No Drugs for Mild Hypertension? (Detailed analysis for health care professionals)

A Cochrane review of the evidence basis of drugs for mild hypertension (stage 1 hypertension: blood pressure (BP) 140-159 mm Hg/90-99 mm Hg) that I co-authored in 2012 concluded that the scientific evidence from randomized controlled trials (RCTs) does not support drug treatment for mild hypertension. Furthermore, drug related side effects severe enough to discontinue treatment occur each year in about 11% of patients treated.

In 2013, JAMA published the long awaited report of the Eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-8) giving updated treatment recommendations. The National Institutes of Health chose the JNC-8 panelists and funded the 5 year project. Just before the publication of the JNC-8 guidelines, the National Institutes of Health declared that it was no longer sponsoring clinical practice guidelines, including the JNC-8 guidelines for blood pressure. Thus the JNC-8 panelists, representing only themselves, ignored our Cochrane review and continued to recommend drugs for mild hypertension. They made a minor change in the threshold for initiating treatment in people > 60-years-old (150/90 mm Hg instead of 140/90 mm Hg). My call for a retraction of the JNC-8 drugs for mild hypertension guidelines as a guest post in the KevinMD blog was also ignored by the JNC-8 panel.

JAMA published a letter to the editor by my Cochrane co-authors and me that challenged the JNC-8 panel and disputed the evidence-basis of drugs for mild hypertension. In response, the panel actually conceded our central point that the evidence does not support using drugs to treat patients with a systolic blood pressure (SBP) of less than 160 mm Hg. Yet, their recommended thresholds for systolic and diastolic blood pressure to initiate drug treatment were the following:

Recommendation 1

In the general population 60 years of age or older, initiate pharmacologic treatment to lower SBP ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg and treat to a goal SBP <150 mm Hg and goal DBP <90 mm Hg. (Strong Recommendation – Grade A)

Their rationale for drug treatment of mild hypertension despite the absence of randomized trial support was tricky, convoluted, and faulty. In their rebuttal to our challenge of their BP thresholds, they said in JAMA in response to our letter to the editor:

Rather than restate the panel’s rationale (question 1 and 2 evidence statements in the online supplement for the article), which we assert is evidence based, we acknowledge that there is controversy regarding the SBP goal in this population.

For the first time, the JNC-8 panelists acknowledged that their case for using drugs to treat mild hypertension was detailed in the supplement to the guidelines article. To figure out what they were talking about, I had to dig deep in the online supplement to find that they came up with two bases for determining the thresholds for drug treatment: “question 1 and question 2.” These were the following:

Question 1: Among adults with hypertension, does initiating antihypertensive pharmacologic therapy at specific BP thresholds improve health outcomes?

Question 2: Among adults with hypertension, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes?

As Cochrane reviewers, my colleagues and I focused our attention entirely on question 1, which we contended was the only evidence-based basis for determining the threshold for beginning drug treatment. However, we found in the JNC-8 online supplement:

Recommendation 1 (i.e., prescribe drugs for mild hypertension) is based on evidence statements 1-3 from Question 2 in which there is moderate to high quality evidence from RCTs that, in the general population 60-years-of-age or older, treating high BP to a goal of <150/90 mm Hg reduces stroke, heart failure, and coronary heart disease (CHD).

So they acknowledged the point that the RCT evidence related to question 1 (initiation of drug treatment) does not support initiating drug treatment for a SBP < 160 mm Hg. However, they issued the Grade A recommendation for initiation of treatment based on evidence related to question 2—what they call moderate to high quality data related to treating to a goal of < 150/90 mm Hg.

However, the evidence they present does not support their convoluted reasoning. Regarding question 2, there were 3 RCTs referenced as pertaining to treating to a goal of SBP < 150 mm Hg:

1. JATOS compared drug treatment of stage 2 hypertension patients to a goal of SBP < 140 mm Hg versus SBP < 160 mm Hg. Findings: Total deaths were 54 in the strict-treatment group (< 140/90) vs. 42 in the mild-treatment (< 160/90 mm Hg) group (P=0.22). Significance: There was a trend toward tight control increasing the death rate. This favors no drugs for mild hypertension.
2. VALISH compared drug treatment of stage 2 hypertension patients to a goal of SBP < 140 mm Hg versus < 150 mm Hg. Findings: The overall rate of the primary composite end point was 10.6 per 1000 patient-years in the strict control group (140/90 mm Hg) and 12.0 per 1000 patient-years in the moderate control (150/90 mm Hg) group (P=0.38). Significance: The non-significant advantage of treating to a goal of 140/90 mm Hg versus 150/90 mm Hg is counter to their recommendation for the treatment goal (< 150/90 mm Hg. However, this has nothing to do with the threshold for initiating treatment.
3. Cardio-Sis compared drug treatment of a mixture of stage 1 and 2 hypertension patients (SBP ≥ 150/90 mm Hg) to a goal of SBP < 140 mm Hg versus < 130 mm Hg. Findings: A composite cardiovascular endpoint occurred in 52 (9.4%) patients in the usual-control group and in 27 (4.8%) in the tight-control group (P=0.003). Significance: The statistically significant advantage of treating to a goal of 130/90 mm Hg versus 140/90 mm Hg—an outlier among other studies—has nothing to do with the threshold for initiating drug treatment.

The other 3 studies referenced regarding question 2 (Syst-Eur, HYVET, and SHEP) were all drug versus placebo RCTs of exclusively stage 2 hypertension patients. In all 3 of these trials, drugs significantly benefited patients with stage 2 patients treated to a goal of 140/90 mm Hg. However, that provides evidence for drug treatment of patients with stage 2 hypertension but provides no evidence for drugs in treating patients with mild hypertension (stage 1) with no previous cardiovascular disease.

The JNC-8’s all important recommendation 1 about the SBP threshold for initiating drug treatment was defended by the panel in their reply to our letter to the editor as follows:

After review of the evidence and many discussions, a supermajority of the panel supported a goal of less than 150 mm Hg based on the clear benefits demonstrated in the 3 RCTs that treated patients with a goal of less than 150 mm Hg and the lack of benefits seen in the other trials that treated to a lower goal.

The reasoning here is beyond convoluted. Of the first three trials that treated to different goals, only VALISH included a treatment arm of less than 150/90 mm Hg. In that trial, the outcome was non-significantly better with treatment to 140/90 mm Hg. Even according to their own logic of connecting initiation of drug treatment threshold in patients with mild hypertension with BP treatment goals in stage 2 hypertension patients, it makes no sense.

The JNC-8 panel did not propose any defense of the evidence-basis for the diastolic BP threshold (i.e. 90 mm Hg versus 100 mm Hg).

According to American Heart Association data, drug treatment of mild hypertension will cost about $41 billion in 2015, well over 1% of all health care costs. Due largely to the aging of baby-boomers, drugs and outpatient clinic visits for mild hypertension will cost more than $500 billion over the next 10 years (2015-2024). This projection assumes that only about half of approximately 50 million people with mild hypertension in the USA will receive drug treatment. To put this cost in perspective, the Congressional Budget Office projected that the net effect of the Affordable Care Act (Obamacare) over the next 10 years will be to increase the federal deficit by $109 billion. Therefore, saving $500 billion in health care spending while benefiting patients should be a big deal.

To date, no major newspaper has reported on the Cochrane review of drugs for mild hypertension. Relatively few thought leaders in medicine and hypertension policy have commented on the review. No evidence has emerged that many physicians have discussed the findings and implications of this review with their patients with mild hypertension.

With a topic of such importance to patients, to medicine, and to the economy, why has this study not engendered much serious debate about using drugs to treat mild hypertension? Your guess is as good as mine.

While the medical establishment and major news outlets have largely ignored the Cochrane review, some people have commented on the Cochrane review findings and implications. For example, British general practitioner Dr. Iona Heath tried to initiate a debate on the issue. Her opinion piece in June 2013 about the Cochrane drugs for mild hypertension review published in JAMA Internal Medicine stated,

Will this landmark conclusion affect clinical practice and slow the inexorable expansion of disease categories? It certainly should because overdiagnosis and overtreatment are potent causes of both waste and harm and seem to be operating in the interests of the pharmaceutical industry rather than in those of the patients whom the industry claims to serve.

Gary Schwitzer Chief Editor of “Health News Watchdog blog” said of Dr. Health’s article,

This is worth noting: I could not find one mainstream news organization that reported on Heath’s article. Why not? Too contrarian? It’s just mild hypertension?

We have news organizations that publish stories about journal articles on case series of one to four patients and make sweeping proclamations based on these. Then why not this?

To date, agencies of the U.S. Department of Health and Human Services have remained silent about the scientific merit and implications of the Cochrane review findings. About 3 weeks after the publication of the Cochrane drugs for mild hypertension review, the Center for Disease control (CDC) published, “Vital Signs: Awareness and Treatment of Uncontrolled Hypertension Among Adults — United States, 2003–2010.” This article in Morbidity and Mortality Weekly Report advocated ramping up the drug treatment for hypertension in general, including for mild hypertension. I called the lead author of this CDC report, Amy Valderrama, PhD, who told me that the CDC was aware of our Cochrane review before the publications of their report. Replying to my question about their lack of response to our challenge to the evidence-basis of drug treatment for mild hypertension, she said the CDC agreed with our statement in the review that more research on drugs for mild hypertension is needed. She also said that the CDC awaited the JNC-8 hypertension treatment guidelines. Million Hearts®, a highly publicized national initiative launched by the U.S. Department of Health and Human Services, continues to endorse drugs for mild hypertension without mentioning any controversy about it.

As documented in the Cochrane review, about about 11% of mild hypertension patients given pills (corresponding to 2 million people in the U.S. each year) suffer side effects serious enough to discontinue medications. Millions more endure impotence, dizzy spells, light headedness, weakness, falls—sometimes with broken hips—and rare life-threatening drug side effects. For example, angioedema (allergic swelling of face and neck) due to commonly prescribed angiotensin converting enzyme (ACE) inhibitors (lisinopril, benazepril, etc.) leads to at least 14,000 emergency room visits per year by mild hypertension patients (about 1 per 500 patients/year) and an unknown number of deaths.
Behind these mind-numbing numbers are real people—patients, doctors, and taxpayers. A friend of mine who had been taking lisinopril 20 mg/day for mild hypertension was found unresponsive at breakfast in a restaurant one morning. When paramedics arrived, they documented that his systolic blood pressure was 90 mm Hg. They brought him to a hospital where the doctors ran tests but failed to make a diagnosis for his syncope. I suggested that his faint was due to the lisinopril. After some consideration, his Kaiser Permanente doctors agreed. However, instead of stopping the lisinopril, the primary care doctor reduced the dose from 20 mg/day to 10 mg/day. Even when several subsequent outpatient clinic visits showed blood pressure readings of around 122/70 mm Hg, my friend couldn’t talk the primary care physician out of ordering lisinopril. Neither would the doctor authorize a referral to a hypertension specialist. I worried about my friend’s risk of another episode of loss of consciousness.

In addition to my concern for my friend, I sympathized with the primary care doctor. Many primary care doctors, including those at Kaiser Permanente, are rated by how well they keep their patients’ blood pressures in the “normal range.” HMO managers consider 85% or more of hypertensive patients “under control” a worthy target for primary care providers to achieve. If the doctor stopped the lisinopril and my friend’s blood pressure shot up to 150/95 mm Hg, the physician’s hypertension control scorecard might be hurt. Worse yet, if my friend had a stroke, the doctor might worry about a medical malpractice suit based on him not adhering to JNC-8 guidelines. On the other hand, if my friend continued lisinopril and suffered a life-threatening attack of angioedema as a complication or lost consciousness while driving his car, the doctor would not be liable because the JNC-8 guidelines deem drug treatment of mild hypertension “standard care.”

The chief of the Kaiser Permanente hypertension service in my area happened to be a friend of mine. He was a medical student when I was a medical resident in training. We have stayed in touch for the subsequent 40 years. It turns out that he was also one of the 17 or so members of the JNC-8 panel. With my lisinopril-taking friend’s consent, I asked my hypertension specialist friend to consult on the advisability of drugs in this case. Fortunately, my doctor friend stopped the lisinopril.

My “hypertensive” friend’s blood pressure has averaged under 140/90 mm Hg for the subsequent 2 years. “Averaged” is the operative word, since he undoubtedly has times when his blood pressure climbs into the hypertensive range (> 140/90). Regarding this, my Cochrane reviewer colleague Dr. Francois Gueyffier alerted my colleagues and me to the very significant over diagnosis of hypertension that comes from using the JNC-8 criteria for making the diagnosis. The JNC-8 guidelines call for using the mean of two blood pressure readings on any two consecutive clinic visits. However, blood pressures have a wide variation, so, on some occasions, most people will have mild hypertension.

Using a computerized Monte Carlo simulation to see the effect of blood pressure variation, Turner and van Schalkwyk found that, with 18 visits to the doctor, people with average blood pressures < 140/90 mm Hg would be spuriously diagnosed with mild hypertension in 27%-76% of cases. My guess is that my friend’s blood pressure was not in the hypertensive range ON AVERAGE in the first place, since it has not been in the hypertensive range on average since stopping the lisinopril.

In the UK, the diagnosis of hypertension is routinely confirmed with an automatically inflating cuff electronically recording frequent readings for at least a 24 hour period as an outpatient. This should be the criteria here.

A non-drug approach for management of mild hypertension and the associated cardiovascular disease risk involves therapeutic lifestyle changes. These include diet, exercise, relaxation therapies, smoking cessation, and alcohol moderation. The DASH diet (“Dietary Approaches to Stop Hypertension”) reduced mean systolic blood pressure by 11.5 mm Hg on average in participants with hypertension as compared to a control diet. In patients at high cardiovascular disease risk, the Mediterranean Diet has been shown to reduce total mortality by 56% and adverse cardiovascular events by 47%. The intensive lifestyle change program of Dr. Dean Ornish for cardiovascular disease patients reduced cardiovascular events in half in 5 years. With a fraction of the half trillion dollars over the next 10 years slated to go to drugs and clinic visits for drug treatment of mild hypertension, innovative lifestyle change interventions for patients with mild hypertension could potentially benefit many people and create many productive health enhancement jobs.

For over 30 years, JNC guidelines have endorsed drug treatment for mild hypertension without evidence that drugs benefit patients. Americans have wasted over $500 billion during that time on drugs for mild hypertension. Mild hypertension patients have suffered hundreds of millions of side effects and an unknown number of deaths from drug side effects. The National Heart, Lung, and Blood Institute as part of the National Institutes of Health, appointed all 8 JNC panels and funded them.

I call on Frances Collins, MD, Director of the National Institutes of Health to direct NIH hypertension experts to respond to this challenge to the evidence-basis of JNC-8 guidelines recommending drugs for mild hypertension.

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