Table 2.
Randomized trials of antihypertensive medications for the prevention of CV events in CKD
| Trial | Intervention | Comparator | Duration (y) | Event no. in CKD | Sample (mean eGFR±SD) | Outcome events |
|---|---|---|---|---|---|---|
| NDD-CKD | ||||||
| RAAS blockade vs. control | ||||||
| RENAAL21 (2001) | Losartan | Placebo | 3.4 | 515 | 1,513 DM pts w/ACR >30 mg/g ×2 & SCr 1.3–3.0 (eGFR NR) | Secondary outcome (CV death, MI, stroke, CHF, unstable angina, or revascularization): risk reduction, 10% (P=0.26) |
| PREVEND IT26 (2004) | Fosinopril | Placebo | 3.8 | 45 | 864 w/ACR >15 in NL (eGFR NR) | Primary outcome (CV death, MI, CHF, PVD, or stroke): HR, 0.60 (0.33–1.10) |
| DIABHYCAR27 (2004) | Ramipril | Placebo | 4.0 | 739 | 4,912 T2DM pts w/albuminuria ≥20 mg/L (eGFR NR) | Primary outcome (CV death, MI, stroke, CHF, or ESRD): HR, 1.03 (0.89–1.20) |
| HOPE CKD subgroup22 (2001) | Ramipril | Placebo | 4.5 | 218 | 9,287 w/vascular disease or DM, of which 980 w/sCr 1.4–2.3 (eGFR NR) | Primary outcome (CV death, MI, or stroke: HR, 0.80 (0.59–1.09) HRs in CKD: 0.59 (0.39–0.91) for CV death, 0.78 (0.54–1.11) for MI, 0.83 (0.44–1.56) for stroke |
| SAVE CKD subgroup23 (2004) | Captopril | Placebo | 3.5 | 327 | 2,183 post-MI pts w/LVEF ≤40 & sCr<2.5 (70.0±20.7), of which 719 w/eGFR <60 | Primary outcome (CV morbidity & mortality): RR in CKD, 0.69 (0.55–0.86) |
| PEACE CKD subgroup24 (2006) | Trandolapril | Placebo | 5.0 | 161 | 8,290 w/CAD (77.6±19.4), of which 1,355 w/eGFR <60 | Primary outcome (all-cause death): HR in CKD, 0.73 (0.54–1.00); P=0.05 |
| PROGRESS CKD subgroup25 (2007) | Perindopril | Placebo | 5.0 | 400 | 6,105 w/CBVD, of which 1,757 w/CrCl <60 (eGFR NR) | Primary outcome (CV death, MI, or stroke): RR in CrCl <60, 0.70 (0.58–0.86); NNT for 5 y=11 |
| ADVANCE CKD subgroup28 (2007) | Perindopril-indapamide | Placebo | 4.3 | 742 | 11,140 T2DM pts, of which 2,862 w/ACR 30-300, 401 w/ACR >300 (eGFR NR) | Primary outcome: major macrovascular (CV death, MI, stroke) or microvascular (incident albuminuria, Scr doubling, ESRD) events: RRs of 0.92 (0.81–1.04) for total study & 1.01 (0.82–1.23) for those w/history of microvascular disease |
| Calcium channel blockers vs. control | ||||||
| BENEDICT-B35 (2011) | Verapamil + trandolapril | Trandolapril alone | 4.5 | 41 | 281 T2DM pts w/HTN & microalbuminuria (eGFR NR) | Major CV events: HR, 0.93 (0.50–1.72) |
| Head-to-head trials of antihypertensive classes | ||||||
| NEPHRON D30 (2013) | Losartan + lisinopril | Losartan | 2.2 | 270 | 1,448 T2DM pts w/eGFR 30–90 & ACR >300 (53.7±16.2 vs. 53.6±15.5) | Tertiary outcome (MI, CHF, or stroke): HR, 0.97 (0.76–1.23) |
| CASE-J CKD subgroup37 (2009) | Candesartan | Amlodipine | 3.2 | 201 | 2,720 JP pts w/HTN & eGFR <60 or dipstick proteinuria (mean eGFR NR) | Primary outcome (CV death, MI, or stroke): HRs of 0.95 (0.72–1.25) overall, 1.24 (0.61–2.54) for CKD1-2, 1.01 (0.73–1.40) for CKD3, 0.45 (0.20–1.00) for CKD4; P=0.048 |
| ONTARGET subgroup29 (2011) | Telmisartan + ramipril | Telmisartan or ramipril | 4.7 | 1,281 in eGFR <60; 902 in ACR 30-300; 403 in ACR >300 | 5,623 w/eGFR <60, of which 3,809 w/ACR 30-300, 1,287 ACR >300 (50.2±8.1) | Primary outcome (CV death, MI, stroke, or CHF): HRs of 0.99 (0.88-1.12) for eGFR <60, 1.02 (0.89-1.17) for ACR 30-300, 0.90 (0.73-1.12) for ACR >300 |
| ALLHAT CKD subgroup34 (2012) | Amlodipine | Chlorthalidone | 8.8 | 984 CV death, 622 CHD, 1,353 CVD | 31,350 HTN pts w/>=1 other CV risk factor, of which 5,545 w/eGFR <60 (50.6±8.5 vs 50.1±8.7) | HRs of 1.01 (0.82-1.23) for CV death in eGFR <60, 0.86 (0.66-1.11) for CHD in eGFR <60, 1.04 (0.88-1.24) for CVD in eGFR <60 |
| ALLHAT subgroup34 (2012) | Lisinopril | Chlorthalidone | 8.8 | 973 CV death, 643 CHD, 1,534 CVD | 31,350 HTN pts w/>=1 other CV risk factor, of which 5,545 w/eGFR <60 (50.1±8.6 vs. 50.1±8.7) | HRs of 0.90 (0.73-1.11) for CV death in eGFR <60, 0.92 (0.72-1.19) for CHD in eGFR <60, 0.99 (0.83-1.18) for CVD in eGFR <60 |
| COPE subgroup36 (2013) | Beta blocker (various) | ARB (various) | 3.6 | 17 | 3,501 HTN pts on benidipine, of which 834 w/CKD3 (58.7±15.2) | Composite CV secondary outcome (CV death, MI, or stroke): HR in CKD, 0.92 (0.36-2.40) |
| COPE subgroup36 (2013) | ARB (various) | Thiazide diuretic (various) | 3.6 | 16 | 3,501 HTN pts on benidipine, of which 834 w/CKD3 (58.7±15.2) | Composite CV secondary outcome (CV death, MI, or stroke): HR in CKD, 1.19 (0.44-3.20) |
| COPE subgroup36 (2013) | Beta blocker (various) | Thiazide diuretic (various) | 3.6 | 15 | 3,501 HTN pts on benidipine, of which 834 w/CKD3 (58.7±15.2) | Composite CV secondary outcome (CV death, MI, or stroke): HR in CKD, 1.10 (0.40-3.04) |
| OSCAR subgroup38 (2013) | ARB uptitration | ARB plus CCB combination | 3.0 | 46 | 1,164 elderly JP HTN pts (67.2±18.7), of which 353 w/eGFR <60 (47.3±8.9 vs. 48.3±9.3) | Primary outcome (all-cause death and CV events): HR in CKD, 2.25 (1.20-4.20) |
| CKD-5D | ||||||
| RAAS blockade vs. control | ||||||
| Zannad, et al., FOSDIAL42 (2006) | Fosinopril | Placebo | 2.0 | 130 | 397 prevalent HD pts | Primary outcome (CV death, resuscitated death, stroke, CHF, MI, or revascularization): RR, 0.93 (0.68-1.26); BP same between groups |
| Takahashi, et al.39 (2006) | Candesartan | Nothing | 3.0 | 24 | 80 prevalent HD pts | Primary outcome (sudden death, MI, unstable angina, CHF, or severe arrhythmia): OR, 0.23 (0.08-0.67) |
| Suzuki, et al.40 (2008) | Various ARBs | No ARB | 3.0 | 93 | 360 prevalent HD pts | Primary outcome (CV death, MI, stroke, CHF, or revascularization): HR, 0.51 (0.33-0.79); BP same between groups |
| Cice, et al.41 (2010) | Telmisartan | Placebo | 3.0 | 149 all-cause death, 123 CV death | 332 prevalent HD pts already taking ACEi | Primary outcomes (all-cause death; CV death; CHF): HRs of 0.51 (0.32-0.82) for All-cause death, 0.42 (0.38-0.61) for CV death |
| Iseki, et al., OCTOPUS43 (2013) | Olmesartan | No ACEi/ARB | 3.5 | 135 | 469 prevalent JP HD pts | Primary outcome (death, stroke, MI, or coronary revascularization): HR, 1.00 (0.71-1.40); BP same between groups |
| Matsumoto, et al.44 (2014) | Spironolactone | Nothing | 3.0 | 32 | 309 prevalent HD pts | Primary outcome (CV death or hospitalization for CV event): HR, 0.38 (0.17-0.83) |
| Lin, et al.45 (2016) | Spironolactone | Placebo | 2.0 | 32 | 253 prevalent HD pts | Primary outcome (CV death or aborted cardiac arrest): HR, 0.42 (0.26-0.78) |
| Beta blockers vs. control | ||||||
| Cice, et al.46 (2003) | Carvedilol | Placebo | 2.0 | 71 All-cause death, 55 CV death, 1 MI | 114 prevalent HD pts w/dilated cardiomyopathy | Primary outcomes: LV end systolic and diastolic volume and EF Secondary outcomes: HRs of 0.51 (0.32-0.82) for All-cause death, 0.32 (0.18-0.57) for CV death, 0.81 (0.61-1.34) for MI BP lower in carvedilol vs placebo |
| Calcium channel blockers vs. control | ||||||
| Tepel, et al.47 (2008) | Amlodipine | Placebo | 4.0 | 51 | 251 prevalent HD pts w/HTN | Primary outcome: all-cause death HR for CV event or all-cause death: 0.55 (0.31-0.97) BP lower in amlodipine vs placebo |
| Head-to-head trials of antihypertensive classes | ||||||
| Agarwal, et al.16(2014) | Lisinopril | Atenolol | 1.0 | 34 | 200 prevalent HD pts w/HTN and LVH | Primary outcome: change in LVMI Serious adverse events: HR of 2.29 (1.07-5.21) for MI, stroke, CV death, CHF (outcome worse in lisinopril group) |
Abbreviations: OR, odds ratio (values in parenthese are 95% confidence intrvals); ACEi, angiotensin converting enzyme inhibitor; ACR, urinary albumin-creatinine ratio (in mg/g); ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ARB, angiotensin receptor blocker; BENEDICT-B, Bergamo Nephrologic Diabetes Complications Trial-B; BP, blood pressure; CAD, coronary artery disease; CASE-J, Candesartan Antihypertensive Survival Evaluation in Japan; CHD, coronary heart disease; CHF, congestive heart failure; CKD-5D, dialysis-dependent chronic kidney disease; COPE, Combination Therapy of Hypertension to Prevent Cardiovascular Events; CrCl, creatinine clearance; CV, cardiovascular; DIABHYCAR, Non-insulin dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); ESRD, end-stage renal disease; FOSDIAL, Fosinopril in Dialysis; HD, hemodialysis; HOPE, Heart Outcomes and Prevention Evaluation; HR, hazard ratio (values in parentheses are 95% confidence intervals); LVEF, left ventricular ejection fraction; MI, myocardial infarction; NDD-CKD, non-dialysis-dependent chronic kidney disease; NNT, number needed to treat; NR, not reported; OCTOPUS, Olmesartan Clinical Trial in Okinawan Patients Under OKIDS; OSCAR, Olmesartan and Calcium Antagonists Randomized; PEACE, Prevention of Events with ACE inhibition; PREVEND IT, Prevention of Renal and Vascular Endstage Disease Intervention Trial; PROGRESS, Perindopril Protection against Recurrent Stroke Study; PVD, peripheral vascular disease; RR, relative risk (values in parenthese are 95% confidence intrvals); SAVE, Survival and Ventricular Enlargement; sCr, serum creatinine (in mg/dL); SD, standard deviation; CBVD, cerebrovascular disease; pts, patients; NL, Netherlands; T2DM, type 2 diabetes mellitus; HTN, hypertension; JP, Japanese; LV, left ventricular; EF, ejection fraction; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index