Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet 2015; published online Nov 6. http://dx.doi.org/10.1016/ S0140-6736(15)00805-3.
Supplementary material Table S1: Characteristics of included studies Table S2: Quality analyses of the trials included in the systematic review and meta-analysis Table S3: Univariate meta-regression of intensive blood pressure lowering on major cardiovascular outcomes Table S4: PRISMA checklist. Figure S1 Effect of intensive vs less intensive BP lowering on the risk of other major vascular events, renal outcomes, and mortality ESKD: end stage kidney disease. Text S1: Search strategy 1
Table 1: Characteristics of included studies Inclusion criteria Study design and country of origin Baseline BP BP target (mm Hg) in active group (mm Hg) BP target in control group (mm Hg) BP achieved in active group (mm Hg) BP achieved in control group (mm Hg) BP target met for most in active group BP target met for most in control group Difference in BP reduction (mmhg) Follow-up (years) Patients (n) Mean age (years) Female patients (%) Diabetes mellitus Primary endpoint Met primary endpoint (n) Major CV Definition of events (n) major CV event Toto et al (1995) 13 Hypertensive Randomised nephrosclerosi unspecified s with serum number of creatinine >1 6 centres; mg/dl or GFR USA <70 ml/min/1 73 m 2 123 1/76 5 DBP 65 80 DBP 85 95 133/81 138/87 No Yes 5/ 6 3 4 77 55 7 37 7% Excluded Rate of decline in GFR NA (9 in ESKD) NR NR HOT trial (1998) 14 Hypertension with DBP 100 115 mm Hg Randomised multicentre; Sweden, Italy, Canada, USA, France, and Germany 169 7/105 4 DBP <80 DBP <85 or <90 139 7/81 1 142 55/82 2 No No 2 9/ 3 1 3 8 18 790 61 5 47% 1501 (8%) Major CV event 683 683 CV death, nonfatal MI/stroke UKPDS-HDS (1998) 15 Newly diagnosed type 2 diabetes with hypertension Randomised 159 3/94 0 BP multicentre; <150/85 UK BP<180/105 144/82 154/87 Yes Yes 10/ 5 8 4 1148 56 44 5% 1148 (100%) a: clinical endpoint related to diabetes; b: death related to diabetes;c: a: 429; b: 144; c: 217 271 CV death, nonfatal MI/stroke 2
death from any cause ABCD (H) study (2000) 16 ABCD (N) study (2001) 17 Type 2 diabetes with DBP 90 mm Hg Type 2 diabetes with normotension (DBP 80 89 mm Hg) Randomised multicentre; USA 155/98 DBP <75 DBP 80 89 132/78 138/86 No Yes 6/ 8 5 470 57 9 32 6% 470 (100%) Change in creatinine clearance Randomised 136 4/84 4 DBP multicentre; reduction USA 10 mm Hg from baseline DBP 80 89 128/75 137/81 Yes Yes 9/ 6 5 3 480 59 1 45 5% 480 (100%) Change in creatinine clearance NA 75 CV death, nonfatal MI/stroke, admission for heart failure NA 76 CV death, nonfatal MI/stroke, admission for heart failure Schrier et al (2002) 18 Autosomal dominant polycystic kidney disease patients with hypertension, left ventricular hypertrophy, and creatinine clearance >30 ml/min/1 73 m 2 Randomised 142 5/95 5 <120/80 135 140/85 single 90 centre; USA NA NA NA NA NA 7 75 41 1 45% NR Not specified NA NA NA AASK 2010 19 African American with hypertension and GFR 20 65 ml/min/1 73 m 2 and no other Randomised multicentre; USA 150 5/95 5 Mean BP <92 Mean BP 102 128/78 141/85 No Yes 13/ 7 8 8 to 107 12 8 1094 54 6 38 8% Excluded Doubling of serum creatinine, end-stage kidney disease, or death 567 225 CV death, nonfatal MI/stroke, admission for heart failure 3
identified causes of renal insufficiency MDRD (2005) 20 Chronic kidney disease with serum creatinine 1 4 7 0 mg/dl in men or 1 2 7 0 mg/dl in women Randomised multicentre; USA 130 5/80 0 Mean BP <92 Mean BP <107 126 2/76 9 133 8/80 7 No Yes 7 6/ 3 8 2 2 840 51 7 40% 43 (5 1%) Rate of decline in GFR NR NR NR REIN-2 (2005) 21 Non-diabetic Randomised 136 7/84 1 BP nephropathy with proteinuria 1 3 g/day and GFR <45 ml/min/1 73 m 2 or proteinuria >3 g/day and GFR <70 ml/min/1 73 m 2 multicentre; Italy <130/80 DBP <90 129 6/79 5 133 7/82 3 Yes Yes 4 1/2 8 1 6 338 53 9 25 7% Excluded ESKD 72 9 CV death nonfatal MI/stroke, admission for heart failure ABCD (2V) (2006) 22 Type 2 diabetic patients with BP <140/80 90 mm Hg without overt albuminuria Randomised single centre; USA 126/84 DBP <75 DBP <90 118/75 124/80 No Yes 6/ 5 1 9 129 56 1 32 6% 129 (100%) Change of creatinine clearance and UAE NA 5 NR 4
JATOS (2008) 23 Cardio-Sis (2009) 24 ESCAPE (2009) 25 Elderly hypertensive patients aged 65 85 years and SBP >160 mm Hg Non-diabetic patients with SBP >150 mm Hg and at least one additional risk factor Chronic kidney disease in children aged 3 18 years and GFR 15 80 ml/min/1 73 m 2 whose 24- h mean BP elevated or controlled by antihypertensi ve agents Randomised multicentre; Japan Randomised multicentre; Italy Randomised multicentre; Germany,Ita ly, Poland, Turkey, France, and Switzerland 171 6/89 1 SBP <140 SBP <160 135 9/74 8 145 6/78 1 Yes Yes 9 7/ 3 3 2 4418 73 6 61 1% 521 (11 8%) Cardiovascul ar event and renal failure 172 100 CV death, nonfatal stroke, and non-fatal MI 163 0/89 6 SBP <130 SBP <140 131 9/77 4 135 6/78 7 No Yes 3 8/ 1 5 2 1111 67 59% Excuded Electrocardi 137 49 Death, MI, ographic left ventricular hypertrophy hospital admission for heart failure, angina or coronary revascularisati on 118 3/73 0 24-h mean BP below the 50th percentile 24-h mean BP in the 50 95th percentile 63 8±14 0# 64 8±12 5# Yes Yes NA 5 385 11 5 41% NR Decline of 50% in GFR or ESKD 115 NR NR ACCORD (2010) 6 Type 2 Randomised 139 2/76 0 SBP <120 SBP <140 119 3/64 4 133 5/70 5 Yes Yes 14 2/ 6 7 4 7 4733 62 2 47 7% 4733 diabetic patients with 40 years older and cardiovascular multicentre; USA, Canada (100%) Major CV event 439 439 CV death, nonfatal stroke, and non-fatal MI 5
disease or 55 years older with risk factors for cardiovascular disease VALISH (2010) 26 Age 70 and Randomised 85 years with multicentre; isolated Japan systolic hypertension (BP >160 mm Hg systolic and <90 mm Hg diastolic) 169 6/81 4 SBP <140 SBP 140 150 136 6/74 8 142 0 /76 5 Yes Yes 5 4/ 1 7 2 85 3260 76 1 62 5% NR Composite of CV event and renal dysfunction 99 69 CV death, nonfatal stroke, and non-fatal MI HOMED-BP (2012) 8 Age 40 years with mild-tomoderate hypertension Randomised 151 6/89 95 BP multicentre; <125/80 Japan BP 125 134/80 84 128 8/76 1 130 4/76 8 No No 1 3/ 0 8 5 31 3518 59 6 50 1% 538 (15 3%) Composite of cardiovascul ar death, non-fatal stroke and non-fatal myocardial infarction 51 106 CV death, nonfatal stroke, non-fatal MI, non-fatal stroke, transient ischaemic attack, angina pectoris, coronary therosclerosis and fatal and non-fatal heart failure SPS3 (2013) 9 Age 40 years with normotensive or Randomised 143 0 /78 5 SBP <130 SBP 130 149 127 138 Yes Yes 11/NA 3 7 3020 63 37% 1106 multicentre/ North America, (36 3%) All stroke 277 348 Both intracerebral and other, and one as both 6
hypertensive had lacunar stroke Latin America, and Spain between intracerebral and subdural or epidural Wei et al (2 013) 10 Age 70 years Randomised 159 5/84 2 BP with multicentre/ 140/90 BP >150/90 China mm Hg or with hypertension currently receiving antihypertensi ve treatment BP 150/90 135 7/76 2 149 7/82 1 Yes Yes 14 0 / 5 9 4 724 76 6 33 7% 169 (23 3%) Fatal/nonfatal stroke, 107 107 Fatal/non-fatal stroke, acute acute myoca rdial infarction, MI, and other cardiovascular deaths and other cardiovascul ar deaths PAST-BP (2015)* Transient ischaemic attack/stroke register Randomised multicentre/ England 142 8/79 8 SBP <130 or a 10 mm Hg reduction if baseline SBP <140 SBP <140 127 4/72 129 4/74 4 Yes Yes 2 0 / 2 4 1 379 72 6 39 6% 40 (10 6%) Major CV events emergency hospital admissions and deaths 6 6 Fatal and nonfatal stroke, MI, fatal coronary heart disease, or other cardiovascular death All trials 158 5/92 2 133 2/76 4 140 4/80 9 Yes in Yes in 16 10 trials trials 6 8/ 3 5 3 8 44 989 63 1 43 8% 11 279 (25 1%) All primary endpoint events 3160 2556 All major CV events Most/all 160 7/93 4 133 3/76 4 140 5/80 9 Yes in 9 Yes in 14 patients with hypertensio n trials trials 6 7/ 3 5 3 8 44 380 63 2 43 8% 10 669 (24 0%) All primary endpoint events 3160 2480 Major CV events 7
Most/all 134 2/84 3 125 8/75 0 142 2/73 0 Yes in 1 Yes in 2 patients without hypertensio n trial trials 8 3/ 5 8 4 6 609 58 4 42 7% 609 (100%) All primary endpoint events 0 76 Major CV events Patients 136 2/77 8 126 5/71 8 136 7/76 7 Yes in 7 Yes in 12 with diabetes, renal disease, or cardiovascul ar disease trials trials 11 2/ 5 7 4 4 21 570 58 7% 41 9% 8148 (61 9%) All primary endpoint events 1911 1435 Major CV events Most/all 167 7/98 3 136 7/78 2 141 7/81 9 Yes in 3 Yes in 4 patients without diabetes, renal disease, or cardiovascul ar trials trials 6 2/ 3 9 3 6 23 419 65 0 44 6 3130 (9 8%) All primary endpoint events 1249 1121 Major CV events BP=blood pressure. CV=cardiovascular. DBP=diastolic blood pressure. GFR=glomerular filtration rate. ESKD=end-stage kidney disease. NA= not Available. NR=not reported. MI=myocardial infarction. SBP=systolic blood pressure. * personal communication from J Mant. # means Mean±SDs 8
Table S2: Quality analyses of the trials included in the systematic review and meta-analysis Study/author (year) Adequate sequence generation Allocation concealment Outcome assessors Blinding Personnel Participants Incomplete outcome data addressed Free of selective outcome reporting Toto (1995) unclear unclear unclear no no unclear unclear HOT (1998) yes yes yes no no unclear yes UKPDS-HDS (1998) yes yes yes no no unclear yes ABCD (H) (2000) yes yes yes no yes unclear yes ABCD (N) (2001) yes yes yes no yes unclear yes AASK (2010) yes yes yes no no yes yes MDRD (2005) yes yes unclear no no yes yes REIN-2 (2005) yes yes ns no no yes unclear ABCD (2V) (2006) yes yes yes no yes yes unclear JATOS (2008) yes yes yes no no yes unclear Cardio-Sis (2009) yes yes yes no no yes yes 9
ESCAPE (2009) yes ns unclear no no yes unclear ACCORD (2010) unclear yes unclear no no unclear yes VANLISH (2010) Yes Unclear yes no no Yes Yes HOMED-BP(2012) yes unclear yes no no yes yes SPS3(2013) yes yes yes no no yes yes Yong Wei(2013) yes unclear yes no no yes yes PAST-BP(2015) yes yes yes no no no yes * The ABCD 2V study was terminated after 5 years due to the funding constrains. Table S3: Univariate meta-regression of intensive blood pressure lowering on major cardiovascular outcomes Proportional change in Variable Studies Scale risk ratio (95% CI) p-value Patients 14 per 100 1.0008(0.9987-1.0028) 0.43 Cardiovascular event rate (per person-year) 14 per 1% 1.0043(0.9180-1.0987) 0.92 Follow-up 14 per year 0.9591(0.9026-1.0192) 0.16 Age 14 per 10 year 0.9382(0.7810-1.1270) 0.46 Baseline systolic blood pressure 14 per 1 mmhg 0.9985 (0.9882-1.0088) 0.75 10
Table S4: PRISMA checklist. Section/topic # Checklist item TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. 1 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 1 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Reported on page # 1 1 Page 2 and review protocol in Text S2 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Page 2 and Text S2 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). 2 2 Page 2 Figure 1 Page 11 of 25
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 2 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis. Section/topic # Checklist item Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Page 2 and Figure 1 Page 2 2 and Table S2 2 Reported on page # 2 2 Page 3 and Figure 1 Page 3 Table S1 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Page 3 Table S2 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Page 3-5 Figure 2-3 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Page 3-5 Figure 2-3 Page 12 of 25
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). Table S2 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). Page 6-7 Figure 4 Table S3 DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 8 7 7-8 FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. 3 Page 13 of 25
Figure S1a Effect of intensive vs less intensive BP lowering on the risk of heart failure. Page 14 of 25
Figure S1b Effect of intensive vs less intensive BP lowering on the risk of ESKD Page 15 of 25
Figure S1c Effect of intensive vs less intensive BP lowering on the risk of albuminuria Page 16 of 25
Figure S1d Effect of intensive vs less intensive BP lowering on the risk of retinopathy progression. Page 17 of 25
Figure S1e Effect of intensive vs less intensive BP lowering on the risk of cardiovascular death. Page 18 of 25
Figure S1f Effect of intensive vs less intensive BP lowering on the risk of non-cardiovascular death. Page 19 of 25
Figure S1g Effect of intensive vs less intensive BP lowering on the risk of mortality. Page 20 of 25
Text S1: Search Strategy MEDLINE (OVID) AND 1. exp antihypertensive agents/ 2. (antihypertensive$ adj (agent$ or drug)).tw. 3. chlorothiazide.tw. 4. chlorthalidone.tw. 5. hydralazine.tw. 6. hydrochlorothiazide.tw. 7. indapamide.tw. 8. minoxidil.tw. 9. exp angiotensin converting enzyme inhibitors/ 10. captopril.tw. 11. enalapril.tw. 12. cilazapril.tw. 13. enalaprilat.tw. 14. fosinopril.tw. 15. lisinopril.tw. 16. perindopril.tw. 17. ramipril.tw. 18. saralasin.tw. 19. teprotide.tw. 20. exp losartan/ 21. losartan.tw. 22. imidazole$.tw. 23. irbesartan.tw. 24. candesartan.tw. 25. eprosartan.tw. 26. valsartan.tw. 27. olmesartan.tw. 28. telmisartan.tw. 29. (ace adj2 inhibitor$).tw. 30. (angiotensin adj2 receptor antagonist$).tw. 31. exp calcium channel blockers/ 32. amlodipine.tw. 33. diltiazem.tw. 34. felodipine.tw. 35. nicardipine.tw. 36. nifedipine.tw. 37. nimodipine.tw. 38. nisoldipine.tw. 39. nitrendipine.tw. 40. verapamil.tw. 41. exp adrenergic beta-antagonists/ 42. alprenolol.tw. 43. atenolol.tw. 43a.carvedilol.tw 43b. bisoprolol.tw 44. metoprolol.tw. Page 21 of 25
45. nadolol.tw. 46. oxprenolol.tw. 47. pindolol.tw. 48. propranolol.tw. 49. exp adrenergic alpha-antagonists/ 50. labetalol.tw. 51. prazosin.tw. 52. beta block$.tw. 53. exp diuretics/ 54. spironolactone.tw. 55. triamterene.tw. 56. bumetanide.tw. 57. furosemide.tw. 58. or/1-57 59.exp Clinical Trial/ 60. exp Random Allocation/ 61. exp Single Blind Method/ 62. exp Double Blind Method/ 63. (random$ adj5 trial$).tw. 64. (random$ adj5 allocation$).tw. 65. (Blind$ adj5 method$).tw. 66. or/59-65 67. (target level).mp 68. (blood pressure adj6 target).mp 69. (BP adj6 target).mp 70. (blood pressure adj6 goal).mp 71. (BP adj6 goal).mp 72. (intensi$ adj6 treatment).mp 73.( intensi$ adj6 control).mp 74.( intensi$ adj6 lowering).mp 75. (intensi$ adj6 blood pressure).mp 76. (intensi$ antihypertensive).mp 77. (tight adj6 control).mp 78. (tight adj6 blood pressure).mp 79. (strict adj6 control).mp 80. (strict adj6 blood pressure).mp 81. or/67-80 82. 58 and 66 and 81 COCHRANE CONTROLLED TRIALS 1. antihypertensive agents explode all trees 2. (antihypertensive$ adj (agent$ or drug)) 3. chlorothiazide 4. chlorthalidone 5. hydralazine 6. hydrochlorothiazide 7. indapamide 8. minoxidil 9. angiotensin converting enzyme inhibitors explode all trees 10. captopril Page 22 of 25
11. enalapril 12. cilazapril 13. enalaprilat 14. fosinopril 15. lisinopril 16. perindopril 17. ramipril 18. saralasin 19. teprotide. 20. losartan explode all trees 21. losartan 22. imidazole 23. irbesartan 24. candesartan 25. eprosartan 26. valsartan 27. olmesartan 28. telmisartan 29. (ace adj2 inhibitor$) 30. (angiotensin adj2 receptor antagonist$) 31. calcium channel blockers explode all trees 32. amlodipine 33. diltiazem 34. felodipine 35. nicardipine 36. nifedipine 37. nimodipine 38. nisoldipine 39. nitrendipine 40. verapamil 41. adrenergic beta-antagonists explode all trees 42. alprenolol 43. atenolol 43a. Carvedilol 43b. bisoprolol 44. metoprolol 45. nadolol 46. oxprenolol 47. pindolol 48. propranolol 49. adrenergic alpha-antagonists explode all trees 50. labetalol 51. prazosin 52. beta block 53. diuretics explode all trees 54. spironolactone 55. triamterene 56. bumetanide 57. furosemide 58. or/1-57 59. (target level).mp 60. (blood pressure adj6 target).mp Page 23 of 25
61. (BP adj6 target).mp 62. (blood pressure adj6 goal).mp 63. (BP adj6 goal).mp 64. (intensi$ adj6 treatment).mp 65.( intensi$ adj6 control).mp 66.( intensi$ adj6 lowering).mp 67. (intensi$ adj6 blood pressure).mp 68. (intensi$ antihypertensive).mp 69. (tight adj6 control).mp 70. (tight adj6 blood pressure).mp 71. (strict adj6 control).mp 72. (strict adj6 blood pressure).mp 73. or/59-72 74. 58 and 73 EMBASE 1. antihypertensive agents 2. chlorothiazide 3. chlorthalidone 4. hydralazine 5. hydrochlorothiazide 6. indapamide 7. minoxidil 8. losartan 8. imidazole 10. irbesartan 11. candesartan 12. eprosartan 13. valsartan 14. olmesartan 15. telmisartan 16. angiotensin converting enzyme inhibitors 17. captopril 18. enalapril 19. fosinopril 20. lisinopril 21. perindopril 22. ramipril 23. saralasin 24. teprotide 25. Angiotensin 2 Receptor Antagonist 26. Angiotensin Receptor Antagonist 27. Angiotensin II Antagonist 28. AT 2 receptor blocker 29. AT 2 receptor antagonist 30. angiotensin receptor antagonist 31. Calcium Channel Blockers 32. amlodipine 33. diltiazem 34. felodipine 35. nicardipine 36. nifedipine Page 24 of 25
37. nimodipine 38. nisoldipine 39. nitrendipine 40. verapamil 41. adrenergic beta-antagonists 42. alprenolol 43. atenolol 44 carvedilol 45. bisoprolol 46. metoprolol 47. nadolol 48. oxprenolol 49. pindolol 50. propranolol 51. adrenergic alpha-antagonists/ 52. labetalol 53. prazosin 54. diuretics 55. spironolactone 56. triamterene 57. bumetanide 58. furosemide 59. clinical and trial 60. randomized and controlled and trial 61. random and allocation 62. single blind and method 63. double blind and method 64. target level 65. target blood pressure 66. Target systolic blood pressure 67. Target diastolic blood pressure 68. Intensive treatment 69. Intensive blood pressure treatment 70. Intensive antihypertensive treatment 71. Intensive control 72. Intensive blood pressure control 73. Tight control 74. Tight blood pressure control 75. Strict control 76. Strict blood pressure control 77. or/1-58 78. or/59-63 79. or/64-76 80. #77 and #78 and #79 Page 25 of 25