Do published SPRINT study results live up to premature NIH news release hype?

blood pressure graphicAfter the NIH announced preliminary findings from the much anticipated SPRINT (Systolic Blood Pressure Intervention Trial) study on managing hypertension in September it received some criticism from the medical community and health journalists for its failure to provide key details about the research. Missing were the evidence, data and the names of the drugs that were used in the trial — despite the fact that the trial was said to be a “landmark” that included “potentially lifesaving information.” The findings were said to be so compelling that the trial was halted early so that the good news could be more widely disseminated.

Today the SPRINT trial results are finally being published in the New England Journal of Medicine. Once a study is released, many other researchers have the opportunity to sift through the study protocol and evidence, looking not only for new knowledge but also weaknesses and limitations in the research. Authors of high profile research expect to be challenged by their peers.

A number of experts have already weighed in on the findings in accompanying NEJM editorials. Expect many more such commentaries to follow elsewhere as the results are slowly picked apart and digested.

We think that the way research findings are communicated through the media plays a critical role in shaping public perceptions about health interventions. So we thought it was important, now that the SPRINT study has actually been published, to ask some experts to take another look at the original news release and compare it with the published study results. Are the statements that were made in the news release backed up by the study itself? Were there important caveats and limitations that should have accompanied the initial announcement but weren’t included?

While one expert commented that the study results were “fascinating,” concerns arose over the reported serious harms observed in some volunteers that were related to the drug therapy. These were not satisfactorily addressed in the news release. The news release was also overly broad in suggesting that the results apply to all older adults, experts said, and it ignored other contextual issues that are of critical importance when deciding on a course of treatment. Another concern was that the “rush” to release a summary of the benefits well before publication suggests it was an effort to help support new, potentially controversial, hypertension treatment guidelines.

In their words:

Lisa Schwartz, MD, and Steven Woloshin, MD, professors of medicine at the Dartmouth Institute and co-chairs of the Medicine in the Media Program:

The press release was a problem because it overstated the magnitude of benefit by only providing relative changes (no absolute numbers). It also ignored harms including side effects and the number of medications people had to take, the increased risk for kidney damage in people who didn’t start out with any, and the uncertainty given short follow-up.

Through its subtitle (Lower blood pressure target greatly reduces cardiovascular complications and deaths in older adults) the release overgeneralized the population. The last point was about “who these findings apply to.” The press release implies that the findings are about all older adults but the article/editorials emphasize that SPRINT is about a high risk population. Their predicted chance of a cardiovascular event in the next 10 years was 20% — which is the risk equivalent of diabetes or heart disease. It’s curious that the minority were taking statins even though their risk was so high.”

Richard M. Hoffman, MD, MPH, professor of internal medicine and epidemiology, and director of internal medicine for the University of Iowa Carver College of Medicine/Iowa City VA Medical Center:

I did think the initial news releases were heralding publication of study results—and the news release was quite misleading. The explanation that the release was actually generated by the announcement that the study was stopped early was buried in the release—the fact that study results wouldn’t be published for several more months doesn’t appear until the penultimate paragraph. The implication of the release was that study data were sufficient to broadly change management for “older” adults. However, the release provided no information on the magnitude of benefit—nor what outcomes were being measured. We don’t find out until the 4th paragraph that this was a select group of patients—at increased risk for heart disease or with kidney disease. It isn’t until the 3rd to last paragraph where a quote from Dr. Fine hints at potential complications from intensive treatment—“beneficial…health results overall” is followed by the recommendation that patients should talk to their doctor about the appropriateness of the lower goal.

The study does show a 25% reduction in a composite endpoint of various cardiovascular endpoints. Unlike many studies where “positive” effects on composite endpoints are based on differences in outcomes that would not concern patients, the SPRINT trial showed that the benefit was driven by cardiovascular death. However, the absolute overall risk benefit for the intervention was 0.5 percentage points a year for the composite endpoint, 0.18 percentage points per year for cardiovascular death.

In deciding whether to implement a new treatment approach in my practice, I want to be able to characterize the subjects, understand the intervention, and know the complications. These patients were at high risk—Framingham 10-year risk scores of 20%. The study enrolled substantial proportions of women, minorities, current/former smokers. By design no patients with diabetes were enrolled. This tells me that the results are likely applicable to a wide range of patients—who are at high risk for cardiovascular events—though the benefits for women, blacks, and those < 75 just failed to reach statistical significance.

Although the intervention subjects received an average of 3 antihypertensive medications compared to 1.9 in controls, overall complications rates were similarly high in both groups. We worry about multiple medications causing problems related to low blood pressure, drug interactions, and drug side effects. The study did find more hypotension and syncope in the intervention group—and more emergency room visits for these problems. The intervention group had significantly more serious adverse events that were attributed to study medications than the control group—4.8% vs. 2.5%. This suggests that intensifying medications should be done cautiously and that the risks of tight BP control should be carefully explained to patients. It’s also important to note that these study subjects were followed closely by the study teams. Subjects were seen monthly for the first 3 months and then every 3 months with continued monthly medication adjustments. Safely translating these results to usual practice—where there will be less frequent follow up and less motivated patients—will present challenges.

The study was intended to continue for 5 years, but was stopped after 3.26 years based on the recommendation of the data and safety monitoring committee. I understand why the study was stopped, but I also recognize that hypertension treatment is lifelong and have to wonder whether intensive treatment will be sustainable (patient adherence) and continue to be effective (and relatively safe) over the much longer span of real-life treatment.”

Doug Campos-Outcalt, MD, medical director for Mercy Care Plan, a Medicaid Health plan in Arizona:

The purpose of the press release and rush to publication of these study results appears to be to influence the development of clinical practice guidelines. The press release says as much. The controversy over when to initiate treatment of HBP [high blood pressure] and what blood pressure level to set as a target led to JNC 8 [the current, also controversial, hypertension treatment guidelines] recommendations that the NIH tried to distance itself from and prevent from being published. The organizations that favor more aggressive approaches have formed another guideline committee to counter the JNC 8 and the NIH appears to be trying to provide some harder evidence to support them.

The results of this trial, in my view, did not merit the extraordinary treatment from the NIH. There are several methodological issues the press release did not address and the findings have yet to be fully assessed.

  • The study was not blinded. Both patients and clinicians knew what group each patient was in.
  • The results need to be assessed by what medications were used. It is possible the results are not due to lower blood pressure but the medications used to achieve it.
  • The study was stopped early, which methodologists never like to see. Results may be different with time due to regression to the mean, early treatment effects that do not carry through with time, etc.
  • There were significant harms associated with the more aggressive treatment that the press release did not even mention.
  • The difficulties in translating a more aggressive approach to real life clinical situations and patients will make the community based results less impressive than those achieved in the controlled environment of this trial. One example is that all the medicines were provided free of charge to the patients.
  • The NNT [number needed to treat] to prevent 1 primary event was 61, to prevent 1 death was 90 and to prevent one cvd [cardiovascular disease] was 172. The press release was very vague about results and did not used absolute reductions.
  • It is not clear why there was lower overall death rates than the reduction in cvd death rates would account for.

The full importance of this study will not be known until the results are scrutinized by those with a critical eye for methodological biases and this study is viewed as part of the totality of evidence available on this important clinical question.”

David Cundiff, MD, an internist who contributed to a 2012 Cochrane Hypertension Group systematic review of randomized controlled trials devoted to “Pharmacotherapy for mild hypertension.” —

It looks like the differences in outcomes favoring intensive drug treatment targeting systolic blood pressure to below 120 are real.

My criticism is that the diet and lifestyle recommendations given to both groups in this trial (The Diet Approaches to Stop Hypertension (DASH diet) plus exercise) have never been validated to reduce cardiovascular events in people with high cardiovascular disease risks. Secondly, the compliance with the DASH diet and exercise recommendations was not monitored. Thirdly, baseline biometric indices (BMI, serum lipids, and fasting glucose (or hemoglobin A1c) were published but not follow up indices. Consequently, there is no way to determine if the diet and lifestyle interventions in both trial arms were effective or not. I suspect that there was little or no improvement in BMI, lipids, or FBS.

In people with mild hypertension, the DASH diet has been shown in a randomized trial to lower blood pressure more than a standard diet (1). However, it has not been used in a randomized trial to see if it reduces cardiovascular events in high cardiovascular disease patients. In contrast, the Mediterranean Diet in a randomized trial with high risk cardiovascular disease patients reduced cardiovascular disease events by 50% or more (2) and in a long term cohort study of initially healthy 70-90 year old Europeans, it reduced cardiovascular and all cause death by over 50% (3). Likewise, a randomized trial of the Ornish diet and lifestyle change program versus standard cardiovascular disease care in high cardiovascular disease risk patients reduced cardiovascular events by over 50% over 5 years.(4)

People will want to know if there are alternatives to the SPRINT intensive blood pressure control drug regime that will not be associated with the adverse effects shown in this trial. For many if not most high cardiovascular risk patients, an intensive diet and lifestyle change program that is evidence-based to work would be preferable to the unvalidated DASH diet and exercise recommendations and the intensive drug treatment in the SPRINT trial.

1. Vollmer WM, Sacks FM, Ard J, et al. Effects of Diet and Sodium Intake on Blood Pressure: Subgroup Analysis of the DASH-Sodium Trial Ann Intern Med. 2001; 135(12):1019-1028. Available at: http://www.annals.org/cgi/content/abstract/135/12/1019
2. de Lorgeril M, Salen P, Martin J-L, Monjaud I, Delaye J, Mamelle N. Mediterranean Diet, Traditional Risk Factors, and the Rate of Cardiovascular Complications After Myocardial Infarction : Final Report of the Lyon Diet Heart Study. Circulation. 1999; 99(6):779-785. Available at: http://circ.ahajournals.org/cgi/content/abstract/99/6/779
3. Knoops KTB, de Groot LCPGM, Kromhout D, et al. Mediterranean Diet, Lifestyle Factors, and 10-Year Mortality in Elderly European Men and Women: The HALE Project. JAMA. 2004; 292(12):1433-1439. Available at: http://jama.ama-assn.org/cgi/content/abstract/292/12/1433
4. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA. 1998; 280(23):2001-2007″


Kathlyn Stone is an associate editor for HealthNewsReview.org.

 

Addenda:

There’s a lot of good followup commentary on the publication of the SPRINT trial data.  One strong commentary is, unfortunately, password-protected on Medscape.  It’s a piece by Dr. John Mandrola, who writes, in part:

Role of shared decisions: Alongside the SPRINT article, the journal offered two editorials and a case presentation in which two experts opined as to whether an elderly woman should have her BP left alone or treated more aggressively

In thousands of words, I found no mention of discussing the trade-offs of the two strategies with patients. That deficiency is remarkable—and I hope it’s due to the excitement of a big trial.

I reached out to Dr Richard Lehman (Oxford University, UK), and he offered this wisdom: “With participants of mean age 65+, quality of remaining life becomes increasingly important. . . . It will take some time for this to sink in and be computable in decision aids for individuals. But that must always be our aim—to be able to clearly explain to patients the benefits and harms of any particular strategy we propose.”

Dr Harlan Krumholz (Yale University) had similar thoughts. “There are trade-offs that mean that we need to help people decide whether this option is best for them. The good news is that it is a terrific study and opens a new treatment option. It will not be easy to implement, as there is a lot of patient education involved in helping people make the right choice.”

It’s 2015; we are long past the era where doctors simply prescribe what they feel is best for people. When it comes to treating risk factors, not diseases, people are the experts in what is best for them. Some older patients may be willing to accept the risk of more aggressive treatment to get the benefits. Others, when told of the absolute benefits and risks, may not want the extra burden of therapy.

Also see the article by Andy Lazris, MD, “The SPRINT Blood Pressure Study: Small Numbers, Questionable Significance.”

You might also like

Comments (2)

We Welcome Comments. But please note: We will delete comments left by anyone who doesn’t leave an actual first and last name and an actual email address.

We will delete comments that include personal attacks, unfounded allegations, unverified facts, product pitches, or profanity. We will also end any thread of repetitive comments. Comments should primarily discuss the quality (or lack thereof) in journalism or other media messages about health and medicine. This is not intended to be a forum for definitive discussions about medicine or science. Nor is it a forum to share your personal story about a disease or treatment -- your comment must relate to media messages about health care. If your comment doesn't adhere to these policies, we won't post it. Questions? Please see more on our comments policy.

cassels@uvic.ca

November 10, 2015 at 6:26 pm

The editor of the Harvard Heart Letter http://www.health.harvard.edu/blog/update-on-the-sprint-trial-preliminary-results-pan-out-201511098597) said that “the results appear to be as practice-changing at it initially seemed, demonstrating a stricter blood pressure goal can reduce the likelihood of dying. In the world of medicine, this is really big news.” Well, that’s that, isn’t it?

Ali Mousa

November 14, 2015 at 3:47 pm

I think that this study would put the controversy about the J-effect to bed and regardless of all that criticism in this short period, the JNC 8 will be something of the past.