SPRINT: Intensive BP management reduces CVD, mortality risk

Keith C. Ferdinand, MD, FACC

This news was exciting, and somewhat unexpected. According to preliminary reports from SPRINT, targeting a systolic BP of less than 120 mm Hg may reduce the huge morbidity and mortality burden associated with hypertension.

The public and practicing clinicians have now heard from NHLBI that, contrary to controversial declarations made in medical papers over the last 2 years, a treatment strategy aimed at reducing systolic BP to a lower goal, rather than loosening our treatment approaches, may help older individuals live longer and avoid catastrophic CVD events. Analysis of outcomes in pre-specified subgroups will be of particular interest, given the disproportionate morbidity and mortality with hypertension among patients with chronic kidney disease (eGFR <60), age of 75 years or older and black race (vs. non-black). Clearly, age is a powerful risk factor for hypertension complications, especially in blacks, women and other high-risk groups.

Hopefully, this recent good news will dampen the potential harm from the 2014 JAMA hypertension guideline by the JNC 8 original panel, which was the only hypertension guideline in the world recommending backing off on BP control among patients aged as young as 60 years.

Although rigorously evidence-based and developed by highly respected researchers and clinicians, the so-called JNC 8 panel report was never proposed as a true JNC guideline. As noted in the text by the authors themselves, the 2014 report should never have been assigned the credibility of past JNC guidelines. The panel was originally formed by NHLBI, similar to other JNCs, but the JAMA report did not go through the approval process required for endorsement by NHLBI and other organizations that had endorsed previous JNCs. Often overlooked, also, is the fact that the grade-A recommendation of loosening BP goals for patients aged 60 years or older caused serious consternation within the JNC 8 panel, and was voted against by five of the 17 voting members (Wright J, et al. Ann Intern Med. 2014;160:499.).

This is not simply an academic point, but unveils the caution necessary when making major public health pronouncements and suggesting substantial changes to how quality-assurance programs, third-party payers and clinical pathways should push clinicians to practice the art of medicine.

In a State-of-the-Art Review published in JACC on the implications of higher goals for hypertension in older adults, I and several other authors strongly disagreed with the new 2014 recommendations to raise the threshold for initiating drug treatment and target systolic BP for older persons, specifically because of the implications for women, who comprise the majority of this elderly hypertensive population; and for blacks, who already suffer disparities from the ravages of poorly treated hypertension. This JACC report was, perhaps, prescient in its concern about potentially exacerbating existing sex and racial/ethnic disparities in CVD morbidity and mortality (Krakoff LR, et al. J Am Coll Cardiol. 2014;64:394–402).

Cautious clinicians who desire to translate the high-level preliminary reports from SPRINT should await final publication in a high-impact medical journal with peer review, detailing specific event rates and the absolute reduction in risk for any of the endpoints, including the primary composite endpoint of MI, ACS, stroke, HF or CVD death.

Major SPRINT exclusion criteria did not include several high-risk groups, including patients with prior stroke, diabetes, congestive HF, nephrotic range proteinuria, CKD with eGFR below 25 mL/min/1.73m2 (MDRD), polycystic kidney disease and glomerulonephritis. Nevertheless, the reduction in event rates was sufficiently large enough for the SPRINT data safety and monitoring board to stop the trial early. Impressively, CV events were cut by 30% and intensive BP reduction reduced all-cause mortality by nearly 25% compared with patients treated to a target of 140 mm Hg.

Fortunately, the American Heart Association and the American College of Cardiology will be updating their high BP guidelines later in 2015 or 2016, and SPRINT may add to the evidence base they can utilize. In the meantime, clinicians must be aware that it is dangerously inappropriate to abandon the target of less than 140/90 mm Hg in patients younger than 80 years of age — especially in women, blacks and other high-risk groups.

Michael A. Weber, MD

This really was quite a dramatic announcement. It stated that for a group of hypertensive patients at high CV risk, achieving a systolic BP less than 120 mm Hg clearly had benefits in terms of CV events and mortality, as compared with patients treated to less than 140 mm Hg. However, I think there are some important questions to be asked, and some important qualifiers to be acknowledged.

First of all, since this study was conducted in patients selected for their vulnerability to CV events, it's important to ask: Would we have seen the same sorts of results in patients who have hypertension, but without CV or renal histories or high CV risk scores?

A second question is: Can we extrapolate to patients outside the age group that was studied? Should we now be thinking about [a target of] less than 120 mm Hg for all adults? What about a patient aged below 50 but at high risk? Or, for that matter, a young adult who is not at high risk: BP is elevated but there is no history of CVD, kidney function is normal and the Framingham Risk Score is not particularly high. Should we consider treating to less than 120 mm Hg?

We would also want to be thinking of people at the other end of the age spectrum. The SPRINT study enrolled people without an upper age limit, but we still want to know what we should do for people aged over 80. I doubt there were sufficient people over 80 in the trial for us to be able to conduct a subgroup analysis and draw clear conclusions, but I hope there will be sufficient information to provide some guidance.

A third question is a little more subtle, but intriguing. On average, people randomized to less than 140 mm Hg needed two drugs, while people randomized to less than 120 mm Hg needed three or more. Now we must ask: What were the drugs?  I am assuming — in the absence of a detailed report — that most patients in the below 140 mm Hg group received a combination of an ACE inhibitor and a diuretic, and that patients in the below 120 mm Hg group received the same two drugs plus amlodipine.

The reason I'm drawing attention to this is that amlodipine, for example, is a good BP-lowering drug, but it also has strong cardioprotective effects, independent of what it does to BP. Could the benefit of achieving less than 120 mm Hg be due, at least partly, to the cardioprotective effects of amlodipine, or other available drugs known to have CV-protective effects, rather than the fact that BP was reduced to less than 120 mm Hg? I'm sure that when the final analysis is completed this question will be taken into account, but to me it's a potentially important issue.

The reason I want us to be cautious about these results, exciting as they are, is that there is a huge implication here. Right now, in the U.S., we believe that about one-third of all adults have hypertension. If 120 mm Hg suddenly became the new threshold for diagnosing hypertension, instead of one-third of adults, we would find that two-thirds of adults in the U.S. have hypertension; maybe even more than that.

That's a very provocative situation.  We really have to think hard about what we're going to do with this information, and what it really means. Should we be strict about interpreting SPRINT and apply its findings only to the types of patients that were studied?  In essence, SPRINT could leave the impression that the blood pressure range of "pre-hypertension" has now been re-defined as "hypertension." I hope we can find some sensible middle path and avoid announcing that large numbers of people who are college age or above are suddenly in need of active BP treatment.

Franz H. Messerli, MD, FACC, FACP

For years and even decades, there has been consensus that treating high BP reduces the risk for stroke, MI and death. However, there remained a good deal of uncertainty over just how much BP should be lowered. This is not surprising since for BP — as for many other biologic variables such as blood sugar, heart rate, BMI and so on — there is a J-shaped relationship with morbidity and mortality, meaning that too high as well as too low values will increase the risk. If the SPRINT results are iron clad (and since the study was prematurely terminated there is little doubt that they will turn out to be), they will reduce some of our current thoughts on the J curve to rubble. Clearly though, the SPRINT results do not mean that the J curve has vanished; a systolic pressure of 0 will still confer a 100% mortality. However the J curve nadir, i.e. the optimal on-treatment BP, is obviously lower than what was previously documented in many post hoc studies including some of our own. The lower nadir of on-treatment BP seems to hold true for all target organs since there was a substantial reduction by almost one-third of CV events, such as MI, HF and stroke. Gary H. Gibbons, MD, director of the NHLBI, called the data from SPRINT ‘potentially lifesaving information,’ and I fully agree with his dictum.

However, before we now shoot for a systolic BP of 120 mmHg in a 78-year-old patient who presents with a systolic pressure of 185 mm Hg, we need to scrutinize the information about the incidence of adverse events in the 120-mm Hg arm of SPRINT. We should remember that the inclusion criterion in SPRINT was systolic BP above 130 mm Hg (untreated or treated). In how many of these patients aged older than 50 years was the systolic BP brought down from > 180 mm Hg to around 120 mm Hg, smoothly, without adverse events? I merely hope that the full publication will provide an answer to this simple but clinically pertinent question since most clinicians treat patients and not systolic BP numbers.

Importantly, since SPRINT was conducted in patients aged older than 50 years, it also proves wrong the controversial decision of members appointed to the panel of the JNC 8 to elevate the on-treatment BP target for elderly patients from < 140 mm Hg to < 150 mm Hg. We merely hope that it will not take long to digest these seminal findings and provide U.S. physicians with evidence-based and clinically useful recommendations.

Randall Zusman, MD

In the broadest view, as with the treatment of patients with hypercholesterolemia, lower [BP] is better. Targets we've been using in the past may have been too conservative, and more aggressive BP control is rewarded with a significant reduction, as they've noted, in death, MI and stroke rates.

The consequence of that is that many patients who previously were thought to be well-controlled now are uncontrolled, and will need more aggressive therapy. That puts a great deal of pressure on drug selection, in order to minimize the side effects, but also I think it re-emphasizes the importance of lifestyle modifications, as well as the potential for non-drug-dependent BP lowering therapies, to be an adjunct to or supplement to drug therapy.

I would envision that there are a lot of people whose drug dosage could simply be increased, and they will come under the new [target]. However, some will be confronted with the need for additional medications, and sometimes the addition of those medications may generate side effects the patient is unwilling to accept. Therefore, re-emphasizing the need to lose weight, alter diet in appropriate ways, exercise in a regular fashion and restrict salt intake may be enough to make a difference in terms of their BP control. And if not, [we should] think about alternative strategies such as relaxation response, which we've used here very effectively to help patients achieve adequate BP control.

The study raises a whole host of additional questions. What about the patients with BP between 120 mm Hg and 140 mm Hg who had not been on therapy before? Do those many millions of people get redefined now as not pre-hypertensive, but hypertensive in light of the results of this trial? There are a lot of very interesting, provocative questions remaining to be answered, but I think as a general rule, all of us need to be more vigilant in terms of diet, exercise, weight and salt intake, in order to lower our BP as much as possible, and then to augment that effort with drug therapy if appropriate.

Every patient I've seen [since the announcement] has asked me today what the impact is of this report. The patients are all aware of it; I think it has made a significant impact, both locally and nationally. I think the real impact will be felt when the article is actually published; right now, even I am responding, as a non-investigator, to the press report from the NIH. Once we can look at the manuscript and really dissect what drugs were used, what outcomes were achieved, how many patients had side effects and what those side effects were, can we really put it into context. However, I don’t think the overall outcome is really going to be in question, and consequently I think we're going to be treating our patients more aggressively.