- Email: [email protected]
Central arteriovenous anastomosis in resistant hypertension?
Comment
Hypertension is a major cardiovascular epidemic that affects an estimated 1 billion adults worldwide. Around 13% of treated adults do not achieve target blood pressures1 despite prescription of three or more antihypertensive medications, and are classed as having resistant hypertension.2 Importantly, resistant hypertension is associated with excess cardiovascular risk.3 Disease frequency is increasing, and one in 50 patients develops resistant hypertension a median of 1·5 years after the start of pharmacotherapy.4 Although lifestyle modifications and appropriate combination drug therapy control blood pressure in most hypertensive patients, side-effects, unwillingness to take lifelong pharmacotherapy, physician inertia, and several other important factors might affect blood-pressure control and require attention. Alternative therapies, however, are also warranted. Several interventional approaches to lower blood pressure have been developed and tested clinically, most notably baroreflex activation therapy5 and renal sympathetic denervation.6,7 These two approaches are based on sound pathophysiological concepts and target mechanisms highly relevant to control of blood pressure and cardiovascular disease.8 In The Lancet, Melvin Lobo and colleagues9 report a study of a novel intervention based on a different mechanism. The ROX CONTROL HTN study is an open-label, multicentre, prospective randomised trial that is assessing the mechanical effects of adding a low-resistance compartment to the arterial tree by creating a central arteriovenous anastomosis of 4 mm diameter between the distal iliac vein and artery with an arteriovenous coupler device. In ROX CONTROL HTN, 83 patients with resistant hypertension were assigned to receive either continued pharmacological treatment plus placement of the arteriovenous coupler (n=44) or continued pharmacological treatment alone (n=39). After 6 months of follow-up, significant reductions from baseline were seen in patients in the arteriovenous coupler group for systolic blood pressure measured in the office (mean reduction 26·9 [SD 23·9] mm Hg) or during 24 h ambulatory assessment (13·5 [18·8] mm Hg), but not in controls (3·7 [21·2] mm Hg and 0·5 [15·8] mm Hg, respectively). Likewise, reductions in diastolic blood pressure were
significantly more pronounced in the arteriovenous coupler group than in the control group, and events related to high blood pressure were less frequent. Late ipsilateral venous stenosis occurred in 12 (29%) of 42 patients and required interventional therapy with venoplasty, alone or with stenting, in all affected patients. This study could prove to be a milestone in the continuing quest for interventional approaches to treat uncontrolled hypertension. While many physicians might be sceptical about the use of interventional approaches to lower blood pressure, that many patients are reluctant to modify their lifestyle and that non-adherence to some or all prescribed antihypertensive medications are not exceptions but rather the rules, particularly in patients with resistant hypertension, must be recognised.10 We commend Lobo and colleagues on testing an approach that might almost have seemed too simple to work. Office, and more importantly ambulatory, blood pressures were substantially reduced in the arteriovenous coupler group compared with in the control group. An immediate drop in blood pressure after creation of the anastomosis seems useful as an indicator of technical success. Additionally, a reduction in events related to high blood pressure lends credibility to the suggested beneficial physiological effects. Although reduction in peripheral resistance through improved arterial compliance was not tested directly in this study, we expect this to be an important mechanism. Clearly, arteriovenous anastomosis is not yet ready for clinical implementation, and Lobo and colleagues’ study9 is merely the first step in a series of investigations. Safety is a paramount feature of any novel interventional approach. The fact that 29% of patients developed venous iliac stenosis proximal to the anastomosis that needed another intervention is an important concern. Longer-term consequences, potential risk of restenosis, and need for antithrombotic therapies are all important issues to be addressed. Similarly, absence of adverse consequences of central arteriovenous anastomosis on cardiac output and central haemodynamics will have to be shown. Perhaps inherent to the mode of action, the diastolic fall in blood pressure was almost as pronounced as that for systolic blood pressure in the arteriovenous coupler group. Whether this response is of potential concern,
www.thelancet.com Published online January 23, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62290-X
Life in View/Science Photo Library
Central arteriovenous anastomosis in resistant hypertension?
Published Online January 23, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)62290-X See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)62053-5
1
Comment
especially in patients with concomitant coronary artery disease or isolated systolic hypertension, will need to be assessed. As expected, not every patient responded to the treatment, which highlights the likelihood that any one approach will not be successful in every patient. Criticisms of Lobo and colleagues’ study9 will arise due to the absence of a sham-treated control group and because medication adherence was not measured. The experience from other device trials in patients with resistant hypertension underscores the relevance of sham controls,5–7,11 and a study including a sham intervention would be useful to design as the next step. We look forward to seeing this interesting story unfold.
2
3
4
5
6
7 8
*Markus Schlaich, Dagmara Hering
9
School of Medicine and Pharmacology Royal Perth Hospital Unit, University of Western Australia, Crawley, WA 6009, Australia (MS); and Baker IDI Heart and Diabetes Institute, Melbourne, Australia (MS, DH) [email protected] We declare no competing interests. 1
2
Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension 2011; 57: 1076–80.
10 11
Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51: 1403–19. Pierdomenico SD, Lapenna D, Bucci A, et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens 2005; 18: 1422–28. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation 2012; 125: 1635–42. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled Rheos pivotal trial. J Am Coll Cardiol 2011; 58: 765–73. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010; 376: 1903–09. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014; 370: 1393–401. Laurent S, Schlaich M, Esler M. New drugs, procedures, and devices for hypertension. Lancet 2012; 380: 591–600. Lobo MD, Sobotka PA, Stanton A, et al, for the ROX CONTROL HTN Investigators. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial. Lancet 2015; published online Jan 23. http://dx.doi.org/10.1016/S0140-6736(14)62053-5. Jung O, Gechter JL, Wunder C, et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens 2013; 31: 766–74. Patel HC, Hayward C, Ozdemir BA, et al. Magnitude of blood pressure reduction in the placebo arms of modern hypertension trials: implications for trials of renal denervation. Hypertension 2014; published online Nov 17. DOI:10.1161/HYPERTENSIONAHA.114.04640.
www.thelancet.com Published online January 23, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62290-X
Hypertension is a major cardiovascular epidemic that affects an estimated 1 billion adults worldwide. Around 13% of treated adults do not achieve target blood pressures1 despite prescription of three or more antihypertensive medications, and are classed as having resistant hypertension.2 Importantly, resistant hypertension is associated with excess cardiovascular risk.3 Disease frequency is increasing, and one in 50 patients develops resistant hypertension a median of 1·5 years after the start of pharmacotherapy.4 Although lifestyle modifications and appropriate combination drug therapy control blood pressure in most hypertensive patients, side-effects, unwillingness to take lifelong pharmacotherapy, physician inertia, and several other important factors might affect blood-pressure control and require attention. Alternative therapies, however, are also warranted. Several interventional approaches to lower blood pressure have been developed and tested clinically, most notably baroreflex activation therapy5 and renal sympathetic denervation.6,7 These two approaches are based on sound pathophysiological concepts and target mechanisms highly relevant to control of blood pressure and cardiovascular disease.8 In The Lancet, Melvin Lobo and colleagues9 report a study of a novel intervention based on a different mechanism. The ROX CONTROL HTN study is an open-label, multicentre, prospective randomised trial that is assessing the mechanical effects of adding a low-resistance compartment to the arterial tree by creating a central arteriovenous anastomosis of 4 mm diameter between the distal iliac vein and artery with an arteriovenous coupler device. In ROX CONTROL HTN, 83 patients with resistant hypertension were assigned to receive either continued pharmacological treatment plus placement of the arteriovenous coupler (n=44) or continued pharmacological treatment alone (n=39). After 6 months of follow-up, significant reductions from baseline were seen in patients in the arteriovenous coupler group for systolic blood pressure measured in the office (mean reduction 26·9 [SD 23·9] mm Hg) or during 24 h ambulatory assessment (13·5 [18·8] mm Hg), but not in controls (3·7 [21·2] mm Hg and 0·5 [15·8] mm Hg, respectively). Likewise, reductions in diastolic blood pressure were
significantly more pronounced in the arteriovenous coupler group than in the control group, and events related to high blood pressure were less frequent. Late ipsilateral venous stenosis occurred in 12 (29%) of 42 patients and required interventional therapy with venoplasty, alone or with stenting, in all affected patients. This study could prove to be a milestone in the continuing quest for interventional approaches to treat uncontrolled hypertension. While many physicians might be sceptical about the use of interventional approaches to lower blood pressure, that many patients are reluctant to modify their lifestyle and that non-adherence to some or all prescribed antihypertensive medications are not exceptions but rather the rules, particularly in patients with resistant hypertension, must be recognised.10 We commend Lobo and colleagues on testing an approach that might almost have seemed too simple to work. Office, and more importantly ambulatory, blood pressures were substantially reduced in the arteriovenous coupler group compared with in the control group. An immediate drop in blood pressure after creation of the anastomosis seems useful as an indicator of technical success. Additionally, a reduction in events related to high blood pressure lends credibility to the suggested beneficial physiological effects. Although reduction in peripheral resistance through improved arterial compliance was not tested directly in this study, we expect this to be an important mechanism. Clearly, arteriovenous anastomosis is not yet ready for clinical implementation, and Lobo and colleagues’ study9 is merely the first step in a series of investigations. Safety is a paramount feature of any novel interventional approach. The fact that 29% of patients developed venous iliac stenosis proximal to the anastomosis that needed another intervention is an important concern. Longer-term consequences, potential risk of restenosis, and need for antithrombotic therapies are all important issues to be addressed. Similarly, absence of adverse consequences of central arteriovenous anastomosis on cardiac output and central haemodynamics will have to be shown. Perhaps inherent to the mode of action, the diastolic fall in blood pressure was almost as pronounced as that for systolic blood pressure in the arteriovenous coupler group. Whether this response is of potential concern,
www.thelancet.com Published online January 23, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62290-X
Life in View/Science Photo Library
Central arteriovenous anastomosis in resistant hypertension?
Published Online January 23, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)62290-X See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)62053-5
1
Comment
especially in patients with concomitant coronary artery disease or isolated systolic hypertension, will need to be assessed. As expected, not every patient responded to the treatment, which highlights the likelihood that any one approach will not be successful in every patient. Criticisms of Lobo and colleagues’ study9 will arise due to the absence of a sham-treated control group and because medication adherence was not measured. The experience from other device trials in patients with resistant hypertension underscores the relevance of sham controls,5–7,11 and a study including a sham intervention would be useful to design as the next step. We look forward to seeing this interesting story unfold.
2
3
4
5
6
7 8
*Markus Schlaich, Dagmara Hering
9
School of Medicine and Pharmacology Royal Perth Hospital Unit, University of Western Australia, Crawley, WA 6009, Australia (MS); and Baker IDI Heart and Diabetes Institute, Melbourne, Australia (MS, DH) [email protected] We declare no competing interests. 1
2
Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension 2011; 57: 1076–80.
10 11
Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51: 1403–19. Pierdomenico SD, Lapenna D, Bucci A, et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens 2005; 18: 1422–28. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation 2012; 125: 1635–42. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled Rheos pivotal trial. J Am Coll Cardiol 2011; 58: 765–73. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010; 376: 1903–09. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014; 370: 1393–401. Laurent S, Schlaich M, Esler M. New drugs, procedures, and devices for hypertension. Lancet 2012; 380: 591–600. Lobo MD, Sobotka PA, Stanton A, et al, for the ROX CONTROL HTN Investigators. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial. Lancet 2015; published online Jan 23. http://dx.doi.org/10.1016/S0140-6736(14)62053-5. Jung O, Gechter JL, Wunder C, et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens 2013; 31: 766–74. Patel HC, Hayward C, Ozdemir BA, et al. Magnitude of blood pressure reduction in the placebo arms of modern hypertension trials: implications for trials of renal denervation. Hypertension 2014; published online Nov 17. DOI:10.1161/HYPERTENSIONAHA.114.04640.
www.thelancet.com Published online January 23, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62290-X