If there is a single lesson to be learned from the (I hope) valuable information in this piece, it is that health-care recommendations are somewhat fluid and also somewhat temporary. Attached to every guideline and recommendation and even to every firmly-stated conclusion in every written or spoken utterance about health care and related medical matter should be a proviso, in bold type: “This is based on what we know at this time. As we get more information, our conclusions may change.”
That applies also to this Doc Gumshoe piece, which is mostly based on a very careful and thorough literature search published in the American Journal of Medicine (“Update in Outpatient General Internal Medicine: Practice-Changing Evidence Published in 2019.” Wingo MT. Am J. Med 133 (2020);7:789-794). That paper, in turn, is based on a search of the most respected medical journals on the planet, including The New England Journal of Medicine, Lancet, Annals of Internal Medicine, Journal of the American Medical Association, British Medical Journal and several others. I list them to support my claim that at this point in time, most of this information is valid.
Persons with atrial fibrillation and stable coronary artery disease can benefit from anticoagulation therapy without antiplatelet therapy.
Both atrial fibrillation and coronary artery disease (CAD) are very common. Up to 6 million persons in the US have atrial fib, and nearly 20 million have CAD. I have no data as to the overlap – how many people have both; however, atrial fibrillation by itself is not a particularly dangerous condition. During episodes of atrial fibrillation, the circulatory system is not working as it should, and the person with atrial fib feels the effects of insufficient oxygen delivery to the tissues. This can include weakness, dizziness, fatigue, chest pain, and others. However, in some cases, atrial fibrillation can lead to strokes and myocardial infarctions.
The atria are the two upper chambers of the heart, which normally receive blood and pump it into the two lower chambers (the ventricles). These then contract and send the blood on its way – the right ventricle sends the blood into the lungs to absorb oxygen, and the left ventricle pumps newly oxygenated blood into the arterial system to be transported into all parts of the body. What happens in atrial fib is that the atria contract at a much faster rate – two to three times the normal heart rate – but these contractions fail to expel all the blood, leaving a part of it in the atrium after each contraction. This is the feature of atrial fib that is most serious. Clots may form in the blood that pools in the atria, and these clots may be carried to other parts of the body, causing strokes or heart attacks. Thus, a treatment goal in atrial fib is the prevention of clot formation. Fortunately, because the atria are separated from the ventricles by a layer of fibrous tissue, atrial fib does not transmit to the ventricles to cause ventricular fibrillation, a much more serious and frequently fatal condition.
Guidelines in the US for patients affected by both atrial fib and coronary artery disease are somewhat confusing: they recommend four to six weeks of dual antiplatelet therapy plus an oral anticoagulant, followed by a P2Y12 inhibitor plus an oral anticoagulant.
Before you click the little X at the upper right hand corner of your screen and banish Doc Gumshoe’s murky maunderings, let me attempt to infuse those guidelines with some clarity. First, is there any real difference between anticoagulants and antiplatelets, since both terms refer to drugs that prevent, or at least slow down, the formation of blood clots? The simple answer is that antiplatelet agents, including aspirin, prevent the aggregation of blood cells by inhibiting thromboxane, the enzyme that causes clot formation. Anticoagulants accomplish much the same result by inhibiting the formation of fibrin, which also favors clot formation. P2Y12 is the adenosine diphosphate receptor on blood platelets; P2Y12 inhibitors include those same antiplatelet agents other than aspirin. Perhaps the use of the term “P2Y12 inhibitors” is shorthand for “antiplatelet agents other than aspirin.”
Drugs considered antiplatelet agents, besides aspirin, include Brilinta (ticagrelor), Effient (prasurgel), Plavix (clopidogrel), and Ticlid (ticlopidine). Anticoagulants include Coumadin (warfarin), heparin, Eliquis (apixaban), Pradaxa (darigatraban), and Xarelto (rivaroxaban). I suspect that the term “anticoagulants” came into use to distinguish the newcomers, like Eliquis, Pradaxa, and Xarelto, from the older established drugs that were in wide use.
The AMJ paper cited above asserts that “evidence was previously lacking for optimal management of coexisting atrial fibrillation and chronic, stable coronary artery disease (beyond 12 months.)” Now, evidence has emerged, based on an open-label multicenter trial in 2,236 Japanese patients meeting those criteria. The subjects were assigned either to treatment with Xarelto alone or to Xarelto plus either aspirin or another antiplatelet agent.
A higher percentage (5.75%) of the subjects on the dual therapy experienced the adverse outcomes (death, stroke, embolism, heart attacks, or unstable angina) than did the subjects taking Xarelto alone (4.14%). This translates to a 36% edge, and it was considered to be highly significant (P < 0.001). The trial was stopped early because of a higher risk of death in the dual treatment group.
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Essentially, what that means is that those patients no longer need to take an antiplatelet agent and can continue treatment with an anticoagulant alone. So in this case, the winners were those newcomers – Eliquis (Bristol Myers Squib/Pfizer), Pradaxa (Boehringer Ingelheim), and Xarelto (Janssen).
In patients with symptomatic atrial fibrillation, catheter ablation improves quality of life, but does not reduce mortality or serious symptoms.
Catheter ablation is by no means first-line treatment for atrial fib. It’s a fairly complex surgical procedure, which is sometimes used when the usual drugs don’t deal with the problem. The surgeon inserts catheters (which are long, thin tubes) into the patient’s heart and uses the catheters to subject certain parts of the heart muscle to extreme heat, or sometimes extreme cold. This results in destruction of some cardiac tissue and the formation of scars, which prevent the transmission of the erratic electric signals that cause atrial fibrillation. Several forms of catheter ablation have been performed, all with the purpose of interrupting those erratic signals.
The study that led to that conclusion about catheter ablation enrolled 2,204 patients with symptomatic atrial fib, 1,108 of whom were randomized to catheter ablation and 1,096 to drug therapy. The median period of treatment was about 4 years, and the primary outcome measures were mortality, disabling stroke, serious bleeding, or cardiac arrest. There were no differences in any of those primary outcome measures between the two groups; however, the patients who received catheter ablation experienced fewer recurrences of atrial fibrillation and fewer incidents of hospitalization than did the patients on drug therapy alone. The overall improvement in quality of life was almost certainly due to the reduction in episodes of atrial fib. Based on that information, the doctor-patient dialogue can arrive at a decision whether those benefits of catheter ablation make that complex surgical procedure worthwhile.
Taking anti-hypertension medications at bedtime improves both blood pressure and cardiovascular outcomes.
This Spanish study followed 19,084 patients with hypertension for a median of five years. Patients were randomly assigned to take their medications either first thing in the morning or at bedtime. The outcome measures consisted of a range of cardiovascular events, including heart attacks, stroke, and cardiovascular death.
Patients who took their medications at bedtime had significantly lower blood pressure when measured in the health-care provider’s office and when measured during sleep, but waking blood pressure was similar in the two groups. The bedtime antihypertensive group had both significantly fewer cardiovascular events and significantly lower mortality (P < 0.001). Patients who took their medications at bedtime also had lower low-density lipoprotein cholesterol (LDL-C) levels and higher high-density lipoprotein cholesterol (HDL-C) levels than did patients who took their medications on waking.
Absent other explanations, it would appear that the differences between morning and bedtime are related to circadian rhythms. A disproportionate number of cardiovascular events occur in the early hours of the morning, when daytime responses take over. The heart switches from the slower night-time tempo to quicker, stronger daytime rhythm. Therefore, it makes intuitive sense to have the beneficial blood pressure-lowering medication on board before that change occurs, rather than after.
This study suggests that a simple change such as switching the time of day when the patient takes his/her antihypertensive medications can make a significant difference to health outcomes, including mortality.
In diabetic patients with kidney disease, Invokana (canagliflozin) improves outcomes.
About one in four persons with type 2 diabetes (T2DM) have some kidney disease, termed diabetic nephropathy. This increases to about 50% in persons who have had diabetes for 20 years. Diabetes is the leading cause of nephropathy in most developed parts of the world, and is responsible for about 40% of all cases of end-stage kidney disease.
In addition to standard treatment for T2DM, which focuses on managing blood glucose levels, patients with diabetic nephropathy have been treated with drugs that inhibit the renin-angiotensin-aldosterone system. These drugs, known as angiotensin-receptor blockers (ARBs) include losartan (Cozaar, from Merck), and irbesartan (Avapro, from Sanofi-Aventis/Bristol Myers Squibb); both of these are commonly used to treat high blood pressure. (We should note that some generic versions of those two drugs, manufactured in India, have been found to contain potentially harmful impurities and have been withdrawn from the market.)
Invokana (canagliflozin, from Janssen) is a drug used to treat patients with T2DM. It is an inhibitor of the sodium-glucose transporter 2 (SLGT-2), and it has been found not only to help keep blood glucose levels in T2DM patients under control, but also to reduce cardiovascular risk and to lead to improvement in kidney disease in these patients.
In a recent trial, 4401 patients with T2DM who were already receiving an ARB were randomly assigned to receive either canagliflozin or placebo. They were followed for a median of 2.6 years. The study outcomes were end-stage kidney disease, a doubling of creatinine levels in the serum, or death from a renal or cardiovascular cause.
The composite of the study outcomes was significantly lower in the patients receiving canagliflozin plus the ARB than in those receiving the ARB plus placebo. In the canagliflozin group, there were 43 of those adverse events per 1000 patient years, compared with 61 per 1000 patient years in the placebo group (P = 0.00001).
As a result of this study, the American Diabetes Association has recommended a practice change. Further research is underway to determine if other agents in the SLGT-2 class have similar renal benefits, beyond their known glucose-lowering and cardiovascular benefits, and also whether these agents can confer renal benefits in patients with Type 1 diabetes and also in patients other than those with diabetes.
Considering the prevalence of kidney disease in persons with diabetes, and also the great prevalence of diabetes in most parts of the world, this finding is likely to have major impact, not only on practice standards, but on the welfare of many individuals.
Pre-exposure prophylaxis (PrEP) with Biktarvy is recommended for all persons at risk of developing HIV’
Almost 38,000 people in the US were newly diagnosed with human immunodeficiency virus (HIV) in 2018, the most recent year for which data are available. The total number of persons age 13 years and older with HIV in the US is estimated to be 1.2 million. That number includes an estimated 161,800 people who have not been diagnosed.
In 14 randomized controlled trials and 8 observational studies, PrEP yielded a risk reduction of 73%. Risk reduction depended on adherence, and the population-wide risk reduction was estimated to be at least 70%. To assign a person to PrEP, baseline assessment and clinical and laboratory follow-up every three months is required. The specific PrEP would consist of tenofovir/emtricitabine, marketed as Biktarvy, from Gilead.
Based on this information, the US Preventive Services Task Force (USPFTS) has released guidelines recommending PrEP in adults at high risk of acquiring HIV through sexual activity or injected narcotics use. This is in line with a stated goal of the Centers for Disease Control (CDC) to reduce the incidence of new HIV infections by 90% by the year 2030.
The guidelines are simple and clear, but they depend on how “high risk of acquiring HIV” is determined. At this time, there is no simple and clear formula for identifying persons at high risk for being infected with HIV. Much of this information would necessarily depend on individuals self-identifying as being at high risk for HIV infection based on their sexual activity and injected drug use. It is by no means evident that all, or even a majority of high risk individuals would self-identify in that way. It has also been pointed out that the effects of PrEP in pregnant and breast-feeding women, adolescents, and the transgender population are at this time not known.
From my perspective, it would appear that the USPFTS guideline and PrEP itself will benefit only those individuals who are willing to acknowledge their need for protection against HIV, which is based on their behavior and life-style.
[An intelligent and highly qualified reader just sent me a correction, noting that Biktarvy is not the drug used for pre-exposure prophylaxis for HIV. My source stated that it was a combination of tenofovir and emtricitabine, which is now marketed under several names, but Biktarvy is NOT one of them. My error for which I apologize, and to the sharp reader who caught my error, many thanks.]
Patients with mild asthma can reduce exacerbations with inhaled Symbicort (budesonide/formoterol)
Budesonide is a corticosteroid which is used in asthma patients to relieve inflammation in the lungs. Formoterol is a beta agonist, which relaxes the muscles in the lungs to facilitate inhalation; it acts as a bronchodilator. In comparison with other beta agonists, formoterol is significantly longer-acting; nonetheless, it has a rapid onset of action. The combination of the two agents is marketed as Symbicort, by AstraZeneca.
The suggested recommendation is primarily based on two clinical trials. In one of the two trials, the budesonide/formoterol combination was compared with budesonide alone plus terbutaline (also a beta agonist) as needed. Patients taking the budesonide/formoterol combination had 34% fewer severe exacerbations than did patients taking budesonide alone plus terbutaline as needed. Combined moderate plus severe exacerbations were also lower (by 30%) in the combination therapy group.
In the other trial, the budesonide/formoterol combination was compared with albuterol (a short-acting beta agonist) alone. Patients on the combination therapy had about 51% fewer exacerbations than those on albuterol alone. In a separate arm of the trial, no differences were observed between patients taking the budesonide/ formoterol combination and those taking budesonide plus albuterol as needed.
Based on the evidence currently available, it appears that the Symbicort combination is a safe and perhaps superior treatment for asthma than treatment with a short-acting beta agonist such as albuterol. The Global Initiative of Asthma now recommends against the use of short-acting beta agonists alone.
However, albuterol is commonly used by a great many people with asthma. It is relatively inexpensive, widely available, and provides the fast relief that many individuals need in the event of an asthma attack. An albuterol inhaler, sold under the brand name ProAir, costs about $80. The estimated retail price for a Symbicort inhaler is about $345. I would not predict that a large proportion of persons with asthma will switch from ProAir (or similar products) to Symbicort, unless their health insurance covered the cost.
Routine testing for tuberculosis no longer recommended for health-care workers
In 2005, the CDC issued guidelines for the prevention of tuberculosis transmission in health-care settings which included recommendations for baseline TB screening of all US health-care personnel and annual testing for health-care workers in settings with potential for ongoing transmission of TB. This was based on data showing that health-care personnel were at significantly increased risk for TB disease and also for latent TB infection. However, the TB rates in the US have substantially declined – by 73% from the rate in 1991 and by 42% from the rate in 2005. A recent cohort study in about 40,000 health-care workers who had tuberculin skin tests showed that about 7% had been exposed to the tuberculosis pathogen, that only 0.3% had experienced conversion of the skin test (meaning potential infection by the pathogen), and that two-thirds of those conversions were false positives.
The National Tuberculosis Controllers Association (NTCA) and the CDC carried out a meta-analysis of evidence dating back to 2005 about TB screening in health-care workers. The meta-analysis included 36 studies, 16 of which were performed in the US and 34 were done in a hospital setting. The analysis found that among 63,975 health-care personnel in the US tested for TB, there were no cases of active infection.
As a result of this analysis, the NTCA/CDC recommended that all health-care workers be initially examined for TB risk assessment and all health-care workers should be educated about TB exposure risks. However, continuing testing for TB is no longer recommended for health-care personnel who do not have latent TB or known exposure to TB.
At least part of the reason for this decision was that the cost of preventing TB by testing all health-care personnel would be in excess of $1 million more per single case prevented than if TB testing were targeted based on risk assessment and known exposure.
Normally, I am dubious about health decisions based largely on economic considerations, although, as Gumshoe habitués probably know by now, I am keenly attuned to health-care costs. If it had merely been that the reason for the NTCA/CDC’s reversal of their previous recommendation was that $1 million is simply too much for preventing a single case of tuberculosis I would strongly disagree. But taking into consideration that the meta-analysis cited above found zero cases of active TB infection among health-care personnel in the US, omitting annual testing seems eminently reasonable.
Further restrictions on saturated fat intake are not recommended by the American College of Cardiology
Saturated fats, whether from meat or from dairy products, have been in the crosshairs of the health-care community for about 50 years. The harms caused by saturated fats are well understood and have been widely accepted, not only by physicians and nutritionists, but by the entire spectrum of persons and organizations connected with food.
In May of this year, the Journal of the American College of Cardiology released a review of recent studies of the relationship between dietary saturated fats/saturated fatty acids and cardiovascular disease risk. (Astrup A. JACC 2020.05.077) These studies were carried out in an environment that had changed since the first warnings about saturated fatty acids emerged. Since 1980, it has been recommended that SFA intake be limited to less than 10% of total calories as a means of reducing the risk of cardiovascular disease. As a result, the dietary habits of many populations have changed significantly. For example, in Finland, the per capita consumption of butter decreased from about 16 kg per year in 1955 to about 3 kg per year in 2005. The studies reviewed in the JACC paper were carried out more recently, and in populations that had already modified their eating habits, at least to some degree.
Note: there is a distinction between saturated fats and saturated fatty acids. The latter, SFAs, are distinct chemically-defined structures, while saturated fats are complex mixtures of all SFAs in different proportions. The studies cited in the JACC paper mostly use the term “saturated fats” when referring to diets, and “saturated fatty acids” when referring to what’s in our bloodstream. In this discussion we will follow that format.
The relationship between dietary saturated fatty acids and heart disease has been studied both in systematic reviews of observational studies and in randomized controlled trials. According to the JACC paper, some meta-analyses have found no evidence that reduction in saturated fat consumption may reduce cardiovascular disease incidence or mortality. Furthermore, some studies have reported a significant (but small) beneficial effect of dietary saturated fat.
Most of these studies were conducted in high-income parts of the world (North America and Europe), but some were conducted in other regions of the world, such that overall the studies represented about 80% of the world’s population. Recently, a very large and diverse study addressed this question. The PURE (Prospective Urban Rural Epidemiological) study enrolled 135,000 individuals from 18 countries, mostly low and middle income, on five continents. In this study increased consumption of all types of fat (saturated, monounsaturated, and polyunsaturated) was associated with lower risk of death and had a neutral association with cardiovascular disease. In contrast, a diet high in carbohydrates was associated with a higher risk of death, but not with a risk of CVD. This study also demonstrated that individuals with the highest saturated fat intake, about 14% of total daily calories, had a lower risk of stroke.
In a study of 195,658 participants from the UK Biobank who were followed for over 10 years, there was no evidence that increased saturated fat intake was associated with increased incidence of CVD. The substitution of polyunsaturated fat for saturated fat, however, was associated with higher CVD risk.
The PREDIMED (Prevención con Dieta Mediterránea) trial compared a low-fat diet to a Mediterranean diet supplemented with nuts and olive oil. Despite an increase in total fat by 4.5%, including slightly higher saturated fat consumption, major cardiovascular events and death were significantly lower in the Mediterranean diet group than in the low-fat diet group.
These studies did not specifically address the question of low-density lipoprotein (LDL) cholesterol concentration and its effect on CVD risk. LDL-cholesterol levels are traditionally used to assess risk for CVD and also to monitor the effect of both pharmacological interventions and lifestyle. And it is also accepted that a diet high in saturated fats will result in the overall elevation of the low-density fraction of lipoprotein- conveying cholesterol. However, a diet-induced reduction in LDL-cholesterol cannot be inferred to result in CVD benefit without a comprehensive evaluation of other physiologic effects from a diet modification. In other words, when there is a change in the diet to reduce the amount of saturated fats, what other changes are there in the diet? What replaces the saturated fat component?
When the diet is considered as a whole, it becomes more evident that dietary carbohydrate intake is directly related to the quantity of saturated fatty acids in the blood. At the same time, significant increases of saturated fats by as much as two- or three-fold have no effect on (or even decrease) saturated fatty acids in the blood, if those increases are accompanied by decreases in carbohydrate intake. Low-carbohydrate diets consistently increase rates of whole-body fat oxidation.
Another factor that needs to be considered is that a reduction in LDL-cholesterol brought about by a reduction in dietary saturated fats mostly results in reduced levels of the large LDL subspecies. These carry more cholesterol, but have a much weaker association with CVD risk than the smaller LDL particles. These smaller LDL particles are generally not affected by dietary saturated fat reductions in most individuals. Moreover, decreasing the intake of saturated fat also tends to lower the levels of high-density lipoprotein (HDL) cholesterol. And since HDL-cholesterol is considered to be generally cardioprotective, the overall benefits of dietary saturated fat reduction would tend to be substantially overestimated by reliance on LDL-cholesterol levels alone.
Here’s my simplification of the above:
The recommendations of the American College of Cardiology are meant for a population that is no longer gorging on high-fat food. Many of us have already considerably cut back on saturated fat consumption. But the mark of Cain on such foods as red meat and full-fat dairy appears to be indelible. When we make changes in our diet to eliminate those foods that have been branded as villains, it matters hugely what we eat instead – and people do certainly tend to eat something instead. Often, cutting back on fats means upping carbohydrate consumption. And, in general our bodies would rather burn carbohydrates than fats, so if we eat a lot of carbohydrates, the fat component stays in our bodies un-burnt. Therefore, substituting carbohydrates for fats in our diet may have the paradoxical effect of increasing saturated fatty acids in our bodies and in our circulation. Also, there is a connection between dietary carbohydrates and the development of insulin resistance, which is the first step in the onset of type 2 diabetes.
That, in general, is the rationale for their conclusion, which I quote:
“Overall, the results of randomized clinical trials and observational studies do not support a rationale for population-wide restriction of dietary saturated fat to a target below current intake levels. Furthermore, lower cardiovascular disease risk cannot be confidently inferred from reduction in plasma low-density lipoprotein cholesterol concentration induced by such a dietary restriction. Conversely, a reciprocal increase in carbohydrate intake can lead to unfavorable changes in cardiometabolic risk factors. A food-based approach to guiding saturated fat intake is warranted particularly since foods have a complex matrix, and their health effects cannot be predicted by the content of any individual nutrient.”
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Whether any of the above affects any member of the Gumshoe congregation in person, I hope you find it valuable and interesting. As always, I welcome comments of any flavor. Thanks for reading! Be well! Best, Michael Jorrin (aka Doc Gumshoe).
[ed. note: Michael Jorrin is a longtime medical writer (not a doctor), who I dubbed “Doc Gumshoe” many years ago — he writes health and medicine-focused columns for our readers a couple times a month, and though he does not generally cover investment ideas he has agreed to our trading restrictions. You can find his past columns here.]