Table 1. Clinical studies evaluating device-based neuromodulation therapies for cardiovascular diseases (main original studies included; case reports and duplicating cohorts were excluded, except reference [9]).
| Author, year | Primary condition |
Age category and groups |
N patients treated using a neuromodulation approach |
Mean patient age (years) |
% of males |
Control group |
Sham- controlled? |
Advanced age associated with less efficacy |
Comments | Primary outcome | Result | |
| *Only studies with a control group with a standard PV isolation. AF: atrial fibrillation; BAT: baroreceptor activation therapy; BNP: brain natriuretic peptide; BP: blood pressure; CTEPH: chronic thromboembolic pulmonary hypertension; GP: ganglionated plexi; HF: heart failure; HFpEF: heart failure with preserved left ventricle ejection fraction; HFrEF: heart failure with reduced left ventricle ejection fraction; HTN: hypertension; LVEDV: left ventricular end diastolic volume; LVEF: left ventricle ejection fraction; LVESV: left ventricular end systolic volume; MIBG: meta-iodobenzylguanidine; MLWHFQ: Minnesota Living with Heart Failure Questionnaire; NT-pro–BNP: N-terminal fragment of the brain natriuretic peptide; NYHA: New York Heart Failure Association; PA: pulmonary artery; PAH: pulmonary arterial hypertension; PH: pulmonary hypertension; PV: pulmonary vein; PVR: pulmonary vascular resistance; 6MWT: six-minute walk test; QoL: quality of life; RND: renal denervation. | ||||||||||||
| Renal denervation | ||||||||||||
| 1. | Ziegler, et al., 2015[91] | HTN | Only patients ≥ 75 years old were included | 24 | ● 75 (75–89) | 46% | No | No | Not analyzed | A significant BP reduction following RND was found | Change in mean systolic office BP at 6-months | Positive |
| 2. | Krum, et al., 2011 (Symplicity HTN-1 trial)[92] |
HTN | ≤ 65 years old and > 65 years old |
88 | 57 ± 11 | 61% | No | No | No | No difference in BP change between groups | Change in office BP | Positive |
| 3. | Esler, et al., 2010 (Symplicity HTN-2 trial)[93] | HTN | None | 53 | 58 ± 12 | 65% | 54 | No | Not analyzed | - | Change in average office systolic BP at 6 months | Positive |
| 4. | Bhatt, et al., 2014 (Symplicity HTN-3 trial)[20] | HTN | None | 535 246 patients < 65 years old 104 patients ≥ 65 years old |
57.9 ± 10.4 | 59.1% | 171 128 patients < 65 years old 104 patients ≥65 years old |
Yes | Yes | In patients ≥ 65 years old, no difference in BP change following either an RND or sham procedure. In patients <65 years old RND produced better BP lowering | Difference in office systolic blood pressure change at 6 months | Neutral |
| 5. | Kandzari, et al., 2015[22] Same population as above |
HTN | None | 535 | 57.9 ± 10.4 | 59.1% | 171 | Same population as above | Maybe | A subanalysis of Symplicity HTN 3. Age < 65 years was not an independent factor associated with the effect | Difference in office systolic blood pressure change at 6 months | The subgroup of patients <65 years in age was associated with SBP change in the RDN group in univariable analysis but not in the multivariable model |
| 6. | Desch, et al., 2015[94] | HTN | None | 35 | 64.5 ± 7.6 | 77% | 36 | Yes | Not analyzed | - | Change in 24-hour systolic BP at 6 months | Neutral |
| 7. | Mathiassen, et al., 2016 (ReSET Study)[95] | HTN | None | 36 | 54.3 ± 7.8 | 75% | 33 | Yes | Not analyzed | - | Mean change in daytime systolic ambulatory BP monitoring from baseline to 3 months | Neutral |
| 8. | Townsend, et al., 2017 (SPYRAL OFF MED)[96] | HTN | None | 166 | 55.8 ± 10.1 | 68.4% | 165 | Yes | No | Treatment differences suggested efficacy of renal denervation for patients of different age | Change in 24-h blood pressure at 3 months | Positive (although not powered for efficacy endpoints) |
| 9. | Schmeider, et al., 2018 (WAVE IV Study)[97] | HTN | None | 42 | 60.3 ± 11.2 | 81.4% | 39 | Yes | Not analyzed | - | Difference in office systolic BP at 24 weeks | Neutral |
| 10. | Azizi, et al., 2018 (RADIANCE HTN SOLO)[98] | HTN | None | 74 | 54.4 ± 10.2 | 62% | 72 | Yes | No | The blood pressure lowering effect of renal denervation was consistent across ages | Mean change in daytime ambulatory systolic BP at 2 months | Positive |
| 11. | Kandzari, et al., 2018 (SPYRAL ON MED)[99] | HTN | None | 38 | 53.9 ± 8,7 | 87% | 42 | Yes | Not analyzed | - | 24h BP reduction at 6 months | Positive |
| 12. | Mahfoud, et al., 2020[23] | HTN | < 65 years and > 65 years | 2466 patients with 3-years follow-up: 1059 ≥65 years old, 1407 <65 years old | NA | NA | No | No | No | Patients aged < 65 and ≥ 65 years had similar efficacy of RND. Patients ≥65 years old had a higher mortality rate during follow-up | Document long-term safety and effectiveness of RDN in a real-world patient population | Positive |
| 13. | Gao, et al., 2019[52] | HFrEF | None | 30 | 60.2 ± 11.6 | 78.3% | 30 | No | Not analyzed | Results for different age groups were not reported | NT-proBNP, LVEF, NYHA class, 6MWT at 6 months | Positive for all outcome measures |
| 14. | Chen, et al., 2016[51] | HFrEF | Patients > 75 years old were excluded | 30 | 48.5 ± 8.4 | 73.3% | 30 | No | Not analyzed | Results for different age groups were not reported | Change in LVEF at 6 months | Positive |
| 15. | Spadaro, et al., 2019[54] | HFrEF (Chagas’ disease) | Patients > 70 years old were excluded | 11 | 52.6 ± 8.7 | 90.9% | 6 | No | Not analyzed | Results for different age groups were not reported | Composite of all-cause death, myocardial infarction, stroke, need for renal artery invasive treatment, or worsening renal function | Neutral |
| 16. | Feyz, et al., 2022 (IMPROVE-HF-I)[53] | HFrEF | None | 24 | 60 ± 9 | 86% | 25 | No | Not analyzed | Results for different age groups were not reported | The change in 123I-MIBG heart-to-mediastinum ratio at 6 months | Neutral |
| 17. | Patel, et al., 2016 (RDT-PEF)[57] | HFpEF | None | 17 | 74.3 ± 6.1 | 60% | 8 | No | Not analyzed | Results for different age groups were not reported | Improvement in at least one parameter: MLWHFQ; VO2 peak; BNP; E/e′; left atrial volume index; LV mass index | Neutral |
| 18. | Kresoja, et al., 2021[56] | HTN + HFpEF | Patients with HF were older | 154 (99 with HF and 65 without HF) | 66 (61–73) | 66% | No | No; retrospective study | Not analyzed | Results for different age groups were not reported | None predefined | Improvements in LV filling |
| 19. | Turagam, et al., 2021 (HFIB studies)[87] | AF + HTN | Patients in the RND group were significantly younger (59 ± 10 vs 68 ± 9 years); p=0.01) | 31 (PV isolation + RND) | 59.1 ± 10.4; 64.2 ± 6.8 |
62% | 39 (PV isolation only) | No | Not analyzed | RND group patients were younger that in the control group | AF-freedom | Neutral |
| 20. | Pokushalov, et al., 2012[85] | AF + HTN | None | 13 (PV isolation+RND) | 57 ± 8 | 84% | 14 (PV isolation only) | No | Not analyzed | Results for different age groups were not reported | AF recurrence at 12 months | Positive |
| 21. | Pokushalov, et al., 2014[86] | AF + HTN | None | 41 (PV isolation + RND) | 56 ± 6 | 76% | 39 (PV isolation only) | No | Not analyzed | Results for different age groups were not reported | AF recurrence | Positive |
| 22. | Kiuchi, et al., 2017[100] | AF + kidney disease | None | 39 (PV isolation + RND) | 60 ± 14 | 62% | 197 (PV isolation only) | No | Not analyzed | Results for different age groups were not reported | AF recurrence | Neutral (Positive in chronic kidney disease stage 4 only – 13 patients) |
| 23. | Steinberg, et al., 2020 (ERADICATE-AF study)[101] | AF+HTN | None | 154 (PV isolation + RND) | 59 [54; 65] | 59.1% | 148 (PV isolation only) | No | Not analyzed | Results for different age groups were not reported | AF freedom at 12 months | Positive |
| Pulmonary artery denervation | ||||||||||||
| 24. | Chen, et al., 2013[102] | PAH | None | 13 | 40 ± 16 | 69% | 8 | No | Not analyzed | Results for different age groups were not reported | Improvement of functional capacity by the 6MWT and mean PA pressure at 3 months | Positive |
| 25. | Zhang, et al., 2019[103] | PAH + PVH | None | 48 | 63.7 ± 11.8 | 62.5% | 50 | Yes | Not analyzed | Results for different age groups were not reported | Change in the 6MWD at 6-month follow-up evaluation at 6 months | Positive |
| 26. | Romanov, et al., 2020[104] | PAH (CTEPH) | None | 25 | 48 ± 14 | 48% | 25 | No | Not analyzed | Results in different age groups were not reported | Change in PVR at 12 months | Positive |
| 27. | Chen, et al., 2015[105] | PAH + PH due to LV dysfunction | None | 66 | 52 ± 16 | 41% | No | No | Not analyzed | Results for different age groups were not reported | Changes in hemodynamic, functional, and clinical responses within 1-year | Positive |
| 28. | Rothman, et al., 2020 (THROPHY1)[106] | PAH | None | 23 | 60.0 ± 11.4 | 22% | No | No | Not analyzed | Results for different age groups were not reported | Secondary endpoints: PH worsening, death at 12 months, change in PVR, mean pulmonary artery pressure, right atrial pressure, 6MWD, QoL, NT-pro–BNP, disease-specific medication at 4–6 months | Positive |
| Baroreflex activation therapy | ||||||||||||
| 29. | Gronda, et al., 2014 (BAT in HF)[43] | HFrEF | None | 11 | 67 ± 9 | 72.7% | No | No | Not analyzed | Results for different age groups were not reported | Muscle sympathetic nerve traffic | Positive |
| 30. | Abraham, et al., 2015 (HOPE4HF)[44] | HFrEF | None | 71 | 64 ± 11 | 81.7% | 69 | No | Not analyzed | Results for different age groups were not reported | Three primary efficacy endpoints: changes in NYHA functional class; QoL, and 6MHW | Positive |
| 31. | Zile, et al., 2020 (BeAT-HF)[45] | HFrEF | 42% of BAT subjects ≥65 years old | 130 | 62 ± 11 | 82% | 134 controls in cohort “D” | No | Not analyzed | Difference in effects in patients ≥65 years old was not reported | Three primary effectiveness endpoints: 6MHW, QoL, and NT-proBNP | (1) Positive (6MHW, QoL, NT-proBNP). (2) Neutral in patients with baseline NT-proBNP > 1600 pg/mL (except QoL) |
| 32. | Bisognano, et al., 2011 (Rheos Pivotal Trial)[107] | HTN | None | 181 | 53.7 ± 10.5 | 60% | 84 | No | Not analyzed | Difference in effects in patients ≥65 years old was not reported | Two co-primary efficacy endpoints: 1) acute efficacy; 2) sustained efficacy | (1) Neutral; (2) Positive |
| 33. | Hoppe, et al., 2012 (Barostim neo trial)[108] | HTN | None | 30 | 57 ± 12 | 46.7% | No | No | Not analyzed | Difference in effects in patients ≥65 years old was not reported | Office systolic blood pressure | Positive |
| 34. | de Leeuw, et al., 2017 (US Rheos Feasibility, DEBuT-HT, Rheos Pivotal)[25] | HTN | None | 383 | 53 ± 10 | 60% | No | No | Yes | Diastolic BP was reduced to a lesser extent in patients > 60 years of age, but these patients already had a lower diastolic pressure at the start of the study | Blood pressure reduction at 6 years | Positive |
| 35. | Beige, et al., 2017[109] | HTN | None | 16 patients with therapy withdrawal after a period of BAT therapy | 56.5 ± 14.4 | 76% | No | No | Not analyzed | Difference in effects in patients ≥65 years old was not reported | Automated office blood pressure | Positive |
| Vagus nerve invasive stimulation | ||||||||||||
| 36. | Schwartz, et al., 2008[36] | HFrEF | None | 8 | 54.1 ± 11.5 (31–70) | 100% | No | No | Not analyzed | Difference in effects in age groups was not reported | Changes in NYHA functional class, QoL, exercise capacity, LVESV, LVEDV, LVEF | Positive |
| 37. | De Ferrari, et al., 2011 (CardioFit trial)[37] | HFrEF | None | 32 | 56 ± 11 | 94% | No | No | Not analyzed | Difference in effects in age groups was not reported | NYHA class, QoL, 6MWT, LVEF, LVEDV, LVESV | Positive |
| 38. | Dicarlo, et al., 2013[38]; Premchand, et al., 2015[39] (ANTHEM-HF) | HFrEF | None | 60 | 51.5 ± 12.2 | 87% | No | No | Not analyzed | Difference in effects in age groups was not reported | Changes in LVEF and LVESV | No statistical data presented |
| 39. | Zannad, et al., 2015; De Ferrari, et al., 2017 (NECTAR-HF)[40,41] | HFrEF | None | 63 | 59.8 ± 12.2 | 89% | 32 | No | Not analyzed | Difference in effects in age groups was not reported | LVESD change | Neutral |
| 40. | Gold, et al., 2016 (INOVATE-HF)[42] | HFrEF | None | 436 | 61.7 ± 10.5 | 77.8% | 271 | No | Not analyzed | Difference in effects in age groups was not reported | Death or heart failure events | Neutral |
| Vagus nerve non-invasive stimulation | ||||||||||||
| 41. | Stavrakis, et al., 2015[88] | AF | None | 20 | 60.9 ± 7.8 | 75% | 20 | Yes | Not analyzed | Difference in effects in age groups was not reported | Pacing-induced AF duration | Positive |
| 42. | Stavrakis, et al., 2020 (TREAT AF)[73] | AF | None | 26 | 65.2 ± 14.5 | 46% | 27 | Yes | Not analyzed | Difference in effects in age groups was not reported | AF burden | Positive |
| 43. | Yu, et al., 2017[89] | Ischemia and reperfusion injury | None | 47 | 59 ± 11 | 78.7% | 48 | Yes | Not analyzed | Difference in effects in age groups was not reported | Myocardial ischemia-reperfusion injury | Positive |
| 44. | Bretherton, et al., 2019[90] | Heart rate variability, QoL, mood and sleep in subjects > 55 years | None | 26 patients in Study-3 | 64.12 (1.02) | 35% | No | No | Not analyzed | Difference in effects in age groups was not reported | Autonomic function, QoL, mood, sleep | Positive in subjects with baseline parameters deviation |
| Splanchnic nerve | ||||||||||||
| 45. | Fudim, et al., 2018[48] | Acute decompensated heart failure | None | 11 | 64 ± 13 | 80% | No | No | Not analyzed | Difference in effects in age groups was not reported | Hemodynamic changes | Positive |
| 46. | Fudim, et al., 2018[49] | Acute heart failure | None | 5 | 56 | 55% | No | No | Not analyzed | Difference in effects in age groups was not reported | Hemodynamic changes | Positive |
| 47. | Fudim, et al., 2020[50] | Chronic heart failure | None | 15 | 58 ± 13 | 53% | No | No | Not analyzed | Difference in effects in age groups was not reported | Cardiac output and exercise capacity | Positive |
| Spinal cord invasive stimulation | ||||||||||||
| 48. | Bondesson, et al., 2008[110] | Angina | None | 44 | 69 (54–87) | 82% | No | No | Not analyzed | Difference in effects in age groups was not reported | Glyceryl trinitrate usage and Canadian Cardiovascular Society classification | Positive |
| 49. | DeJongste, et al., 1994[111] | Angina | None | 17 (8 treatment; 9 control) | 62.5 ± 2.6 | 88% | No | No | Not analyzed | Difference in effects in age groups was not reported | Exercise tolerance test and QoL | Positive |
| 50. | Eddicks, et al., 2006[112] | Angina | None | 12 (patients were randomly assigned to different study phases, including a placebo phase) | 65 ± 8 | 66.7% | No | Yes | Not analyzed | Difference in effects in age groups was not reported | Functional status and symptoms | Positive in conventional or subthreshold stimulation |
| 51. | Greco, et al., 1999[113] | Angina | None | 23 | 69 ± 11 (38–83) | NA | No | No | Not analyzed | Difference in effects in age groups was not reported | Number of angina episodes | Positive |
| 52. | Hautvast, et al., 1998[114] | Angina | Only ≤ 75 years old were included | 13 | 62 ± 8 | 46% | 12 | Yes | Not analyzed | Difference in effects in age groups was not reported | Exercise duration, time to angina, anginal attacks, nitrate consumption, number of ischemic episodes | Positive |
| 53. | Lanza, et al., 2010[115] | Angina | None | 10 with high-voltage stimulation; 7 with low-voltage stimulation |
67.5 ± 13 | 78% | 8 | Yes | Not analyzed | Difference in effects in age groups was not reported | Angina episodes, nitroglycerin use, angina class, quality of life | Positive in the treatment “paresthetic” arm |
| 54. | Mannheimer, et al., 1988[116] | Angina | None | 10 | 51–74 years | 80% | No | No | Not analyzed | Difference in effects in age groups was not reported | Exercise tolerance test | Positive |
| 55. | McNab, et al., 2006[117] | Angina | None | 32 | 64.2 ± 7.3 | 85% | 33 (laser revascularization) | No | Not analyzed | Difference in effects in age groups was not reported | Time to angina during Exercise tolerance test | Positive |
| 56. | Jesserun, et al., 1999[118] | Angina | None | 26 | 61.3 ± 7 | 50% | No | No | Not analyzed | Difference in effects in age groups was not reported | QoL | Positive |
| 57. | Zipes, et al., 2012 (STARTSTIM)[119] | Angina | None | 32 (high stimulation) | 61.3 ± 9.1 (high stimulation) and 60.9 ± 12.1 (low stimulation) | 75% | 36 (low stimulation) | Yes (high- and low-stimulation groups) | Not analyzed | Difference in effects in age groups was not reported | Number of angina attacks | Neutral |
| 58. | Tse, et al., 2015 (SCS HEART study)[46] | Heart failure (HFrEF) | None | 17 | 62.9 ± 10.1 | 100% | 4 | No | Not analyzed | Difference in effects in age groups was not reported | Heart failure symptoms, functional status, and LV function and remodeling | Positive |
| 59. | Zipes, et al., 2016 (DEFEAT-HF study)[47] | Heart failure (HFrEF) | Treatment arm was younger that controls | 42 | 58 ± 11 | 76.2% | 24 | Yes | Not analyzed | Difference in effects in age groups was not reported | Heart failure metrics: heart size, biomarkers, functional capacity, and symptoms | Neutral |
| GP ablation* | ||||||||||||
| 60. | Barta, et al., 2017[79] | AF (surgical epicardial ablation) | None | 35 (PV isolation+GP ablation) | 69 ± 6.4 | 51% | 65 (PV isolation only) | No | Not analyzed | Difference in effects in age groups was not reported | Duration of sinus rhythm during 1 year | Neutral |
| 61. | Driessen, et al., 2016 (AFACT study)[80] | AF (surgical epicardial ablation) | Age ≥65 years – 28% of patients | 117 (PV isolation+GP ablation) | 60.2 ± 8.2 | 73% | 123 (PV isolation only) | No | Analyzed effects in patients <65 years and > 65 years old | No difference in effects between age groups | AF recurrence at 1 year | Neutral. More complications in the treatment arm. |
| 62. | Gelsomino, et al., 2016[81] | AF (surgical MAZE IV with or without epicardial GP ablation) | None | 213 (PV isolation+GP ablation) | 63 ± 7 | 64% | 306 (PV isolation only) | No | Not analyzed | Difference in effects in age groups was not reported | AF-freedom (median follow-up 36.7 months) | Neutral |
| 63. | Katritsis, et al., 2013[83] | AF (catheter ablation) | None | 82 (PV isolation+GP ablation) | 56 ± 8.1 | 60%, 70% | 78 (PV isolation only) | No | Not analyzed | Difference in effects in age groups was not reported | AF-freedom during 2 years of follow-up | Positive |
| 64. | Mikhaylov, et al., 2011[82] | AF (catheter ablation) | Age <65 years only | 35 (GP ablation only) | 56.9 ± 10.1 | 51% | 35 (PV isolation only) | No | Only patients <65 years were included | Difference in effects in age groups was not reported | AF-freedom at 3 years | Negative |
| 65. | Onorati, et al., 2008[84] | AF (surgical ablation) | Age > 65 years – 47.7% | 31 (mini-Maze procedure+GP ablation) | 64.2 ± 9.8 | 75% | 44 (mini-Maze procedure only) | No | Not analyzed | Difference in effects in age groups was not reported | AF-freedom at 3 months following amiodarone stop | Positive |
| Spinal cord non-invasive stimulation | ||||||||||||
| 66. | Mikhaylov, et al., 2020[61] | Blood pressure control (no structural heart disease) | None | 9 | 58 ± 12 | 55% | No | No | Not analyzed | Difference in effects in age groups was not reported | BP elevation; atrioventricular refractoriness change | Positive |
| 67. | Phillips, et al., 2018[60] | Orthostatic hypotension (spinal trauma) | None | 5 | 23–32 years old | 75% | No | No | Not analyzed | Difference in effects in age groups was not reported | BP correction | Positive |