| Study | Reason for exclusion |
|---|---|
| ADVANCE 2007 | Randomised controlled trial that includes 11,140 adults with type 2 diabetes at elevated risk of vascular disease. Following 6 weeks on open‐label perindopril‐indapamide combination, eligible individuals were randomised to continued perindopril‐indapamide or matching placebo, and to an intensive gliclazide MR‐based glucose control regimen (aiming for HbA1c of 6.5% or lower) or usual guidelines‐based therapy for a mean of 4·3 years of follow‐up. More than 75% of patients had hypertension at baseline. Excluded because control group included non‐specific antihypertensive therapy |
| ALLHAT 1996 | Head‐to‐head comparison of different drug therapies without a non‐drug control group |
| BENEDICT 2004 | Multi‐centre DBRCT in 1204 patients, 40 years of age or older who had hypertension and a known history of type 2 diabetes mellitus. Eligible patients were randomly assigned to receive one of the study treatments: the non‐dihydropyridine calcium channel blocker verapamil (in a sustained‐release formulation, at a dose of 240 mg per day), the ACE inhibitor trandolapril (2 mg per day), the combination of verapamil (in a sustained‐release formulation, 180 mg per day) plus trandolapril (2 mg per day), or placebo for a median follow‐up of 3.6 years. Additional antihypertensive drugs were allowed, to achieve the target blood pressure of 120/80 mmHg. At baseline, 56% of patients in placebo group received antihypertensive medications; this was increased to 67% of patients at end of follow‐up. Excluded because there is no true placebo group |
| BENEDICT A 2006 | Randomised double‐blind placebo‐controlled study in 590 hypertensive patients (age 30 to 70 years) with type 2 diabetes and microalbuminuria. Patients were randomly assigned to receive irbesartan at a dose of 150 mg once daily, irbesartan at a dose of 300 mg once daily, or matching placebo once daily. There is no true placebo group, as 56% of patients in the placebo group were receiving blood pressure–lowering therapy at the end of 2 years of follow‐up |
| Berglund 1981 | Drug‐drug comparison of bendrofluazide 2.5 mg vs propranolol 160 mg with no placebo or untreated control group |
| CASTEL 1994 | This study was included in the original Mulrow 1998 review. However we excluded it in the first update, as it is a drug‐drug comparison with no placebo or untreated control group. Control group included non‐specific antihypertensive therapy |
| DIABHYCAR 2004 | This is a randomised double‐blind parallel‐group trial comparing ramipril (1.25 mg/d) with placebo (on top of usual treatment) for cardiovascular and renal outcomes for at least 3 years in 4937 patients with type 2 diabetes and high urinary albumin excretion. 56% of patients had hypertension at baseline. There is no true placebo control group |
| EUROPA 2003 | Randomised double‐blind trial conducted in 13,655 patients with previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%), coronary revascularisation (55%), or a positive stress test only (5%). After a run‐in period of 4 weeks, in which all patients received perindopril, 12,218 patients were randomly assigned perindopril 8 mg once daily (n = 6110) or matching placebo (n = 6108). Mean follow‐up was 4·2 years. There is no true placebo group |
| Fuchs 2011 | Randomised double‐blind clinical trial, controlled by placebo in people 30 to 70 years of age with pre‐hypertension. Excluded as people did not have hypertension |
| Generic 2010 | Single‐centre randomised double‐blind placebo‐controlled cross‐over trial comparing effects of moexipril and placebo on insulin sensitivity and 24‐hour blood pressure control in postmenopausal women with essential hypertension. It is not 1 year in duration |
| GENRES 2007 | Prospective randomised double‐blind placebo‐controlled cross‐over study in 208 moderately hypertensive Finnish men (aged 35 to 60 years) treated with 4 weeks of antihypertensive drugs with 4 weeks placebo in between treatment periods. This study does not meet the minimum duration of 52 weeks criterion |
| GLANT 1995 | This study employed alternate allocation (i.e. not random allocation). Drug‐drug comparison of delapril 30 to 120 mg vs several dihydropyridine CCBs with no placebo or untreated control group |
| HAPPHY 1987 | This study is a drug‐drug comparison of bendrofluazide 5 mg or HCTZ 50 mg vs atenolol 100 mg or metoprolol 200 mg with no placebo or untreated control group |
| HDFP 1984 | Based on comments received regarding improper inclusion of this trial in the previous systematic review, we excluded this study because the intervention was multi‐factorial. Treated group included various lifestyle measures in addition to antihypertensive drug therapy. Control group was given usual care and did not necessarily consist of untreated controls |
| Hood 2007 | Placebo‐controlled double‐blind randomised cross‐over trial. Patients received 10 cycles of double‐blind treatment comprising spironolactone 50 to 100 mg, amiloride 20 to 40 mg, bendroflumethiazide 2.5 to 5 mg at the 2 doses shown, losartan 100 mg, and placebo. Order of drugs and doses were randomised, except that higher doses of diuretic and placebo were administered in alternate cycles, and the 2 doses of each diuretic were separated by at least 3 intervening cycles. Each cycle of treatment lasted 5 weeks. There were no washout periods, and the entire study lasted 44 weeks for each patient. Study treatment was not given for minimum duration of 1 year |
| HOPE 3 2016 | Double‐blind RCT of 12,705 women 65 years or older and men 55 years or older with at least 1 CV risk factor, no known CV disease, and without any clear indication or contraindication to the study drugs. Patients were randomised to rosuvastatin 10 mg/d or placebo and to candesartan/ hydrochlorothiazide 16/12.5 mg/d or placebo (22 factorial design) and were followed for a mean of 5.8 years. Persons with a history of hypertension could be enrolled if blood pressure was adequately controlled (in the assessment of the recruiting physician) with lifestyle or drugs other than an ARB, ACE inhibitor, or thiazides. Only 38% of patients had hypertension at baseline; 29% were taking antihypertensive agents (other than ARBs, ACE inhibitors, or thiazides). Participants were allowed open‐label use of ARBs, ACE inhibitors, thiazides, and other blood pressure‐lowering drugs; therefore it was excluded |
| HOT 1995 | RCT that evaluates the effects of achieving prespecified levels of diastolic blood pressure control with all patients receiving antihypertensive treatment. There is no true placebo control group |
| IDM 2001 | This RCT is excluded, as there is no true placebo control group. Patients in the control group (56%) received other antihypertensive drugs |
| IDNT 2003 | Randomised double‐blind placebo‐controlled trial with median follow‐up of 2.6 years in 1715 adults with type 2 diabetic nephropathy and hypertension treated with irbesartan, amlodipine, or placebo. The placebo group received an average of 3.3 non‐study drugs, and the other 2 groups received an average of 3.0 drugs. There was no true placebo control group |
| IMAGINE 2008 | Double‐blind placebo‐controlled study of 2553 patients after CABG who were randomly assigned to quinapril, target dose 40 mg/d, or placebo, and were followed up to a maximum of 43 months. 47% had hypertension at baseline; baseline SBP/DBP was 122/70 mmHg. There was no true placebo control group |
| Imai 2011 | RCT in 577 patients treated with antihypertensive therapy (73.5% (n = 424) received concomitant ACEI) who were given either once‐daily olmesartan (10 to 40 mg) (n = 288) or placebo (n = 289) over 3.2 ± 0.6 years (mean ± SD). 282 received olmesartan and 284 received placebo in addition to conventional antihypertensive therapy. There was no true placebo control group |
| INSIGHT 1996 | This RCT is excluded as there was no placebo or untreated control group |
| Jikei 2007 | This RCT did not truly randomise patients to treatment arms; control group included non‐specific antihypertensive therapy |
| Kondo 2003 | This RCT included patients with a history of coronary intervention and no significant coronary stenosis on follow‐up angiography 6 months after intervention. Patients were randomly assigned to a candesartan group (n = 203; baseline treatment plus candesartan 4 mg/d) or a control group (n = 203; baseline treatment alone). No placebo tablets were administered in the control group |
| Kuramoto 1994 | RCT with head‐to‐head comparison of different drug therapies (nicardipine vs trichlormethiazide) without a non‐drug control group |
| Lewis 1993 | Randomised controlled trial in 207 comparing captopril with placebo in patients with insulin‐dependent diabetes mellitus. 75.5% of patients were hypertensive at baseline. Median follow‐up was 1.7 years. Patients receiving CCB or ACE inhibitors were eligible provided their blood pressure could be maintained with BP goals required by the trial. There is no true placebo group, and not all patients had hypertension at baseline |
| Lewis 2001 | RCT that was excluded as there was no true placebo control group; average of 3.3 antihypertensive drugs received per patient during the study |
| MacMahon 2000 | DBRCT in patients aged 75 years or younger if they had a hospital diagnosis (within 5 years of enrolment) of any of the following: acute myocardial infarction (MI), angina with coronary disease confirmed by angiography or exercise electrocardiogram, transient ischaemic attack (TIA), or intermittent claudication. Patients (N = 617) were randomised to ramipril 5 mg or 10 mg daily or placebo for a duration of 4 years. At baseline, 42% of patients were on beta blocker and 25% on calcium antagonists. The percentage of patients at baseline with hypertension has not been reported. Average BP at entry was 133/79 mmHg |
| MAPHY 1988 | Represents a subgroup of the patients included in the HAPPHY trial. RCT was excluded as drug‐drug comparison of bendrofluazide 5 mg or HCTZ 50 mg vs atenolol 100 mg or metoprolol 200 mg with no placebo or untreated control group |
| MIDAS 1996 | RCT that was excluded as it is a drug‐drug comparison of HCTZ 25 mg vs isradipine 5 mg with no placebo or untreated control group |
| Morgan 1980 | RCT that was excluded as allocation to the 4 study groups (no treatment, reduced salt intake, thiazide diuretic, beta blocker) was non‐random (i.e. "based on their week of presentation at the clinic") |
| NAVIGATOR 2010 | DBRCT in 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. 77.5% of patients were hypertensive at baseline. Use of diuretics and calcium channel blockers was similar in the 2 groups. At the last study visit, 20.4% of patients in the valsartan group and 24.0% of those in the placebo group were receiving an open‐label renin–angiotensin inhibitor. There was no placebo or untreated control group |
| NICOLE 2003 | DBRCT in 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. 77.5% of patients were hypertensive at baseline. At the last study visit, 20.4% of patients in the valsartan group and 24.0% of those in the placebo group were receiving an open‐label renin–angiotensin inhibitor. There was no placebo or untreated control group |
| NORDIL 2000 | RCT that was excluded as there is no placebo or untreated control group |
| Oslo 1986 | Open randomised trial conducted in ambulatory young male patients 40 to 49 years old randomised to treatment or no treatment in Norway. This trial does not include patients 60 years or older |
| PEACE 2004 | DBPCT in which 8290 patients with stable coronary artery disease and normal or slightly reduced left ventricular function were randomly assigned to receive either trandolapril at a target dose of 4 mg per day (4158 patients) or matching placebo (4132 patients) for a median follow‐up of 4.8 years. 45.5% of patients were hypertensive at baseline. 68.6% of the treated group and 77.7% of the placebo group were taking the target dose of 4 mg of trandolapril or placebo, respectively, per day. There was no placebo or untreated control group |
| Pool 2007 | An 8‐week multi‐centre randomised double‐blind placebo‐controlled parallel‐group trial that compared the efficacy and tolerability of the combination of valsartan/HCTZ at doses up to 320 mg/25 mg with monotherapy of both drugs. Does not meet the minimum inclusion criterion of 52 weeks' duration |
| PRoFESS 2008 | Multi‐centre trial in 20,332 patients who recently had an ischaemic stroke and were randomly assigned to receive telmisartan (80 mg daily) and placebo for a mean follow‐up of 2.5 years. 74% of patients at baseline had a history of hypertension. By the end of the study, the use of diuretics, ACE inhibitors, calcium channel blockers, and beta blockers was more frequent in the placebo group than in the telmisartan group. There was no placebo or untreated control group in this study |
| PROGRESS 2001 | RCT that included less than 50% of patients with elevated blood pressure with about 50% of patients receiving other antihypertensive therapy at baseline and throughout the trial. There was no placebo or untreated control group |
| QUIET 2001 | RCT in which most patients did not have elevated blood pressure. 25% of patients were receiving a beta blocker. There was no placebo or untreated control group |
| REIN 1997 | Prospective double‐blind trial in 352 patients classified according to baseline proteinuria and randomly assigned to ramipril or placebo plus conventional antihypertensive therapy targeted at achieving diastolic blood pressure under 90 mmHg. There was no placebo or untreated control group |
| RENAAL 2001 | Double‐blind randomised placebo‐controlled study designed to evaluate the renoprotective effects of losartan in 1513 patients with type 2 diabetes and nephropathy. Not all included patients had hypertension at baseline. Patients with hypertension in this trial received open‐label diuretics, CCBs, alpha or beta blockers, centrally acting drugs, or a combination in the control group There was no placebo or untreated control group |
| ROAD 2007 | Prospective randomised open blinded endpoint (PROBE) study with median follow‐up of 3.7 years in 360 patients with chronic renal insufficiency. They were randomly assigned to 4 groups. Patients received open‐label treatment with a conventional dosage of benazepril (10 mg/d), individual up‐titration of benazepril (median 20 mg/d; range 10 to 40), a conventional dosage of losartan (50 mg/d), or individual up‐titration of losartan (median 100 mg/d; range 50 to 200). There was no placebo or untreated control group |
| ROADMAP 2011 | DBRCT in 4447 patients with type 2 diabetes comparing olmesartan 40 mg once daily or placebo for a median duration of 3.2 years. 82% of patients had hypertension at baseline. Additional antihypertensive drugs (except angiotensin‐converting enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mmHg. There was no placebo or untreated control group |
| SCAST 2015 | Randomised placebo‐controlled double‐masked trial in 2029 patients presenting within 30 hours of acute ischaemic or haemorrhagic stroke and with high systolic blood pressure (> 140 mmHg). Patients were treated with candesartan or placebo for 7 days, with doses increasing from 4 to 16 mg once daily during the first 3 days, and were followed for 6 months. Minimum duration of 1 year criterion is not met |
| SCAT 2000 | Multi‐centre randomised double‐blind placebo‐controlled trial in 460 patients: 230 received simvastatin and 230 received a simvastatin placebo; 229 received enalapril and 231 received an enalapril placebo (some patients received both drugs and some received a double placebo). Over 60% did not have hypertension, and about half were taking beta blockers at baseline and throughout. There was no true placebo control group |
| Scheimder 2012 | Randomised double‐blind multi‐centre placebo‐controlled study. 1124 patients were randomised to aliskiren 150 mg, hydrochlorothiazide 12.5 mg, or placebo once daily. Forced titration (to aliskiren 300 mg or hydrochlorothiazide 25 mg) occurred at week 3; at week 6, patients receiving placebo were reassigned (1:1 ratio) to aliskiren 300 mg or hydrochlorothiazide 25 mg. From week 12, amlodipine 5 mg was added, and it was titrated to 10 mg from week 18 for patients whose BP remained uncontrolled. There was no true placebo control group |
| SCOPE 2003 | Study of 4964 patients aged 70 to 89 years, with systolic blood pressure 160 to 179 mmHg and/or diastolic blood pressure 90 to 99 mmHg, and a Mini Mental State Examination (MMSE) test score > 24. Patients were assigned randomly to receive the angiotensin receptor blocker candesartan or placebo, with open‐label active antihypertensive therapy added as needed. As a consequence, active antihypertensive therapy was extensively used in the control group (84% of patients). Mean follow‐up was 3.7 years. There was no placebo or untreated control group |
| SHELL 1994 | Randomised study was excluded as it is a head‐to‐head comparison of different drug therapies without a non‐drug control group |
| STONE 1996 | Single‐blind trial in 1632 patients aged 60 to 79 years, alternatively allocated by entry order numbers to either nifedipine or placebo with a mean follow‐up of 30 months. No randomised allocation |
| STOP‐2 1993 | This study was excluded as it is a head‐to‐head comparison of different drug therapies without a non‐drug control group |
| Strandberg 1991 | This study was excluded as the treatment group had multiple interventions. Control group was given usual treatment and there was no untreated control |
| Syst‐China 1993 | This study was excluded as allocation to treatment and control groups was not random (i.e. alternate allocation was employed) |
| TRANSCEND 2008 | 5926 patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end‐organ damage were randomised to receive telmisartan 80 mg/d (n = 2954) or placebo (n = 2972). 76.4% of patients had hypertension at baseline. Other non‐study blood pressure‐lowering agents were used more frequently in the placebo group than in the telmisartan group by the end of the study (telmisartan vs placebo—diuretics: 888 (33.7%) vs 1059 (40.0%); P < 0·0001; calcium channel blockers: 1003 (38.0%) vs 1215 (45.9%); P < 0·0001; β blockers: 1492 (56.6%) vs 1561 (59.0%); P = 0.081; α blockers: 140 (5.3%) vs 197 (7.5%); P = 0·002). There was no placebo or untreated control group |
| USPHSHCSG 1977 | Randomised double‐blind placebo‐controlled trial conducted in young ambulatory patients 21 to 55 years old in the USA. This trial did not include patients 60 years of age or older |
| VACS 1982 | This study was excluded as it is a drug‐drug comparison of HCTZ 50 mg vs propranolol 80 mg with no placebo or untreated control group |
| VANHLBI 1978 | Randomised double‐blind placebo‐controlled trial conducted in ambulatory patients 21 to 50 years old in the USA. This trial did not include patients 60 years of age or older |
| VHAS 1997 | This study was excluded as it is a drug‐drug comparison of chlorthalidone 25 mg vs verapamil 240 mg with no placebo or untreated control group |
| White 1995 | This study was excluded as it is a drug‐drug comparison of different drug therapies without a non‐drug control group |
ACE: angiotensin‐converting enzyme.
ACEI: angiotensin‐converting enzyme inhibitor.
ARB: angiotensin‐receptor blocker.
CCB: calcium channel blocker.
CV: cardiovascular.
DBRCT: double‐blind randomised controlled trial.
HbA1c: glycated haemoglobin.
HCTZ: hydrochlorothiazide.
MI: myocardial infarction.
MMSE: Mini Mental State Examination.
MR: modified release.
RCT: randomised controlled trial.
SD: standard deviation.
TIA: transient ischaemic attack.