almost all the direct patient care. I would occasionally visit with the patient who was not content to interact exclusively with my designated assistant or when an earnest trainee felt that I needed to assess a patient’s unique situation or concern.
Related: Keeping an Open Mind on HRT
But a small miracle has enveloped me since I began working at the Oxnard clinic. I have found that I enjoy taking care of the nonstop parade of dyslipidemic hypertensive diabetic patients who constitute the huge majority of those I see. Yes, there are many times when I wish I could sit back in my chair and unravel knotty organizational problems as I did at my previous job. And I also have persistent fantasies of sitting in my beach chair, drinking strong martinis while staring at the ever-fascinating waves of the nearby Pacific.
However, I have come to realize that I am truly a restless person. As long as there is some potential medical good to be achieved, I am hell- bent on making it happen if I can. While not all physicians share this philosophy, I strongly believe that the practice of medicine is a lifelong professional commitment that can be very difficult for many of us to walk away from. I certainly don’t know how long I’ll last in my new post. What could well drive me away is the almost-frantic pace of modern health care delivery, a pace that is largely determined by the tyranny of the electronic medical record, a monster who must be fed at all costs (more on this in the future). But for now, the need to contribute to the medical endeavor has proven considerably stronger than the countervailing desire for a quiet and comfortable retirement.
Related: Landmark Initiative Signed for Homeless Veterans
Don’t call me crazy just yet; instead, please follow the lead of my mostly grateful patients and call me doctor. That’s an honorific that’s still meaningful to me, and it keeps me slogging onward in spite of the many obstacles.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.
Okay, so I didn’t last long as a VA retiree. My original plan was to hang it up entirely when I stepped down from my longstanding (27 years!) position as chief of medicine at the Phoenix VA Health Care System (VAHCS) at the end of June 2014. As some longtime readers may recall, my wife, Susan, has had a severe case of Sjögren’s syndrome for many years, and her symptoms have worsened progressively recently.
Our vacation home seemed a logical place to retire to, since it is in a more humid and oceanside California climate, and my wife could have some hope of breathing easier. As long as our youngest son was in high school in Phoenix, I had an excuse to stay in Arizona, but he graduated at the end of June.
Related: What's Wrong With My Wife?
Thus, all the stars aligned and I made my formal e-mail announcement to my troops in the Department of Medicine on February 14. The access scandal whose epicenter was the Phoenix VAHCS hit a couple of months later in April, and the horrendous press that ensued seemed to confirm that I should retire.
I mention these dates to counter the suspicion that I got out of Dodge because things got rough. Nothing could be further from the truth: I had to be practically dragged kicking and screaming from my office when the time arrived. I was not an enthusiastic retiree.
By early May I was already worrying about the idleness and boredom I assumed would be the hallmarks of true retirement. So I began to search frantically online for employment opportunities near our home. As it turned out, the best employment opportunity in the area was at a VA contract clinic in Oxnard. The clinic is a fully integrated part of the Greater Los Angeles VAHCS operated by Humana Government Services, not the VA.
I surprised myself by jumping at the opportunity to continue to work in a medical setting, especially one with a strong VA flavor. But I became increasingly apprehensive as the planned start date of August 4 approached. After all, for years I had had a vast array of hardworking medical helpers standing between me and the patients, including medical students, interns, residents, endocrine fellows, nurse practitioners, and physician assistants who would do almost all the direct patient care. I would occasionally visit with the patient who was not content to interact exclusively with my designated assistant or when an earnest trainee felt that I needed to assess a patient’s unique situation or concern.
Related: Keeping an Open Mind on HRT
But a small miracle has enveloped me since I began working at the Oxnard clinic. I have found that I enjoy taking care of the nonstop parade of dyslipidemic hypertensive diabetic patients who constitute the huge majority of those I see. Yes, there are many times when I wish I could sit back in my chair and unravel knotty organizational problems as I did at my previous job. And I also have persistent fantasies of sitting in my beach chair, drinking strong martinis while staring at the ever-fascinating waves of the nearby Pacific.
However, I have come to realize that I am truly a restless person. As long as there is some potential medical good to be achieved, I am hell- bent on making it happen if I can. While not all physicians share this philosophy, I strongly believe that the practice of medicine is a lifelong professional commitment that can be very difficult for many of us to walk away from. I certainly don’t know how long I’ll last in my new post. What could well drive me away is the almost-frantic pace of modern health care delivery, a pace that is largely determined by the tyranny of the electronic medical record, a monster who must be fed at all costs (more on this in the future). But for now, the need to contribute to the medical endeavor has proven considerably stronger than the countervailing desire for a quiet and comfortable retirement.
Related: Landmark Initiative Signed for Homeless Veterans
Don’t call me crazy just yet; instead, please follow the lead of my mostly grateful patients and call me doctor. That’s an honorific that’s still meaningful to me, and it keeps me slogging onward in spite of the many obstacles.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.
Okay, so I didn’t last long as a VA retiree. My original plan was to hang it up entirely when I stepped down from my longstanding (27 years!) position as chief of medicine at the Phoenix VA Health Care System (VAHCS) at the end of June 2014. As some longtime readers may recall, my wife, Susan, has had a severe case of Sjögren’s syndrome for many years, and her symptoms have worsened progressively recently.
Our vacation home seemed a logical place to retire to, since it is in a more humid and oceanside California climate, and my wife could have some hope of breathing easier. As long as our youngest son was in high school in Phoenix, I had an excuse to stay in Arizona, but he graduated at the end of June.
Related: What's Wrong With My Wife?
Thus, all the stars aligned and I made my formal e-mail announcement to my troops in the Department of Medicine on February 14. The access scandal whose epicenter was the Phoenix VAHCS hit a couple of months later in April, and the horrendous press that ensued seemed to confirm that I should retire.
I mention these dates to counter the suspicion that I got out of Dodge because things got rough. Nothing could be further from the truth: I had to be practically dragged kicking and screaming from my office when the time arrived. I was not an enthusiastic retiree.
By early May I was already worrying about the idleness and boredom I assumed would be the hallmarks of true retirement. So I began to search frantically online for employment opportunities near our home. As it turned out, the best employment opportunity in the area was at a VA contract clinic in Oxnard. The clinic is a fully integrated part of the Greater Los Angeles VAHCS operated by Humana Government Services, not the VA.
I surprised myself by jumping at the opportunity to continue to work in a medical setting, especially one with a strong VA flavor. But I became increasingly apprehensive as the planned start date of August 4 approached. After all, for years I had had a vast array of hardworking medical helpers standing between me and the patients, including medical students, interns, residents, endocrine fellows, nurse practitioners, and physician assistants who would do almost all the direct patient care. I would occasionally visit with the patient who was not content to interact exclusively with my designated assistant or when an earnest trainee felt that I needed to assess a patient’s unique situation or concern.
Related: Keeping an Open Mind on HRT
But a small miracle has enveloped me since I began working at the Oxnard clinic. I have found that I enjoy taking care of the nonstop parade of dyslipidemic hypertensive diabetic patients who constitute the huge majority of those I see. Yes, there are many times when I wish I could sit back in my chair and unravel knotty organizational problems as I did at my previous job. And I also have persistent fantasies of sitting in my beach chair, drinking strong martinis while staring at the ever-fascinating waves of the nearby Pacific.
However, I have come to realize that I am truly a restless person. As long as there is some potential medical good to be achieved, I am hell- bent on making it happen if I can. While not all physicians share this philosophy, I strongly believe that the practice of medicine is a lifelong professional commitment that can be very difficult for many of us to walk away from. I certainly don’t know how long I’ll last in my new post. What could well drive me away is the almost-frantic pace of modern health care delivery, a pace that is largely determined by the tyranny of the electronic medical record, a monster who must be fed at all costs (more on this in the future). But for now, the need to contribute to the medical endeavor has proven considerably stronger than the countervailing desire for a quiet and comfortable retirement.
Related: Landmark Initiative Signed for Homeless Veterans
Don’t call me crazy just yet; instead, please follow the lead of my mostly grateful patients and call me doctor. That’s an honorific that’s still meaningful to me, and it keeps me slogging onward in spite of the many obstacles.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.
Keeping an Open Mind on HRT
This month, I’m going to wade headfirst into a dangerous and controversial area of medicine: Whether or not hormone replacement therapy (HRT) might be a reasonable, long-term option for postmenopausal women. Many of you are probably wondering whether I’ve completely lost it, because you’re thinking that this issue has already been definitively, irrevocably settled by the landmark Women’s Health Initiative (WHI) trial. I’ll admit upfront that I can’t give you any definitive answers, but I’m hoping that I may be able to persuade you that things are not nearly as cut-and-dried as you may have been led to believe.
As a self-styled (and overly opinionated) cardiovascular endocrinologist, I’m especially interested in the question of whether or not postmenopausal HRT might actually have a beneficial role in retarding the progression of atherosclerotic cardiovascular disease in older women. This, after all, is a pretty relevant question, because the numero uno cause of death in American women today is cardiovascular disease, notwithstanding the huge amount of attention and money that the breast cancer lobby has been able to attract.
Let’s go back a few decades and review the standard medical practices of the 1990s, before the estrogen waters became very, very muddied. Postmenopausal estrogens were routinely prescribed in that blessedly naive era, both to treat disconcerting symptoms such as hot flushes and mood fluctuations, and also for their purported benefits to reduce the progression of cardiovascular disease. After all, a large number of observational studies, upward of 30, had all demonstrated rather convincingly that there is a very strong correlation between the use of postmenopausal HRT and a lower incidence of adverse cardiovascular events.
This made very good sense, because estrogens are very potent vasodilators, and they also increase high-density lipoprotein (Lp) cholesterol levels quite smartly (and reduce Lp(a) levels to boot). But the fundamental problem here is that these were strictly observational studies with the inherent selection biases that are part and parcel of such studies. It seems probable in retrospect that the women who were taking postmenopausal estrogens were a rather select group of health-conscious patients who were less likely to develop heart disease than were those women not on estrogens, simply because the former group was living a much healthier lifestyle with better diet, more exercise, and better medical care.
Then along came the era of controlled randomized trials in this area. The Heart and Estrogen/progestin Replacement Study (HERS) trial in the late 1990s was the first to begin to shake our faith in the value of postmenopausal HRT. This trial seemed to show that women had an increased incidence of heart attacks and other thrombotic events in the first few years after initiating HRT, compared with their counterparts who were randomized to placebo therapy. But those who looked closely at the data noted that this apparent negative effect waned dramatically in the fourth and fifth years of the study, suggesting that perhaps there was an unfortunate early effect to promote thrombotic events by revving up the coagulation machinery, but which was then followed by a counter-balancing beneficial effect of estrogens on the rate of progression of cardiovascular disease over time.
But the HERS trial was completely overshadowed several years later by WHI, a huge NIH-funded trial that aimed to provide final answers as to whether or not postmenopausal women should take HRT. The WHI was actually 2 separate studies, one of combined estrogen/progestin replacement therapy, and one of estrogen therapy alone in women who previously had a hysterectomy and, hence, had no need of the cancer protection that progestins offer in women with intact uteruses.
The combined therapy study included nearly 16,000 postmenopausal women with an average age of 63 years. Those randomized to active therapy received conjugated estrogens in a dose of 0.625 mg, along with medroxyprogesterone acetate 2.5 mg, for the planned study duration of 5 years. But the combined study was terminated early because of a modestly increased occurrence of breast cancer in the treated group. Most relevant here is that the early reports of the WHI results suggested a hazard ratio for coronary heart disease (nonfatal myocardial infarction or death due to coronary artery disease) in the treated cohort of 1.24 (24% more events than in the placebo group), a number that is not very impressive at all in the grand scheme of things.
Subsequently, more detailed analyses of the data suggested that any increase in cardiovascular risk was confined to the older (aged ≥ late 60s) women of the combined-therapy cohort.
The estrogen-only wing of the WHI continued for a while longer. Its results were not very concerning at all when it came to cardiovascular events. The hazard ratio for cardiovascular events in the treatment group was only 0.95, hardly a concerning number, since it actually hinted ever so gently at a beneficial effect of HRT on cardiovascular events. And there was a stronger suggestion of such a possible cardioprotective effect in the subset of younger women enrolled in the estrogen-only trial, those aged 50 to 59 years when they entered the study. Might it be that estrogens are actually beneficial in slowing the rapid acceleration in atherosclerosis that occurs in the early postmenopausal years, particularly in the absence of progestins, if only one can avoid the exceptionally bad luck of an early estrogen-induced thrombotic event?
Those questions are still largely unanswered, but a very interesting trial published recently aimed to reopen the question of the true effects of HRT on cardiovascular outcomes in postmenopausal women. The findings of the Kronos Early Estrogen Prevention Study (KEEPS) came out recently.1 The lead author and lead investigator Dr. S. Mitchell Harman is a close friend of mine who served recently as my Chief of Endocrinology at the Phoenix VA and then became my interim successor as Chief of Medicine when I moved to the Greater Los Angeles VAMC because of my wife’s Sjogren’s-driven need for a more humid climate.
The KEEPS trial was a 4-year, randomized, double-blind, placebo-controlled trial in 727 women aged 45 to 54 years who were all newly menopausal, so that the effects of HRT could be assessed right after the onset of menopause. The KEEPS investigators hoped to demonstrate a favorable effect on cardiovascular outcomes with the administration of HRT so early on, but the trial was unfortunately too small to come up with those results. However, the trial went for its full planned duration, because there were absolutely no harmful effects seen with either oral conjugated estrogen therapy or with transdermal estrogen therapy, each of which was given together with oral progesterone.
There was a trend toward a slower increase in coronary artery calcium (CAC) scores in the minority of women who had elevated scores to begin with. But overall there was no difference in the rate of progression of either CAC scores or of carotid
intima-media thickness as measured by ultrasound; the latter is a standard research measure used to detect subtle differences in the rate of progression of cardiovascular disease. A pessimist would observe quite correctly that estrogens did not show a protective effect on cardiovascular outcomes, apart from the hint of a slower rate of progression of CAC scores in those with elevated levels at the onset. But an optimist would say that these results demonstrate the cardiovascular safety of early postmenopausal HRT, since there was no signal at all of a harmful effect.
So where does this leave us now? Unfortunately, we are completely bereft of definitive answers, and we are unlikely to get meaningful new data anytime soon, as there is currently zero enthusiasm at the NIH for devoting scarce resources to a re-examination of these same issues.
The bottom line is that we can agree that cardiovascular worries need to be put into proper perspective and that they have been overblown, at least in the lay press. I further believe that younger postmenopausal women who have solid indications for such therapy, be they hot flushes or advanced osteoporosis, should not be denied the benefits of HRT because of cardiovascular concerns.
I would be willing to consider long-term open-ended therapy in at least some of these patients. And let’s also not forget that estrogens clearly reduce the incidence of colon cancer and may well reduce the prevalence of the much-dreaded Alzheimer disease that awaits many older women.
I’ll be the first to acknowledge that this editorial is ending with not a bang, but a whimper. But that’s about the best I can come up with given the extremely severe limitations of the data available to us. I’ll consider this editorial a success if it encourages you to at least keep an open mind on the issue of the cardiovascular effects of estrogens and to accept my premise that we still lack so much of the data we truly need to reach definitive conclusions.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
This month, I’m going to wade headfirst into a dangerous and controversial area of medicine: Whether or not hormone replacement therapy (HRT) might be a reasonable, long-term option for postmenopausal women. Many of you are probably wondering whether I’ve completely lost it, because you’re thinking that this issue has already been definitively, irrevocably settled by the landmark Women’s Health Initiative (WHI) trial. I’ll admit upfront that I can’t give you any definitive answers, but I’m hoping that I may be able to persuade you that things are not nearly as cut-and-dried as you may have been led to believe.
As a self-styled (and overly opinionated) cardiovascular endocrinologist, I’m especially interested in the question of whether or not postmenopausal HRT might actually have a beneficial role in retarding the progression of atherosclerotic cardiovascular disease in older women. This, after all, is a pretty relevant question, because the numero uno cause of death in American women today is cardiovascular disease, notwithstanding the huge amount of attention and money that the breast cancer lobby has been able to attract.
Let’s go back a few decades and review the standard medical practices of the 1990s, before the estrogen waters became very, very muddied. Postmenopausal estrogens were routinely prescribed in that blessedly naive era, both to treat disconcerting symptoms such as hot flushes and mood fluctuations, and also for their purported benefits to reduce the progression of cardiovascular disease. After all, a large number of observational studies, upward of 30, had all demonstrated rather convincingly that there is a very strong correlation between the use of postmenopausal HRT and a lower incidence of adverse cardiovascular events.
This made very good sense, because estrogens are very potent vasodilators, and they also increase high-density lipoprotein (Lp) cholesterol levels quite smartly (and reduce Lp(a) levels to boot). But the fundamental problem here is that these were strictly observational studies with the inherent selection biases that are part and parcel of such studies. It seems probable in retrospect that the women who were taking postmenopausal estrogens were a rather select group of health-conscious patients who were less likely to develop heart disease than were those women not on estrogens, simply because the former group was living a much healthier lifestyle with better diet, more exercise, and better medical care.
Then along came the era of controlled randomized trials in this area. The Heart and Estrogen/progestin Replacement Study (HERS) trial in the late 1990s was the first to begin to shake our faith in the value of postmenopausal HRT. This trial seemed to show that women had an increased incidence of heart attacks and other thrombotic events in the first few years after initiating HRT, compared with their counterparts who were randomized to placebo therapy. But those who looked closely at the data noted that this apparent negative effect waned dramatically in the fourth and fifth years of the study, suggesting that perhaps there was an unfortunate early effect to promote thrombotic events by revving up the coagulation machinery, but which was then followed by a counter-balancing beneficial effect of estrogens on the rate of progression of cardiovascular disease over time.
But the HERS trial was completely overshadowed several years later by WHI, a huge NIH-funded trial that aimed to provide final answers as to whether or not postmenopausal women should take HRT. The WHI was actually 2 separate studies, one of combined estrogen/progestin replacement therapy, and one of estrogen therapy alone in women who previously had a hysterectomy and, hence, had no need of the cancer protection that progestins offer in women with intact uteruses.
The combined therapy study included nearly 16,000 postmenopausal women with an average age of 63 years. Those randomized to active therapy received conjugated estrogens in a dose of 0.625 mg, along with medroxyprogesterone acetate 2.5 mg, for the planned study duration of 5 years. But the combined study was terminated early because of a modestly increased occurrence of breast cancer in the treated group. Most relevant here is that the early reports of the WHI results suggested a hazard ratio for coronary heart disease (nonfatal myocardial infarction or death due to coronary artery disease) in the treated cohort of 1.24 (24% more events than in the placebo group), a number that is not very impressive at all in the grand scheme of things.
Subsequently, more detailed analyses of the data suggested that any increase in cardiovascular risk was confined to the older (aged ≥ late 60s) women of the combined-therapy cohort.
The estrogen-only wing of the WHI continued for a while longer. Its results were not very concerning at all when it came to cardiovascular events. The hazard ratio for cardiovascular events in the treatment group was only 0.95, hardly a concerning number, since it actually hinted ever so gently at a beneficial effect of HRT on cardiovascular events. And there was a stronger suggestion of such a possible cardioprotective effect in the subset of younger women enrolled in the estrogen-only trial, those aged 50 to 59 years when they entered the study. Might it be that estrogens are actually beneficial in slowing the rapid acceleration in atherosclerosis that occurs in the early postmenopausal years, particularly in the absence of progestins, if only one can avoid the exceptionally bad luck of an early estrogen-induced thrombotic event?
Those questions are still largely unanswered, but a very interesting trial published recently aimed to reopen the question of the true effects of HRT on cardiovascular outcomes in postmenopausal women. The findings of the Kronos Early Estrogen Prevention Study (KEEPS) came out recently.1 The lead author and lead investigator Dr. S. Mitchell Harman is a close friend of mine who served recently as my Chief of Endocrinology at the Phoenix VA and then became my interim successor as Chief of Medicine when I moved to the Greater Los Angeles VAMC because of my wife’s Sjogren’s-driven need for a more humid climate.
The KEEPS trial was a 4-year, randomized, double-blind, placebo-controlled trial in 727 women aged 45 to 54 years who were all newly menopausal, so that the effects of HRT could be assessed right after the onset of menopause. The KEEPS investigators hoped to demonstrate a favorable effect on cardiovascular outcomes with the administration of HRT so early on, but the trial was unfortunately too small to come up with those results. However, the trial went for its full planned duration, because there were absolutely no harmful effects seen with either oral conjugated estrogen therapy or with transdermal estrogen therapy, each of which was given together with oral progesterone.
There was a trend toward a slower increase in coronary artery calcium (CAC) scores in the minority of women who had elevated scores to begin with. But overall there was no difference in the rate of progression of either CAC scores or of carotid
intima-media thickness as measured by ultrasound; the latter is a standard research measure used to detect subtle differences in the rate of progression of cardiovascular disease. A pessimist would observe quite correctly that estrogens did not show a protective effect on cardiovascular outcomes, apart from the hint of a slower rate of progression of CAC scores in those with elevated levels at the onset. But an optimist would say that these results demonstrate the cardiovascular safety of early postmenopausal HRT, since there was no signal at all of a harmful effect.
So where does this leave us now? Unfortunately, we are completely bereft of definitive answers, and we are unlikely to get meaningful new data anytime soon, as there is currently zero enthusiasm at the NIH for devoting scarce resources to a re-examination of these same issues.
The bottom line is that we can agree that cardiovascular worries need to be put into proper perspective and that they have been overblown, at least in the lay press. I further believe that younger postmenopausal women who have solid indications for such therapy, be they hot flushes or advanced osteoporosis, should not be denied the benefits of HRT because of cardiovascular concerns.
I would be willing to consider long-term open-ended therapy in at least some of these patients. And let’s also not forget that estrogens clearly reduce the incidence of colon cancer and may well reduce the prevalence of the much-dreaded Alzheimer disease that awaits many older women.
I’ll be the first to acknowledge that this editorial is ending with not a bang, but a whimper. But that’s about the best I can come up with given the extremely severe limitations of the data available to us. I’ll consider this editorial a success if it encourages you to at least keep an open mind on the issue of the cardiovascular effects of estrogens and to accept my premise that we still lack so much of the data we truly need to reach definitive conclusions.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
This month, I’m going to wade headfirst into a dangerous and controversial area of medicine: Whether or not hormone replacement therapy (HRT) might be a reasonable, long-term option for postmenopausal women. Many of you are probably wondering whether I’ve completely lost it, because you’re thinking that this issue has already been definitively, irrevocably settled by the landmark Women’s Health Initiative (WHI) trial. I’ll admit upfront that I can’t give you any definitive answers, but I’m hoping that I may be able to persuade you that things are not nearly as cut-and-dried as you may have been led to believe.
As a self-styled (and overly opinionated) cardiovascular endocrinologist, I’m especially interested in the question of whether or not postmenopausal HRT might actually have a beneficial role in retarding the progression of atherosclerotic cardiovascular disease in older women. This, after all, is a pretty relevant question, because the numero uno cause of death in American women today is cardiovascular disease, notwithstanding the huge amount of attention and money that the breast cancer lobby has been able to attract.
Let’s go back a few decades and review the standard medical practices of the 1990s, before the estrogen waters became very, very muddied. Postmenopausal estrogens were routinely prescribed in that blessedly naive era, both to treat disconcerting symptoms such as hot flushes and mood fluctuations, and also for their purported benefits to reduce the progression of cardiovascular disease. After all, a large number of observational studies, upward of 30, had all demonstrated rather convincingly that there is a very strong correlation between the use of postmenopausal HRT and a lower incidence of adverse cardiovascular events.
This made very good sense, because estrogens are very potent vasodilators, and they also increase high-density lipoprotein (Lp) cholesterol levels quite smartly (and reduce Lp(a) levels to boot). But the fundamental problem here is that these were strictly observational studies with the inherent selection biases that are part and parcel of such studies. It seems probable in retrospect that the women who were taking postmenopausal estrogens were a rather select group of health-conscious patients who were less likely to develop heart disease than were those women not on estrogens, simply because the former group was living a much healthier lifestyle with better diet, more exercise, and better medical care.
Then along came the era of controlled randomized trials in this area. The Heart and Estrogen/progestin Replacement Study (HERS) trial in the late 1990s was the first to begin to shake our faith in the value of postmenopausal HRT. This trial seemed to show that women had an increased incidence of heart attacks and other thrombotic events in the first few years after initiating HRT, compared with their counterparts who were randomized to placebo therapy. But those who looked closely at the data noted that this apparent negative effect waned dramatically in the fourth and fifth years of the study, suggesting that perhaps there was an unfortunate early effect to promote thrombotic events by revving up the coagulation machinery, but which was then followed by a counter-balancing beneficial effect of estrogens on the rate of progression of cardiovascular disease over time.
But the HERS trial was completely overshadowed several years later by WHI, a huge NIH-funded trial that aimed to provide final answers as to whether or not postmenopausal women should take HRT. The WHI was actually 2 separate studies, one of combined estrogen/progestin replacement therapy, and one of estrogen therapy alone in women who previously had a hysterectomy and, hence, had no need of the cancer protection that progestins offer in women with intact uteruses.
The combined therapy study included nearly 16,000 postmenopausal women with an average age of 63 years. Those randomized to active therapy received conjugated estrogens in a dose of 0.625 mg, along with medroxyprogesterone acetate 2.5 mg, for the planned study duration of 5 years. But the combined study was terminated early because of a modestly increased occurrence of breast cancer in the treated group. Most relevant here is that the early reports of the WHI results suggested a hazard ratio for coronary heart disease (nonfatal myocardial infarction or death due to coronary artery disease) in the treated cohort of 1.24 (24% more events than in the placebo group), a number that is not very impressive at all in the grand scheme of things.
Subsequently, more detailed analyses of the data suggested that any increase in cardiovascular risk was confined to the older (aged ≥ late 60s) women of the combined-therapy cohort.
The estrogen-only wing of the WHI continued for a while longer. Its results were not very concerning at all when it came to cardiovascular events. The hazard ratio for cardiovascular events in the treatment group was only 0.95, hardly a concerning number, since it actually hinted ever so gently at a beneficial effect of HRT on cardiovascular events. And there was a stronger suggestion of such a possible cardioprotective effect in the subset of younger women enrolled in the estrogen-only trial, those aged 50 to 59 years when they entered the study. Might it be that estrogens are actually beneficial in slowing the rapid acceleration in atherosclerosis that occurs in the early postmenopausal years, particularly in the absence of progestins, if only one can avoid the exceptionally bad luck of an early estrogen-induced thrombotic event?
Those questions are still largely unanswered, but a very interesting trial published recently aimed to reopen the question of the true effects of HRT on cardiovascular outcomes in postmenopausal women. The findings of the Kronos Early Estrogen Prevention Study (KEEPS) came out recently.1 The lead author and lead investigator Dr. S. Mitchell Harman is a close friend of mine who served recently as my Chief of Endocrinology at the Phoenix VA and then became my interim successor as Chief of Medicine when I moved to the Greater Los Angeles VAMC because of my wife’s Sjogren’s-driven need for a more humid climate.
The KEEPS trial was a 4-year, randomized, double-blind, placebo-controlled trial in 727 women aged 45 to 54 years who were all newly menopausal, so that the effects of HRT could be assessed right after the onset of menopause. The KEEPS investigators hoped to demonstrate a favorable effect on cardiovascular outcomes with the administration of HRT so early on, but the trial was unfortunately too small to come up with those results. However, the trial went for its full planned duration, because there were absolutely no harmful effects seen with either oral conjugated estrogen therapy or with transdermal estrogen therapy, each of which was given together with oral progesterone.
There was a trend toward a slower increase in coronary artery calcium (CAC) scores in the minority of women who had elevated scores to begin with. But overall there was no difference in the rate of progression of either CAC scores or of carotid
intima-media thickness as measured by ultrasound; the latter is a standard research measure used to detect subtle differences in the rate of progression of cardiovascular disease. A pessimist would observe quite correctly that estrogens did not show a protective effect on cardiovascular outcomes, apart from the hint of a slower rate of progression of CAC scores in those with elevated levels at the onset. But an optimist would say that these results demonstrate the cardiovascular safety of early postmenopausal HRT, since there was no signal at all of a harmful effect.
So where does this leave us now? Unfortunately, we are completely bereft of definitive answers, and we are unlikely to get meaningful new data anytime soon, as there is currently zero enthusiasm at the NIH for devoting scarce resources to a re-examination of these same issues.
The bottom line is that we can agree that cardiovascular worries need to be put into proper perspective and that they have been overblown, at least in the lay press. I further believe that younger postmenopausal women who have solid indications for such therapy, be they hot flushes or advanced osteoporosis, should not be denied the benefits of HRT because of cardiovascular concerns.
I would be willing to consider long-term open-ended therapy in at least some of these patients. And let’s also not forget that estrogens clearly reduce the incidence of colon cancer and may well reduce the prevalence of the much-dreaded Alzheimer disease that awaits many older women.
I’ll be the first to acknowledge that this editorial is ending with not a bang, but a whimper. But that’s about the best I can come up with given the extremely severe limitations of the data available to us. I’ll consider this editorial a success if it encourages you to at least keep an open mind on the issue of the cardiovascular effects of estrogens and to accept my premise that we still lack so much of the data we truly need to reach definitive conclusions.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.