Wednesday, November 18, 2015

What does SPRINT mean for HTN and CKD?

There has been much fanfare regarding the release of the SPRINT trial in the last several weeks. Finally, evidence that intensive blood pressure reduction is good! But, does this apply to everyone? Is there adverse risk to lowing BP this low? Also, what does this mean for our patients in the CKD clinic?

Let’s take a look at the SPRINT study and try to answer these questions.

What was SPRINT? 
SPRINT was a large randomized controlled trial with over 9,000 non-diabetic patients, funded by the NIH, to study the effect of intensive blood pressure control on cardiovascular health. The trial was terminated early (after a mean follow-up of 3.3 years) due to a significantly lower rate of the primary composite outcome (MI, ACS not resulting in MI, stroke, acute decompensated HF, or death from cardiovascular causes) in the intensive-treatment compared to the standard-treatment group. For more coverage of SPRINT go to NephJC.

The basics of the enrolled population are as follows:
  • All patients were over the age of 50 (mean 68). 36% were female.
  • Patients had elevated cardiac risk based on: a 10 year Framingham risk ≥ 15%, clinical or subclinical CVD, CKD with eGFR 20-60 ml/min/1.73 m2, or being over age 75.
  • 28% of patients (~2,600) had CKD with minimal proteinuria (patients with > 1 g proteinuria or >; 600 mg of albuminuria were excluded). 
  • 28% of patients were over age 75 at enrollment, their mean age was 80.
  • 43-45% of patients were on statins and ~50% were on aspirin.
  • Over 60% of patients started the trial with a SBP of > 145 mmHg.
  • Chlorthalidone was encouraged as the primary thiazide-type diuretic. 
  • The suggested initial triad of medications was a diuretic, CCB (preferably amlodipine), and ACEi or ARB. 
The main results were: 


Intensive Treatment
Standard Treatment
Results
Mean SBP at 1 year
121 mmHg
136 mmHg

Mean # Medications
2.8
1.8

Primary Outcome (ACS, CVA, CHF, CV death)
1.65 %/year
5.2 % (over 3.3 years)
2.19 %/year
6.8 % (over 3.3 years)
HR 0.75 (0.64-0.89)
RR reduction 25%/year (*driven by CHF and CV death)
NNT 61 (over 3.3 years)
All-Cause Mortality
1.03 %/year
3.3 % (over 3.3 years)
1.40 %/year
4.5 % (over 3.3 years)
HR 0.78 (0.67-0.90)
RR reduction 26%/year
NNT 90 (over 3.3 years)


What about CKD? 
First, SPRINT was not designed to be a CKD progression trial. However, it did include a large group of patients with CKD. In the patients with baseline CKD, intensive blood pressure control had no effect on the composite renal outcome (reduction in eGFR of 50% or more, dialysis or transplantation), nor on the development of incident albuminuria. Indeed, in patients without baseline CKD intensive blood pressure control led to higher rates of developing an eGFR < 60 ml/min/1.73 m2 (patients had to have at least a 30% drop in eGFR). The significance of this is unclear. Importantly, in the pre-specified subgroup analysis, the cardiovascular benefits of intensive blood pressure management were similar in patients with and without CKD. The caveat to all of this discussion was that the trial was not powered to answer this question.

What were the costs of aggressive treatment? 
While overall serious adverse events were not statistically more common (38% vs 37%), there were more episodes of hypotension, syncope, AKI, hyponatremia, and hypokalemia in the intensive group. Interestingly, orthostatic hypotension was actually higher in the standard treatment group and there was no increase in falls with intensive therapy. Patients were seen on a monthly basis by protocol if not at goal. Those in the intensive group had “Milepost Visits” every 6 months where the addition of medication was protocolized for patients with SBP < 120 mmHg (unless compelling contraindications existed). Notably, despite these aggressive measures half the patients were still unable to reach the intensive goal.

What did we know about aggressive BP control prior to SPRINT? 
 Nephrology dogma, codified in guidelines, has long argued for lower BP targets in patients with proteinuric CKD. A meta-analysis from 2011 combined the three key trials on aggressive blood pressure reduction (MDRD, AASK, and REIN-2) with a total of almost 2,300 primarily non-diabetic patients. The results suggested that aggressive blood pressure control (goals ranged approximately 125-130/75-80) on the whole does not improve CKD outcomes however sub-group analyses of proteinuric patients indicate the possibility of a benefit to stricter blood pressure control in terms of CKD progression. This possible benefit was seen in patients with greater than 0.22 g/g of proteinuria in AASK and greater than 1000 mg/d in MDRD. The recent JNC-8 guidelines argued however that this same data represented moderate quality evidence that lower BP targets do not slow CKD progression. For additional discussion of the post-hoc analyses of MDRD and AASK click here (previous review by Graham Abra on RFN). Given this potential equipoise perhaps it is unfortunate that patients with higher proteinuria were excluded from SPRINT.

What do we know then going forward? 
Hypertension is a strong risk factor for CKD. While the exact goal remains unclear, controlling blood pressure to < 140/90 is likely to be beneficial. Importantly, as the nuances of SPRINT are discussed – including additional outcomes such as the effect of intensive control on cognitive function in the elderly – hypertension in general is still very undertreated. Based on a recent CDC report 65% of US adults over the age of 60 have hypertension but only ½ are controlled. While this represents improvement from around 30% at the turn of the Millennium this still means that ½ of the population is not meeting the more conservative goal of 140/90. Increasing the percentage of patients controlled to 140/90 should have a profound and meaningful effect on the incidence of ESRD. SPRINT shows us however that for some of our patients with CKD, aggressive SBP control to < 120 can provide tangible, though not dramatic, improvements in cardiovascular risk.

Post by Robert Rope, Nephrology Fellow, Stanford

2 comments:

Nilang Patel said...

1). Primary difference in outcome coming from Heart failure/death response. But no difference in Stroke outcome. One should remember ACCORD trial where the aggressive BP control has benefit in Stroke outcome. In general, Stroke outcome is very sensitive to BP control but SPRINT failed to show any difference in this regards.

2). Look Supplements page 31 - Higher use of thiazide diuretics, spironolactone, betablockers and ACEI/ARB in intensive group --> likely leading difference in Heart failure outcome which is the ultimate driving force for change in primary composite outcome.

3). 33% patient at baseline BP < 132, another 33% BP at baseline SBP 132-145. On subgroup analysis, No difference in outcome in patient with baseline BP > 132. Suggesting that its simply sub-selecting population who tolerate low BP and they are doing better.

Nilang Patel said...

1). Primary difference in outcome coming from Heart failure/death response. No difference in Stroke outcome. One should keep in mind that ACCORD trial showed benefit in Stroke outcome with aggressive BP control. In general, Stroke outcome is very BP sensitive across the most of the BP trials in the past. That create the question why then mostly difference in Heart failure outcome between two group. If you look supplements page 31 - Higher use of thiazide diuretics (more hyponatremia, hypokalemia in intensive group), spironolactone, beta blockers and ACEI/ARB in intensive group likely leading difference in Heart failure outcome which is the ultimately the driving force for change in primary composite outcome.

2). 33% patient at baseline BP < 132, another 33% BP at baseline 132-145. No difference in outcome in patient with baseline BP > 132. This might suggest that its simply sub-selecting population who tolerate low BP and they are doing better in trial.

3). Although, author underplayed side effect in trial mainly - AKI. One should keep in mind adverse consequences of syncopal episode/ER visits/electrolyte disturbances and probably long term effect of CKD progression from these AKIs.