Treatment resistant hypertension has been an issue which has been bugging medical practitioners for a long time now. The first human trial on renal sympathetic denervation for treatment of this condition, the results of which have been recently published in The Lancet, show some promise. This prospective, multicenter, randomized trial included non-diabetic patients with a baseline systolic blood pressure of 160 mm of Hg and already on 3 or more anti-hypertensives. For diabetic patients, this was defined to be 150 mm of Hg.
Now, before I go in to discuss the study per se, it would be worthwhile to take a look at how renal sympathetic nervous system plays a key role in the pathogenesis of essential hypertension. Whilst the pathophysiology of essential hypertension is a complex one, with the interplay of several factors contributing to it, there is a large body of evidence supporting the fact that there is a neurogenic player setting up the hypertensive state. A study in small, homogeneous hypertensive cohorts has shown that (1) though the precise causal mechanisms leading to sympathetic overactivity are poorly explained, the roles of:
- Increased rate of sympathetic nerve firing
- Reduced neuronal norepinephrine uptake
are unambiguous. Other mechanisms, which, initially believed to be a part of this pathogenesis trail, included:
- Diminished arterial baroreflex buffering of sympathetic nerve traffic
- Facilitation of NE release by neurohumoral factors such as angiotensin II.
They were, however, shown to have little or no bearing in the referred study. Anyways, the main end point is the spilling over of the excess norepinephrine into the systemic circulation, leading to the end point changes precipitating the essential hypertension. This escaped amount of NE, therefore, had a major role to play in mediating the hypertension. It is a plausible theory that there is development of the hypertension through the interaction of the overactive sympathetic nervous system with several related factors, like, renin release, glomerular filtration rate, renal tubular sodium reabsorption, cardiac growth and pumping activity. This study also referred in passing to the hypothesis of a functional cardiac renin-angiotensin system (which, in itself, is a topic which can provide fodder for thought for another post!) which may also have a role to play in this whole game. Whether the data of this study can be extrapolated to the entire essential hypertensive population remains a question, but what it does, is that, it establishes, on a firm footing the neurogenic theory of systemic essential hypertension.
Anyways, so, to come back to the study at hand now. There have been reports and case studies (2) which have shown the efficacy of renal sympathetic nerve ablation for uncontrolled hypertension, but there have been no human RCTs till this one. There was a multicenter safety and proof-of-principle cohort study last year (also published in The Lancet) (3) which reported favorable results, and then, led to the conceptualization of the RCT in question.
In this RCT, a random one to one allocation into study group (renal sympathetic denervation) and control group (continue previous antihypertensive therapy) was done. The primary effectiveness end point was simple: seated office-based measurement of systolic blood pressure at 6 months after follow up. The results are promising, to say the least:
Office-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (SD 23/11, baseline of 178/96 mm Hg, p<0·0001), whereas they did not differ from baseline in the control group (change of 1/0 mm Hg [21/10], baseline of 178/97 mm Hg, p=0·77 systolic and p=0·83 diastolic). Between-group differences in blood pressure at 6 months were 33/11 mm Hg (p<0·0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mm Hg or more, compared with 18 (35%) of 51 controls (p<0·0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not differ between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment.
However, as with every study, there remain some questions.
- The data analyzers were not masked as to the allocation of treatment. Since I cannot access the full paper (hello there open access advocates: look!), I remain skeptical due to the lack of blinding, and my, erm, blind faith in the ability of blinding to obliviate some bias.
- The results were followed up after just 6 months. Which is not a long enough time period. Following these patients up in a longitudinal study is therefore essential to understand the long term implications of the same.
- Another necessity of dong the long term follow up is to understand the kind of impact this has on other organ systems. While essential hypertension is itself a major risk factor in the saga of end organ damage, sympathetic overdrive is not too good for the body either. So, I feel, a longitudinal follow up is of essential importance to understand the kind of impact it has on delaying (or not) of end organ damage.
- While there is considerable debate raging around the issue of early diagnosis and management of hypertension pharmacologically and whether it offers any benefits eventually (or is it just a bunch of conspiration theorists lobbying against big pharma? What do you think?), another modality of (potentially expensive=lucrative business) treatment is heading out. What to make of this without hard data showing long term benefits?
- And of course, in my case, what is the cost of this whole thing? Will it be feasible to apply it to the developing nations, where the teeming masses of younger adult are just waiting to fall into the lap of this disease?
What do you think? Go, or No-go?
1. Schlaich MP, Lambert E, Kaye DM, et al. Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension2004;43:169-175
2. Markus P. Schlaich et al. Renal Sympathetic-Nerve Ablation for Uncontrolled Hypertension. N Engl J Med 2009; 361:932-934
3. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009 Apr 11;373(9671):1275-81. Epub 2009 Mar 28.
Study in Focus:
Symplicity HTN-2 Investigators (2010) (2010). Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial The Lancet, 376 (9756), 1903-1909 DOI: 10.1016/S0140-6736(10)62039-9