Adding yet another BP med helps alot, from SPRINT

Analysis from SPRINT confirmed that adding an additional antihypertensive drug to the regimen led to major decreases in blood pressure and cardiovascular events, despite some concerns that adding yet another drug had diminishing returns (see htn more drugs help BMJ2017 in dropbox, or doi.org/10.1136/bmj.j5542 ).

Details:

--SPRINT trial: 9361 patients with hypertension and high cardiovascular risk, mean age 66, racially diverse, BMI 30, NO diabetes or prior stroke, randomized to systolic BP of <120 vs <140 mmHg, achieving SBP of 121.4 vs 136.2 mmHg

--the trial was stopped early because of clear benefit of intensive treatment, at median follow-up of 3.25 years

--using data from this trial, researchers assessed the BP response and clinical effects of adding an additional BP medication in 9092 participants

--at baseline: 9% of these patients were not on any BP med, 29% on 1 med, 35% on meds from 2 distinct classes, 26% from 3 or more classes

Results:

--adding a drug from a new class led to:

    --decreases in systolic blood pressure (SBP) of 14.4 mmHg (-15.6 to -13.3 mmHg)

    --decreases in major cardiovascular events, absolute risk decrease of 6.2/1000 person-yrs (-10.9 to -1.3).

        --heart failure: absolute risk reduction of  3.97/1000 person-yrs

        --death from cardiovasc cause: absolute risk reduction of  1.85/1000 person-yrs

        --death from any cause or a composite cardiovasc outcome: absolute risk reduction of  6.93/1000 person-yrs

--the incremental reduction in blood pressure was large and similar in magnitude if the patient were already on drugs from 0, 1, 2, or 3 or more drug classes

--this incremental benefit was true across all subgroups of patients: age > vs <75, sex, race, obesity, smoking status, history of cardiovascular disease, history of CKD

--the addition of another BP drug was not associated with composite serious adverse events, though there was an increase in 3 components of adverse events: hypotension, electrolyte imbalance, and acute kidney injury

Commentary:

--for more information and evaluation of the SPRINT trial, see http://gmodestmedblogs.blogspot.com/2015/11/tighter-blood-pressure-control-sprint.html for the overall trial, and http://gmodestmedblogs.blogspot.com/2016/05/sprint-trial-elderly-subgroup-study-of.html  for the elderly subgroup

--the concern addressed above is that there is controversy in the literature about the efficacy of adding an additional medication to lower blood pressure, with some studies finding smaller reductions of BP from the additional med

--and controlling blood pressure is becoming an increasing problem, with more difficult-to-treat populations: the number of adults with hypertension worldwide has doubled in the past 25 years from 442 million to 874 million. and there are more older patients and Black patients, who on average have more resistant hypertension and harder to control blood pressure

--one concern about observational studies is confounding by indication: are those patients who have harder to treat hypertension different from those who are easier to treat.  are they sicker? have important comorbidities which we may not be controlled for retrospectively?  so, the SPRINT trial is helpful since the initial group was randomized for the different interventions (so these differences in comorbidities etc should be equally represented in the intensive and less-intensive groups).

--this study found that the efficacy of adding an additional med to decrease in SBP was the same, whether the new med was being added to a baseline of one drug or >= 4 drugs​: each led to about a 14mmHg decrease; AND, this study also found that the effect of adding another med led to a decrease of 6/1000 person-yrs in cardiovascular outcomes. this latter finding is especially important because many BP trials have just looked at the surrogate marker of systolic BP and not on actual clinical events. And though the only individual med increment that reached statistical significance was adding it to a 4th drug or more, all of the other baseline number of meds showed a pretty clear trend to incremental benefit

--As noted in the blog  http://gmodestmedblogs.blogspot.com/2017/02/blood-pressure-guidelines-for-older.html  : "the SPRINT study, which did achieve lower blood pressure in the tight control group than often found in other trials (123/62, in the elderly subgroup), they measured the blood pressure as follows: the staff person would tell a patient that they needed to rest for 5 minutes before taking the blood pressure, would leave the room completely, would return but not speak a word with the patient and immediately take the blood pressure. Argument has been raised in the literature that the blood pressure measured in randomized controlled trials is typically 5 to 10 mmHg lower than the clinic-based blood pressure (i.e. a randomized trial with an achieved systolic blood pressure of 123, as above, may be equivalent to a clinic-based blood pressure of 130 or so). So, strictly following the SPRINT study BP goal could lead to overtreatment using even accurately determined clinic blood pressures."

--there are a few other caveats about the above trial: SPRINT was not designed to look at the effect of adding another medication (it was designed just to achieve different blood pressure goals); these researchers did try to compensate for this methodologically (and in fact the intensive group did get 1 additional BP med on average).  there are no data on the drug doses used or medication adherence. there was also no granular data on which drugs were chosen to add on (were they synergistic or not??, were some combinations better than others??). no data on behavioral changes that might have differentially applied to the SPRINT groups. And patients with diabetes or prior stroke were excluded from SPRINT. Also, as with studies overall, the conditions are pretty different in the setting of a study (research assistants, more patient education, patients being screened for non-adherence), so the actual results in practice may not be quite what was found here

--another blog of a retrospective analysis of older studies noted efficacy of adding multiple low-dose antihypertensives found that using only 1/4 standard med dose was reasonably effective for blood pressure control and that having 4 drugs at quarter-dose therapy led to BP reductions of 22/13 mmHg with no adverse effects found vs the groups on the usual higher doses (see http://gmodestmedblogs.blogspot.com/2017/06/low-dose-hypertension-therapy.html  )

--the data on adding spironolactone to those with "treatment resistant hypertension", after already being on 3 drugs at maximal dose including a diuretic, is really impressive, with reductions in the 10+ mmHg range, though other studies have found even greater reductions (see http://gmodestmedblogs.blogspot.com/2015/09/spironolactone-in-drug-resistant.html 

--as a somewhat tangential issue, the results of this study are also consistent with those in a prior study finding that doubling the dose of an antihypertensive was only 20% as effective as adding another drug, also noting high reductions in SBP with the additional drug (see htn combo vs dbling dose ajm 2009 in dropbox, or Wald DS. Am J Med 2009; 122:290). see figure below

--so, this study does reinforce the potency of blood pressure lowering and decreasing cardiovascular events by adding another BP med to the cocktail. but, one conclusion from this study is that we should be gingerly in adding the med, even if the patient has not responded satisfactorily to their current regimen: the added drug may well have a profound effect on their blood pressure, reinforcing the "start low, go slow" mantra​. and as per the above caveat about the SPRINT trial, the target office systolic should probably be around 130 mmHg (which is consistent with the new AHA guidelines: http://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html .

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