- Email: [email protected]
Renal sympathetic denervation: the jury is still out
Comment
its development should be fostered by the proposed interprofessional courses starting at an early stage. In the past 7 years, international health-care students recognised the importance of interprofessional education, and launched an international forum which brings together students of medicine, nursing, pharmacy, and allied health professions. During these annual World Healthcare Students Symposia, students learn to understand the different professions and discuss the best ways of effective and fruitful collaboration.3 What students try to teach themselves through laborious but successful efforts should not be neglected by their educational institutions. The proposed focus on the implementation of innovative and promising information and communication technologies merits attention. Although it is not predictable where the movement of evolving new technologies might lead to, we do believe in its potential benefits for the education of medical students. One example of such an emerging innovation is Health Sciences Online, a website that provides hand-picked learning resources from renowned institutions for free.4 Students from low-income countries with a lack of resources can especially benefit from such initiatives, although such free initiatives should not counteract the proposal to focus development assistance more strongly on health professionals’ education. The institutional reforms laid out by the commission also receive our support and endorsement. Joint planning mechanisms should meet the needs of the population, and students should be especially involved in these processes. Global learning systems will be crucial within a globalised world, and they can especially empower resource-poor settings. Furthermore, we believe in the ability of educational institutions and
health-care professionals as agents for sustainable social transformation. Through representative bodies, students have already shown the strength of such advocacy campaigns if planned properly and delivered skilfully. Student initiatives have tackled climate change, migrant health, and other issues of global and national relevance.5,6 As health-care students, we encourage all stakeholders to use the Global Commission’s report as a basis for further discussion and action. We emphasise the importance of involving students from different healthcare professions in the implementation process, and the contribution students already provide to meet the recommendations. We strongly believe in the benefits of this effort, based on the understanding that the ultimate goal of health professionals’ education is to improve the health of society. Florian L Stigler, *Robbert J Duvivier, Margot Weggemans, Helmut J F Salzer Medical University of Graz, Graz, Austria (FLS, HJFS); Maastricht University, 6200 MD Maastricht, Netherlands (RJD); and University of Utrecht, Utrecht, Netherlands (MW) [email protected] We declare that we have no conflicts of interest. 1
2 3
4 5 6
Frenk J, Chen L, Bhutta ZA, et al. Health professionals for a new century: transforming education to strengthen health systems in an interdependent world. Lancet 2010; published online Nov 29. DOI:10.1016/ S0140-6736(10)61854-5. IFMSA, EMSA, Hilgers J, De Roos P. European core curriculum—the students’ perspective. Med Teach 2006; 29: 270–75. World Healthcare Students Symposium. Nov 29, 2007. http://www.who. int/patientsafety/events/07/26_11_07/en/index.html (accessed Oct 14, 2010). Health Sciences Online. http://www.hso.info (accessed Oct 14, 2010). Duvivier R, Mansouri M, Iemmi D, Rukavina S. Migrants and the right to health: the students’ perspective. Lancet 2010; 375: 376. Duvivier R, Brouwer E, Weggemans M. Medical education in global health: student initiatives in the Netherlands. Med Educ 2010; 44: 527–30.
Renal sympathetic denervation: the jury is still out Published Online November 17, 2010 DOI:10.1016/S01406736(10)62111-3 See Articles page 1903
1878
The Symplicity HTN-2 Investigators1 deserve credit for building on the proof-of-principle study,2 and for addressing a substantial concern3 (the need for a randomised trial) by undertaking the first RCT of renal sympathetic denervation in patients with treatmentresistant hypertension. Hypertension is the most common indication for lifelong treatment, mainly because of the incontrovertible reductions in cardiovascular events.
Despite the abundance of antihypertensive drugs, control of blood pressure rates remains disappointingly low worldwide. Many patients who are uncontrolled present resistant hypertension (ie, uncontrolled blood pressure despite the use of optimum doses of three antihypertensive drugs, one being a diuretic).4–6 Although salt restriction and spironolactone treatment are effective for resistant hypertension, they have not gained www.thelancet.com Vol 376 December 4, 2010
Comment
wide application. Darusentan—an endothelin receptor antagonist—and carotid baroreceptor stimulation showed promising preliminary results; however, reports have cast doubt on their efficacy.7–9 The Symplicity HTN-2 trial assessed 106 patients with treatment-resistant hypertension (ie, systolic blood pressure ≥160 mm Hg [≥150 mm Hg for patients with diabetes] despite the use of three or more antihypertensive drugs). Patients were randomly assigned to renal sympathetic denervation (52 patients) or control (54) groups. Renal denervation resulted in impressive reductions in mean, office-based measurements of blood pressure (32/12 mm Hg at 6 months), whereas blood pressure remained almost unchanged in the control group. Home and ambulatory measurements of blood pressure followed a similar pattern; the corresponding reductions were 20/12 mm Hg and 11/7 mm Hg with renal denervation, whereas no reductions were observed in the control group. The absence of a placebo effect in the control group underlines the careful selection of included patients, because the study was undertaken in specialist hypertension centres. Although the procedure was safe with no substantial adverse events, there are several limitations of the study design. The control group did not undergo sham operation, which would have provided double-blinding and reduced potential bias. Furthermore, secondary and white-coat hypertension were not defined as exclusion criteria. Past studies have shown increased prevalence of primary aldosteronism, sleep apnoea, and white-coat hypertension in resistant hypertension.4,5,10 Although the study was done in centres that specialised in hypertension, we believe that per-protocol exclusion of secondary and white-coat hypertension would have been more appropriate. Finally, despite the impressive reduction in blood pressure, the control rate with renal denervation was only 39%. The investigators report some predictors of increased reduction in blood pressure (increased baseline blood pressure and reduced heart rate), which are not specific enough to enable patient selection. Meticulous investigation to identify specific predictors of treatment success at baseline should be undertaken in future studies. Sympathetic reinnervation presents another important concern.11 Although the functionality of efferent reinnervation in humans remains dubious, reinnervation of afferent renal nerves has not been described. In our www.thelancet.com Vol 376 December 4, 2010
opinion, the most valid argument against a clinically meaningful effect of reinnervation comes from clinical practice. Antihypertensive efficiency persisted for the 2-year follow-up after renal denervation, and the beneficial effects of splanchnicectomy were maintained in most patients for 14 years.12 The effects of renal denervation on target organ damage, and the pathophysiological mechanisms mediating these effects, present a priority for future research (panel). Other research targets include specific subgroups of patients with hypertension, such as patients with isolated systolic hypertension, diabetes, chronic kidney disease, heart failure, obesity, sleep apnoea, and elderly patients. Another important aspect is the possibility of drastic de-escalation of antihypertensive drugs. Finally, the effects of alternative methods of renal denervation, other than radiofrequency ablation as used in the present study, such as ultrasound, microwaves, lasers, cryotherapy, and robotic surgery, merit investigation. Once-and-forever treatment of hypertension represents the holy grail of research in the field. The appalling death toll of hypertension, combined with the financial costs of lifelong antihypertensive therapy and the sideeffects of antihypertensive drugs, make efforts for Panel: Research targets for renal sympathetic denervation • Clarification of pathophysiological mechanisms that mediate reductions in blood pressure • Effects on target organ damage • Left ventricular hypertrophy • Carotid intima-media thickness • Albuminuria • Pulse-wave velocity • Ankle brachial pressure index • Retinopathy • Efficiency in subgroups of patients with hypertension • Elderly patients • Isolated systolic hypertension • Chronic kidney disease • Heart failure • Diabetes • Obesity • Sleep-apnoea syndrome • Efficiency in milder forms of essential hypertension • Efficiency at initial stages of hypertension • Alternative methods for achieving renal denervation • Ultrasound • Microwaves • Laser • Cryotherapy • Robotic surgery
1879
Comment
permanent therapy of hypertension very appealing. Past efforts with aggressive therapy at initial stages of hypertension, gene therapy, and vaccination have not been successful. Although renal denervation might prove to be a revolutionary treatment for hypertension, the complexity of its pathophysiology discourages the simplistic notion that inhibition of one factor will be effective in all patients, and over-optimism should be avoided. Only the future can tell whether renal denervation will change the way we treat hypertension in everyday clinical practice. However, the exciting results of the Symplicity study generate great expectations, and the investigators have paved the way for interventional management of patients with resistant hypertension.
1
2
3 4 5 6 7
8
9
*Michael Doumas, Stella Douma Veteran Affairs Medical Center, George Washington University, Washington, DC 20422, USA (MD); and 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece (SD) [email protected] We declare that we have no conflicts of interest.
10
11 12
Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010; published online Nov 17. DOI:10.1016/S0140-6736(10)62039-9. Krum H, Schlaich M, Whitbourn R, et al. Catheter based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; 373: 1275–81. Doumas M, Douma S. Interventional management of resistant hypertension. Lancet 2009; 373: 1228–30. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation and treatment. Circulation 2008; 117: e510–26. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol 2008; 52: 1749–57. Williams B. Resistant hypertension: an unmet treatment need. Lancet 2009; 374: 1396–98. Weber MA, Black H, Bakris G, et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomized, double-blind, placebo-controlled trial. Lancet 2009; 374: 1423–31. Bakris GL, Lindholm LH, Black HR, et al. Divergent results using clinic and ambulatory blood pressures: report of a darusentan-resistant hypertension trial. Hypertension 2010; 56: 824–30. Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010; 56: 1254–58. Douma S, Petidis K, Doumas M, et al. Prevalence of primary hyperaldosteronism: a retrospective observational study. Lancet 2008; 371: 1921–26. Doumas M, Faselis C, Papademetriou V. Renal sympathetic denervation and systemic hypertension. Am J Cardiol 2010; 105: 570–76. Peet MM. Hypertension and its surgical treatment by bilateral supradiaphragmatic splanchnicectomy. Am J Surg 1948; 75: 48–68.
Cost-effective use of prereferral treatment for severe malaria Published Online November 30, 2010 DOI:10.1016/S01406736(10)61969-1 See Articles page 1910
1880
Notwithstanding the optimism surrounding falling malaria transmission, the harsh reality for billions of people in endemic areas remains that, where access to health facilities is poor, this otherwise curable disease can rapidly deteriorate to severe illness and death.1,2 In The Lancet, Yeşim Tozan and colleagues3 describe the cost-effectiveness of prereferral rectal artesunate in children with severe malaria. The rationale is that the administration of an effective antimalarial suppository can halt malaria progression until the patient reaches facilities where parenteral treatment is available. Prereferral use of artesunate was investigated by Gomes and colleagues,4 who found that, for patients who face extensive delays in attending health facilities, this intervention significantly reduced mortality and severe disability. For patients living closer to a health facility, there was no evidence of advantage in the use of prereferral artesunate. This finding would be expected in view of the 6–12 h required for artesunate to reduce parasitaemia. Tozan and colleagues take the field further by showing that prereferral artesunate could be cost effective.
However, the intervention’s cost-effectiveness is specific to areas where access to health facilities is limited but not impossible, where the likelihood of malaria being the cause of illness is high, and where community health workers are already in place. These caveats are important. Tozan and colleagues assumed high effectiveness for prereferral treatment in a hypothetical community where access to health facilities is limited. The analysis also showed that the cost-effectiveness is to a great extent driven by the probability of attending a health facility after receiving prereferral treatment. Adherence to referral advice is probably a function of the health facilities’ accessibility. Consequently, the intervention seems to be highly cost effective in that middle ground, where health facilities are not immediately accessible, but not too inaccessible to deter carers completely from attendance after the child receives the suppository. Although partly restricted access to health care might be the reality for a large proportion of people at risk of malaria, it should be noted that the cost-effectiveness of the intervention will vary considerably between settings. www.thelancet.com Vol 376 December 4, 2010
its development should be fostered by the proposed interprofessional courses starting at an early stage. In the past 7 years, international health-care students recognised the importance of interprofessional education, and launched an international forum which brings together students of medicine, nursing, pharmacy, and allied health professions. During these annual World Healthcare Students Symposia, students learn to understand the different professions and discuss the best ways of effective and fruitful collaboration.3 What students try to teach themselves through laborious but successful efforts should not be neglected by their educational institutions. The proposed focus on the implementation of innovative and promising information and communication technologies merits attention. Although it is not predictable where the movement of evolving new technologies might lead to, we do believe in its potential benefits for the education of medical students. One example of such an emerging innovation is Health Sciences Online, a website that provides hand-picked learning resources from renowned institutions for free.4 Students from low-income countries with a lack of resources can especially benefit from such initiatives, although such free initiatives should not counteract the proposal to focus development assistance more strongly on health professionals’ education. The institutional reforms laid out by the commission also receive our support and endorsement. Joint planning mechanisms should meet the needs of the population, and students should be especially involved in these processes. Global learning systems will be crucial within a globalised world, and they can especially empower resource-poor settings. Furthermore, we believe in the ability of educational institutions and
health-care professionals as agents for sustainable social transformation. Through representative bodies, students have already shown the strength of such advocacy campaigns if planned properly and delivered skilfully. Student initiatives have tackled climate change, migrant health, and other issues of global and national relevance.5,6 As health-care students, we encourage all stakeholders to use the Global Commission’s report as a basis for further discussion and action. We emphasise the importance of involving students from different healthcare professions in the implementation process, and the contribution students already provide to meet the recommendations. We strongly believe in the benefits of this effort, based on the understanding that the ultimate goal of health professionals’ education is to improve the health of society. Florian L Stigler, *Robbert J Duvivier, Margot Weggemans, Helmut J F Salzer Medical University of Graz, Graz, Austria (FLS, HJFS); Maastricht University, 6200 MD Maastricht, Netherlands (RJD); and University of Utrecht, Utrecht, Netherlands (MW) [email protected] We declare that we have no conflicts of interest. 1
2 3
4 5 6
Frenk J, Chen L, Bhutta ZA, et al. Health professionals for a new century: transforming education to strengthen health systems in an interdependent world. Lancet 2010; published online Nov 29. DOI:10.1016/ S0140-6736(10)61854-5. IFMSA, EMSA, Hilgers J, De Roos P. European core curriculum—the students’ perspective. Med Teach 2006; 29: 270–75. World Healthcare Students Symposium. Nov 29, 2007. http://www.who. int/patientsafety/events/07/26_11_07/en/index.html (accessed Oct 14, 2010). Health Sciences Online. http://www.hso.info (accessed Oct 14, 2010). Duvivier R, Mansouri M, Iemmi D, Rukavina S. Migrants and the right to health: the students’ perspective. Lancet 2010; 375: 376. Duvivier R, Brouwer E, Weggemans M. Medical education in global health: student initiatives in the Netherlands. Med Educ 2010; 44: 527–30.
Renal sympathetic denervation: the jury is still out Published Online November 17, 2010 DOI:10.1016/S01406736(10)62111-3 See Articles page 1903
1878
The Symplicity HTN-2 Investigators1 deserve credit for building on the proof-of-principle study,2 and for addressing a substantial concern3 (the need for a randomised trial) by undertaking the first RCT of renal sympathetic denervation in patients with treatmentresistant hypertension. Hypertension is the most common indication for lifelong treatment, mainly because of the incontrovertible reductions in cardiovascular events.
Despite the abundance of antihypertensive drugs, control of blood pressure rates remains disappointingly low worldwide. Many patients who are uncontrolled present resistant hypertension (ie, uncontrolled blood pressure despite the use of optimum doses of three antihypertensive drugs, one being a diuretic).4–6 Although salt restriction and spironolactone treatment are effective for resistant hypertension, they have not gained www.thelancet.com Vol 376 December 4, 2010
Comment
wide application. Darusentan—an endothelin receptor antagonist—and carotid baroreceptor stimulation showed promising preliminary results; however, reports have cast doubt on their efficacy.7–9 The Symplicity HTN-2 trial assessed 106 patients with treatment-resistant hypertension (ie, systolic blood pressure ≥160 mm Hg [≥150 mm Hg for patients with diabetes] despite the use of three or more antihypertensive drugs). Patients were randomly assigned to renal sympathetic denervation (52 patients) or control (54) groups. Renal denervation resulted in impressive reductions in mean, office-based measurements of blood pressure (32/12 mm Hg at 6 months), whereas blood pressure remained almost unchanged in the control group. Home and ambulatory measurements of blood pressure followed a similar pattern; the corresponding reductions were 20/12 mm Hg and 11/7 mm Hg with renal denervation, whereas no reductions were observed in the control group. The absence of a placebo effect in the control group underlines the careful selection of included patients, because the study was undertaken in specialist hypertension centres. Although the procedure was safe with no substantial adverse events, there are several limitations of the study design. The control group did not undergo sham operation, which would have provided double-blinding and reduced potential bias. Furthermore, secondary and white-coat hypertension were not defined as exclusion criteria. Past studies have shown increased prevalence of primary aldosteronism, sleep apnoea, and white-coat hypertension in resistant hypertension.4,5,10 Although the study was done in centres that specialised in hypertension, we believe that per-protocol exclusion of secondary and white-coat hypertension would have been more appropriate. Finally, despite the impressive reduction in blood pressure, the control rate with renal denervation was only 39%. The investigators report some predictors of increased reduction in blood pressure (increased baseline blood pressure and reduced heart rate), which are not specific enough to enable patient selection. Meticulous investigation to identify specific predictors of treatment success at baseline should be undertaken in future studies. Sympathetic reinnervation presents another important concern.11 Although the functionality of efferent reinnervation in humans remains dubious, reinnervation of afferent renal nerves has not been described. In our www.thelancet.com Vol 376 December 4, 2010
opinion, the most valid argument against a clinically meaningful effect of reinnervation comes from clinical practice. Antihypertensive efficiency persisted for the 2-year follow-up after renal denervation, and the beneficial effects of splanchnicectomy were maintained in most patients for 14 years.12 The effects of renal denervation on target organ damage, and the pathophysiological mechanisms mediating these effects, present a priority for future research (panel). Other research targets include specific subgroups of patients with hypertension, such as patients with isolated systolic hypertension, diabetes, chronic kidney disease, heart failure, obesity, sleep apnoea, and elderly patients. Another important aspect is the possibility of drastic de-escalation of antihypertensive drugs. Finally, the effects of alternative methods of renal denervation, other than radiofrequency ablation as used in the present study, such as ultrasound, microwaves, lasers, cryotherapy, and robotic surgery, merit investigation. Once-and-forever treatment of hypertension represents the holy grail of research in the field. The appalling death toll of hypertension, combined with the financial costs of lifelong antihypertensive therapy and the sideeffects of antihypertensive drugs, make efforts for Panel: Research targets for renal sympathetic denervation • Clarification of pathophysiological mechanisms that mediate reductions in blood pressure • Effects on target organ damage • Left ventricular hypertrophy • Carotid intima-media thickness • Albuminuria • Pulse-wave velocity • Ankle brachial pressure index • Retinopathy • Efficiency in subgroups of patients with hypertension • Elderly patients • Isolated systolic hypertension • Chronic kidney disease • Heart failure • Diabetes • Obesity • Sleep-apnoea syndrome • Efficiency in milder forms of essential hypertension • Efficiency at initial stages of hypertension • Alternative methods for achieving renal denervation • Ultrasound • Microwaves • Laser • Cryotherapy • Robotic surgery
1879
Comment
permanent therapy of hypertension very appealing. Past efforts with aggressive therapy at initial stages of hypertension, gene therapy, and vaccination have not been successful. Although renal denervation might prove to be a revolutionary treatment for hypertension, the complexity of its pathophysiology discourages the simplistic notion that inhibition of one factor will be effective in all patients, and over-optimism should be avoided. Only the future can tell whether renal denervation will change the way we treat hypertension in everyday clinical practice. However, the exciting results of the Symplicity study generate great expectations, and the investigators have paved the way for interventional management of patients with resistant hypertension.
1
2
3 4 5 6 7
8
9
*Michael Doumas, Stella Douma Veteran Affairs Medical Center, George Washington University, Washington, DC 20422, USA (MD); and 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece (SD) [email protected] We declare that we have no conflicts of interest.
10
11 12
Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010; published online Nov 17. DOI:10.1016/S0140-6736(10)62039-9. Krum H, Schlaich M, Whitbourn R, et al. Catheter based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; 373: 1275–81. Doumas M, Douma S. Interventional management of resistant hypertension. Lancet 2009; 373: 1228–30. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation and treatment. Circulation 2008; 117: e510–26. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol 2008; 52: 1749–57. Williams B. Resistant hypertension: an unmet treatment need. Lancet 2009; 374: 1396–98. Weber MA, Black H, Bakris G, et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomized, double-blind, placebo-controlled trial. Lancet 2009; 374: 1423–31. Bakris GL, Lindholm LH, Black HR, et al. Divergent results using clinic and ambulatory blood pressures: report of a darusentan-resistant hypertension trial. Hypertension 2010; 56: 824–30. Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010; 56: 1254–58. Douma S, Petidis K, Doumas M, et al. Prevalence of primary hyperaldosteronism: a retrospective observational study. Lancet 2008; 371: 1921–26. Doumas M, Faselis C, Papademetriou V. Renal sympathetic denervation and systemic hypertension. Am J Cardiol 2010; 105: 570–76. Peet MM. Hypertension and its surgical treatment by bilateral supradiaphragmatic splanchnicectomy. Am J Surg 1948; 75: 48–68.
Cost-effective use of prereferral treatment for severe malaria Published Online November 30, 2010 DOI:10.1016/S01406736(10)61969-1 See Articles page 1910
1880
Notwithstanding the optimism surrounding falling malaria transmission, the harsh reality for billions of people in endemic areas remains that, where access to health facilities is poor, this otherwise curable disease can rapidly deteriorate to severe illness and death.1,2 In The Lancet, Yeşim Tozan and colleagues3 describe the cost-effectiveness of prereferral rectal artesunate in children with severe malaria. The rationale is that the administration of an effective antimalarial suppository can halt malaria progression until the patient reaches facilities where parenteral treatment is available. Prereferral use of artesunate was investigated by Gomes and colleagues,4 who found that, for patients who face extensive delays in attending health facilities, this intervention significantly reduced mortality and severe disability. For patients living closer to a health facility, there was no evidence of advantage in the use of prereferral artesunate. This finding would be expected in view of the 6–12 h required for artesunate to reduce parasitaemia. Tozan and colleagues take the field further by showing that prereferral artesunate could be cost effective.
However, the intervention’s cost-effectiveness is specific to areas where access to health facilities is limited but not impossible, where the likelihood of malaria being the cause of illness is high, and where community health workers are already in place. These caveats are important. Tozan and colleagues assumed high effectiveness for prereferral treatment in a hypothetical community where access to health facilities is limited. The analysis also showed that the cost-effectiveness is to a great extent driven by the probability of attending a health facility after receiving prereferral treatment. Adherence to referral advice is probably a function of the health facilities’ accessibility. Consequently, the intervention seems to be highly cost effective in that middle ground, where health facilities are not immediately accessible, but not too inaccessible to deter carers completely from attendance after the child receives the suppository. Although partly restricted access to health care might be the reality for a large proportion of people at risk of malaria, it should be noted that the cost-effectiveness of the intervention will vary considerably between settings. www.thelancet.com Vol 376 December 4, 2010