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Combination RAS inhibition vs Renal artery therapies

Winner: Renal artery therapies

This was a battle of disappointments, RAS inhibition’s season was reeling from ALTITUDE and ONTARGET. The last hope for salvaging the season came with the VA NEPHRON-D study and again, combination therapy dropped the ball. Combo RAS blockade began with the disgraced and retracted COOPERATE trial and closed with the definitive shutter of multiple RCTs. Put a fork in dual RAS inhibition, it is done.

However, this disappointment cannot hold a candle to the grand daddy of disappointments that was renal artery therapies. This package includes two potential all-conference players: a power forward playing renal revascularization and a point guard playing renal sympathetic denervation.

Revascularization is the type of therapy that makes so much intuitive sense that it would be pretty easy to accept without evidence. If atherosclerosis is choking the kidney’s blood supply, opening up the artery with a balloon and stent should preserve renal function and reverse or at least improve renal vascular hypertension. Talk to an old nephrologist for an hour or two and she will tell a story of a patient with progressive renal failure that was saved by a well-timed revascularization or a patient with resistant hypertension that was reversed by a cath cowboy. The rub is that multiple studies have tried and failed to show a consistent benefit from the procedure. Four times RCTs have tried to protocolize who would benefit from revascularization and four times they have failed to show improvement in blood pressure or renal survival:

1. CORAL
2. ASTRAL
3. DRASTIC
4. EMMA

The other half of the renal artery duo is radiofrequency ablation of the renal artery. Blocking sympathetic stimulation of the kidney in order to lower peripheral blood pressure. It worked in two trials but in the pivotal third trial in order to get licensed in the US, it was unable to lower blood pressure. The early work was impressive enough for the procedure to be approved in Europe and get the nephrology community excited for this novel approach. The shock and disappointment when Symplicity-3 was halted secondary to futility was palpable. This Saturday at the American College of Cardiology we will get the first data on the halted Symplicity-3 trial since the press release.

In the end this shock is what turned the tide in favor of renal artery therapies being more important than combination therapy. Renal Artery therapies come from the eighth seed to upset combination RAS inhibition.

Systolic blood pressure versus diastolic blood pressure

Winner: Systolic blood pressure

The selection committee tries to separate in-state rivals, so they don’t meet in the opening round but this battle must have slipped through a loop hole.

Systolic blood pressure has long ruled this rivalry. Increases in systolic blood pressure are associated with increased stroke risk and interventions that lower systolic blood pressure reduce strokes. Diastolic pressure is more nuanced, especially among people over the age of 65 where diastolic blood pressure has a U-shaped curve, so that low diastolic blood pressures are associated with cardiovascular events. This u-shaped phenomena is also seen in post MI patients.

It was hard scrapped fight but the linear reduction in CVA with reductions in SBP helped SBP drain a three at the buzzer to avoid overtime and advance to the next round.

Chlorthalidone versus hydrochlorothiazide

Winner: Chlorthalidone

Chlorthalidone and HCTZ used to be single team, in fact in the MRFIT trial patients randomized to the Special Intervention group could be given either diuretic. A few years into the study the investigators noticed a mortality difference based on which thiazide they were given with the advantage tilting towards chlorthalidone.

This difference became more important after the publication and impact of ALLHAT, the largest hypertension trial ever. The supremacy of thiazides as initial management of hypertension was sealed in the publication of JNC7. ALLHAT used chlorthalidone but JNC7 advised use of any thiazide, most of which turned out to be HCTZ.

This choice began to look foolish when in ACCOMPLISH HCTZ plus an ACEi was inferior to amlodipine and an ACEi. Was this finding due to the superiority of the amlodipine or the weakness the specific thiazide used, HCTZ.

The HCTZ versus chlorthalidone debate has spawned an academic industry of authors writing papers examining the difference but for this contest, chlorthalidone takes it.

Blood pressure guidelines: JNC8 versus KDIGO

Winner: JNC8

If you think clinical practice guidelines are a snooze, try to watch the authors of said guidelines play basketball. Pathetic. Neither team could shoot, dribble or pass. The final score was football-like 17 to 14. These codgers better step it up or it will be a short tournament for the winners.

Both teams emerged in the last days of 2013 and have been eating up publicity since publication. The JNC8 is the last guideline to be initiated by the National Heart Lung and Blood Institute, NHLBI (but in a confusing twist, the NHLBI does not endorse these blood pressure guidelines) and it is a doozy. This is massive simplification of blood pressure management. No more splitting hairs for diabetes, or proteinuria. The JNC 8 guidelines are pretty simple, especially in regards to CKD patients:

Table by Dr. Joel Topf

Reading the KDIGO guidelines, one is overwhelmed by the amount of opinion based recommendations. 2C and 2D recs pepper the guidelines. Too often policy makers adopt guidelines with no regard to the strength of the evidence and it is time that guideline authors realize that and try to limit themselves to strong, high quality evidence based recommendations.

This round goes to JNC8.

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