[ed. note: Michael Jorrin, who I dubbed “Doc Gumshoe” years ago, is a longtime medical writer (not a doctor) who writes for us a couple times a month about health issues and trends. He does not typically focus on specific investment opportunities, but has agreed to our trading restrictions… as with all of our authors, he chooses his own topics and his words and opinions are his alone]
In the past month or so there have been a couple of disquieting pronouncements about health matters that rattled around the media world, not quite rivaling the happenings in the political arena as a focus of speculation and concern, but which surely have captured the attention of a good many people, including perhaps some denizens of Planet Gumshoe.
Pronouncement number one was that that for anyone whose ten-year risk of sustaining a significant cardiac incident (such as a heart attack or a stroke) is 10% or higher, systolic blood pressure should be less than 130 mmHg. Virtually all the medical organizations that focus on heart health have gone along with this recommendation, which considerably tightens previous blood pressure guidelines. Limiting that recommendation to persons with a 10% ten-year risk doesn’t amount to much, since just about every human over the age of 65 is at that risk level or greater, due to age alone. Based on that recommendation, half the population of the US would be defined as having high blood pressure.
Pronouncement number two was that women using hormonal contraceptives, whether the pill or the patch, were at a higher risk of breast cancer than women who did not use hormonal contraceptives. There was no specific recommendation associated with this announcement, but it got rapidly linked with previous concerns about hormone replacement therapy, which took a colossal hit when the early results of the Women’s Health Initiative were presented to the public. I can readily predict that many, many women would immediately think about switching contraceptive methods, with what outcomes it’s impossible at this early stage to predict.
Doc Gumshoe is here to tell you to view both of those announcements with a healthy dose of skepticism.
The 2017 blood pressure guidelines
Let’s look first at the blood pressure recommendation. This came about mostly based on the results of the Systolic Blood Pressure Intervention Trial (SPRINT), which was published in the New England Journal of Medicine on 26 November 2015 and widely discussed in the medical community (N Engl J Med 2015;376:2103-2116). The one-sentence take-away was that in non-diabetic patients at high risk for cardiovascular events, treating elevated blood pressure to a target level of 120 mmHg, compared with a target level of 140 mmHg, resulted in lower rates of signal cardiac events.
The results of the SPRINT trial reverberated through the entire cardiology community, and about two years later, on 13 November 2017 the American College of Cardiology, the American Heart Association, and about eight other prestigious medical societies came out with the recommendation to treat blood pressure in patients like those in the SPRINT trial to a target blood pressure of less than 130 mmHg. The case seems to be open and shut.
So where does Doc Gumshoe get off raising any doubts about this? Before you conclude that Doc Gumshoe is nothing more than a pig-headed contrarian, let me assure you that I am by no means alone in my skepticism; numerous eminent health professionals have voiced their doubts that the results of the SPRINT trial would be replicated in the population at large. Moreover, “at large” should be in 144-point type, since the number of people who would need to be medicated according to the new guidelines is large indeed.
Here’s what the SPRINT trial did. It was conducted at 102 clinical sites in the US, including Puerto Rico. Participants had to be at least 50 years of age, have a baseline BP between 130 and 180 mmHg, and be at increased risk for cardiovascular events, which were defined as established CV disease, or chronic kidney disease, or a 10-year risk of 15% or higher based on the Framingham risk calculator, or age 75 years or higher. Patients with diabetes or who had sustained strokes were excluded.
A total of 9,361 individuals with a baseline systolic blood pressure (BP) above 130 mmHg were enrolled and assigned to two treatment cohorts. The target BP in one group was less than 120 mmHg, while in the other group it was less than 140 mmHg. At baseline, systolic BP in the two groups was identical (139.7 mmHg), while diastolic BP was two-tenths of a millimeter of mercury apart (78.2 vs. 78.0). All the subjects were taking BP medications at baseline, an average of 1.8 medications per subject in both groups.
The procedures for recording BP were painstaking in the extreme in the effort to prevent what is called “white coat” hypertension, meaning that persons having their BP measured by a health professional tend to register significantly higher readings. Blood pressure changes quickly and by quite large intervals due to many different factors, including external physical activity, internal stress, surroundings, and miscellaneous incidental events. For example, I used to have my annual physical at the office of my excellent regular physician. I would walk briskly to his office, be greeted by his nurse/office manager, who would immediately prepare me for the examination and do a BP reading. It was invariably pretty high. Once I sneezed while the cuff was on my arm, and the BP reading went through the roof. Then I would have my going over, and my physician would discuss all the results with me. And then he would do a second BP reading, at which point the systolic BP would usually be 30 or 40 points lower.
In the SPRINT trial, BP readings were recorded as an average of three readings taken while the patient was seated in a quiet room after five minutes of rest with no staff members in the room. This was meant to assure that the BP was not elevated due to external factors, but really represented the subject’s resting, stress-free BP.
This is far from the usual standard practice.
The trend favoring the more intensive treatment regimen emerged fairly early, and the trial was suspended after about 39 months, when it emerged that the rate of significant outcome events in the intensive treatment group was about 25% lower than in the standard treatment group. Those results sounded like a big deal in the cardiology community.
However, on closer examination, how big a deal is this? The real numbers – not the relative risk numbers, but the actual results – are somewhat more modest. Of the 4,678 participants in the intensive treatment group, 243 sustained a primary outcome event, while of the 4,683 in the standard treatment group, 319 sustained such an event. During the 39 months of the study, in percentage terms, 5.2% of the intensive treatment group had a significant cardiac event, compared with 6.8% of the standard treatment group. The annual incidence of primary outcome events was 1.65% in the intensive treatment group versus 2.19% in the standard treatment group. That’s about half a percentage point difference.
Of course, that half a percentage point, applied to a potential population of a hundred million or more, would make a real and important difference in the lives of many thousands of people. The question is, could the standards employed in the SPRINT trial be duplicated in general practice across the nation?
It’s also worth looking at the adverse events that emerged in the trial. Similar numbers of subjects experienced serious adverse events in each arm of the trial – 1,793 in the intensive treatment arm versus 1,736 in the standard treatment arm. However, for some of the adverse events that are specifically related to blood pressure, the differences are more striking. Of the subjects in the intensive treatment arm, 158 experienced low blood pressure requiring emergency department visits, versus 93 in the standard treatment arm, and 163 versus 113 had fainting episodes. Intensive treatment subjects also had much higher rates of acute kidney injury or kidney failure and electrolyte abnormality.
The question is, is it worth it?
For more perspective on this, let’s look back a few years. In March of 2014, the Eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), relaxed the BP goal in adults aged 60 years and older to 150/90 mmHg, instead of the previous goal of 140/90 mmHg. This could result in 5.8 million US adults no longer needing hypertension medication, and that an estimated 13.5 million adults would now be considered as having achieved goal blood pressure, primarily older adults. The JNC 8 recommendation was not meant to be taken as intended to prevent the treatment of BP in those groups, but to restore a degree of balance, which was threatened by the rigid application of strict guidelines.
The new guidelines, if rigidly implemented, would, in my opinion, indeed threaten balance. Although individual physicians, treating individual patients, might shy away from the “one size fits all” approach, the incursions of the health-care industry might push physicians to comply with what, after all, is a recommendation with the imprimatur of the most eminent medical societies in the nation. Or, to put it another way, physicians are apt to worry that if they don’t toe the line with regard to that specific recommendation, they might be downgraded or in some way disfavored, particularly by health insurers, or by hospitals concerned about their ratings.
It’s certainly possible that for many or even most patients, being treated to the less than 130 mmHg systolic BP standard might be beneficial. My doubts are whether this particular guideline should be applied to all patients across the board. An important question to consider is, what will it take to get every patient that fits into that exceedingly broad category to that new standard?
In the SPRINT trial, the patients on the intensive treatment regimen received on average 2.8 antihypertensive drugs, while the patients on standard treatment received 1.8 medications. Those figures suggest that the majority of the intensive treatment cohort got at least three drugs for hypertension, and in some cases, four drugs.
While the most commonly used antihypertensives – diuretics, beta blockers, ACE inhibitors, calcium-channel blockers, ARBs – are generally considered safe, they all have side effects, and in some cases the side effects can be reinforced by taking these drugs in combination. For example, the side effect that is probably of greatest concern with diuretics is that these drugs make it somewhat more difficult for persons with diabetes to control their blood sugar levels. Beta-blockers, whose mechanism of action is to lower both the pace and the force of cardiac contractions, can produce dizziness and weakness, and in some cases, sexual dysfunction. ACE (angiotensin converting enzyme) inhibitors can sometimes foster a kind of dry non-productive cough. Calcium-channel blockers act by reducing the constricting action of the arterial system, and may cause light-headedness, constipation, and edema in the ankles and lower legs. And ARBs (angiotensin-receptor blockers) can also lead to some dizziness and weakness. Clinicians tend to combine these drugs rather than upping the dose of any single drug, in the hopes that BP can be more effectively lowered through differing mechanisms of action, and also avoid increasing the risk of any side effects. But taking three or four of these in combination might up the odds that the patient would experience one, or several, of these side effects.
My perspective on this, from the official Doc Gumshoe viewpoint, is that the stricter guidelines might work very well for some patients, while attempting to adhere to those guidelines might cause considerable distress for some other patients. A sensible physician would discuss the whole matter with the patient and come to a balanced conclusion. After all, it’s worth bearing in mind that in the SPRINT trial, a huge majority of the participants in both arms of the trial experienced none of the signal cardiovascular events. The percentages of subjects in the two arms that had no events during the trial were very close – 94.8% in the intensive treatment arm versus 93.2% in the standard treatment arm. Is that 1.6% difference between the two arms worth putting just about everybody on intensive treatment?
I doubt it.
A small but real increase in adverse events in patients switching from brand-name to generic antihypertensive drugs
… and while we’re on the subject of treating elevated blood pressure, a study in Canada turned up a disquieting trend. One month after generic versions of three widely-used blood pressure drugs became available in Canada, hospital visits for adverse events spiked in generic drug users. The specific drugs were generic versions of Cozaar (losartan), Diovan (valsartan), and Atacand (candesartan), all angiotensin-receptor blockers (ARBs). Compared with the mean incidence of adverse events for branded drugs, the rates of adverse events for generic losartan increased by 8%, for valsartan by 11.7%, and for candesartan by 14%. (These are relative increases, not absolute increases, of course.)
The study was based on data on 136,177 patients at least 66 years of age who had hospital or emergency department consultations due to those adverse events, and who had taken one of those three antihypertensives both as branded drugs and after their generic versions became available.
A possible cause of the increase in adverse events is that the generic versions are different from the branded versions in terms of pharmacokinetics by margins of 6% to 21%. This means that while the essential molecule in the drugs are identical, the generic version may differ from the original version in such matters as the time it takes for the drug to be absorbed, reach optimum blood concentrations, its half-life, and other factors that may be related to the way it behaves in the patient’s body.
The study’s authors were hesitant to predict any difference in the long-term effectiveness of generics versus the branded originals. However, at least in the short term, it seems that caution is warranted.
A link between hormonal contraceptives and breast cancer
Hormonal contraceptives include not only birth control pills, but skin patches and vaginal rings that contain estrogen and progesterone, or, in some cases, progestin only. Essentially, these methods of contraceptive interfere with the precise hormonal balance that controls ovulation and other conditions of a woman’s reproductive organs. In some cases, eggs are prevented from being released from the ovaries, the cervical mucus may be thickened so that sperm cannot enter the uterus, or the lining of the uterus is thinned in such a way that fertilized eggs cannot be implanted.
I’m focusing on this because it reminds me of what happened after the results of the Women’s Health Initiative were released in 2002. If you don’t remember that far back, or weren’t paying attention, the way that study was presented in the media immediately reduced by about 60% the number of women employing hormone replacement therapy (HRT) to help them through the vexations of menopause.
What happened in that study was that very small increases in absolute risk, in most case less than 0.1% were disseminated to the media as large and alarming increases in relative risk. For example, the MI rate for women taking HRT was 37 per 10,000 patient-years, compared with 30 for those taking placebo – an absolute difference of 7 per 10,000 patient years. This was announced as a 23% increase in relative risk (7 on a base of 30) rather than as an increase in the absolute risk. For other outcomes in which the total numbers of women affected were smaller, the announced relative risk increases were even larger. The increases in absolute risk with the study drug were minuscule – fewer than 10 cases in 10,000 patient-years each for MI, stroke, and breast cancer. These were somewhat offset by a decrease in colorectal cancer and hip fractures. And there was no increase in overall mortality in women taking the study drug.
My concern is that millions of women, hearing or reading the media’s version of the study that indeed found a link between hormonal contraceptives and breast cancer, will dump their contraceptives in the trash bin and take their chances on becoming pregnant. I hope I am not being an alarmist when I maintain that an unwanted pregnancy is of considerably greater concern than hot flashes.
Here’s how CNN, for example, summarized the study, published in The New England Journal of Medicine on December 7, 2017 (Mørch LS, N Engl J Med 2017;377(23)2228-2239:
“Birth control can increase a woman’s risk of breast cancer by up to 38%, depending on how long she has taken it, a new study finds. The risk was associated with all forms of hormonal contraception — such as the pill, injections or IUDs — when compared with women who have never used them.
Researchers from the University of Copenhagen analyzed data from 1.8 million women under the age of 50 in Denmark. They followed the women for nearly 11 years, on average.”
Where exactly did CNN get that 38% figure? Planet Gumshoe denizens have no doubt already surmised that it’s not an absolute risk, but a comparative risk. It turns out that it compares the absolute risk of breast cancer in the cohort of women who had never used any form of hormonal contraception with the cohort of women who had used hormonal contraception for 10 years. CNN didn’t say that, of course. And what CNN also failed to mention was that the actual increase in breast cancers among all users of hormonal contraception came to 13 cases per 100,000 person-years, or 1 case of breast cancer per year for every 7690 women using hormone contraceptives.
An oncologist not involved in the study that was consulted by CNN (Dr David Hunter) also pointed out that “breast cancer remains a relatively rare disease in younger women.”
Here are SEER (Surveillance, Epidemiology and End Results) data from the National Cancer Institute for breast cancer incidence by age:
- Age 30 . . . . . . 0.44 percent (or 1 in 227)
- Age 40 . . . . . . 1.47 percent (or 1 in 68)
- Age 50 . . . . . . 2.38 percent (or 1 in 42)
- Age 60 . . . . . . 3.56 percent (or 1 in 28)
- Age 70 . . . . . . 3.82 percent (or 1 in 26)
It’s reasonably safe to assume that the great majority of women employing contraceptives of any kind are in their 30s. Some may be in their 40s, but very, very few would be older than that. If the relative increase in breast cancer risk in women in their 30s who used hormonal contraceptives for 10 years or more increased by 38%, that increase would put the cancer incidence at 0.61 percent, or 1 case in 164 women.
What women need to consider is whether that risk of less than 1% is worth the risk of unplanned/unwanted pregnancy. Of course, there are many other contraceptive methods, but many or most young, sexually-active women, may have been reluctant to use these older, less convenient, and, crucially, more obvious methods.
All pregnancies are accompanied by risks, some of them serious. These risks are aggravated by a range of pre-existing conditions, such as hypertension, and according to the National Heart, Lung, and Blood Institute, a surprising 6% to 8% of pregnant women in the US are hypertensive.
Some specific risks are preeclampsia, which affects up to 7% of pregnancies in the US, and gestational diabetes, which affects up to 10% of pregnancies. Preeclampsia can result in a sudden increase in blood pressure, with potential injury to several organs, and an increase in the risk of stroke. Gestational diabetes sometimes resolves with minimal treatment, other than dietary methods, but it significantly increases the risk of developing type 2 diabetes.
My guess is that both of those risks are much higher in women with unplanned/ unwanted pregnancies.
Whether to discard birth control pills and other hormonal contraceptives in order to avoid that very small increased risk of breast cancer is a question that needs to be weighed not only by the women whom it directly affects, but by the wider community as well. If that increased risk was publically presented as less than 1% in the women most likely to be affected, they would be much less likely to throw their birth control pills in the trash than if they hear on television or see on the internet that the increase in risk is 38%. The latter figure is scary. Stating it in that way is nothing less than alarmist and irresponsible, and could potentially cause great harm to some women.
To be fair, the authors of the study concluded by noting that “absolute increases in risk were small.” But this is not the way it was presented to the public. The skeptic in me wonders whether the study authors were reluctant to state right up front that their lengthy and arduous research didn’t amount to much.
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Gumshoe citizens likely regard me as a deep-dyed skeptic when it comes to alternative medicine, supplements, and the like. I have even been characterized from time to time as being in cahoots with the conspiracy perpetrated by the Big Pharma / Establishment Medicine / FDA cabal to hide inexpensive and effective treatment options from the American public, in the interest of continuing to reap outrageous profits. But I have regularly acknowledged that some of these supplements may actually deliver some real benefits. I’m going to try to give an objective look at some of the supplements (I’m using that word loosely to cover the panoply of non-FDA-approved treatments), not in the context of the many over-the-top promotions, but based on whatever reliable information I can dig up. I’m starting out by looking through the recommendations and questions posted by readers in the comment threads. I promise not to be turned off by suggestions that this supplement comes from hidden books of the Bible, and that one brings about the amazing longevity of natives in exotic and seldom visited parts of our planet. Thanks for the suggestions, and best to all in the New Year! Michael Jorrin (aka Doc Gumshoe)
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