Study	Reason for exclusion
ACTIVE I 2011	RCT comparing irbesartan 300 mg/day or double‐blind placebo for a mean follow‐up of 4.1 years in patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mmHg. Patients at study entry were required to have one of the following risk factors: an age of 75 years or older; treatment for hypertension; a history of stroke, transient ischemic attack, or non‐central nervous system systemic embolism; a left ventricular ejection fraction of less than 45%; peripheral vascular disease; or an age of 55 to 74 years, plus either diabetes mellitus or coronary artery disease. Not all patients had hypertension. 52% patients had hypertension at baseline.
ADVANCE 2007	The study is a 2 x 2 factorial randomized 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 randomized 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% patients had hypertension at baseline. Control group included non‐specific antihypertensive therapy.
ALLHAT 2000	Drug‐drug comparison of different drug classes with no placebo or untreated control group.
BENEDICT 2004	This is a multicenter DBRCT in 1204 subjects, 40 years of age or older, who had hypertension and a known history of type 2 diabetes mellitus not exceeding 25 years, a urinary albumin excretion rate of less than 20 µg per minute in at least two of three consecutive, sterile, overnight samples, and a serum creatinine concentration of no more than 1.5 mg/dL (133 µmol/L). After a six‐week washout period during which any previous therapy with agents that inhibit the renin–angiotensin system was discontinued, and a three‐week washout period during which any previous therapy with non‐dihydropyridine calcium channel blockers was discontinued, eligible subjects 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% patients received antihypertensive medications in placebo group, which was increased to 67% patients at the end of follow‐up. There was no true placebo group.
BENEDICT A 2006	This is a randomized, double‐blind placebo‐controlled study in 590 hypertensive patients (age 30 to 70 years) with type 2 diabetes and microalbuminuria. The patients were randomly assigned to receive irbesartan in a dose of 150 mg once daily, irbesartan in a dose of 300 mg once daily, or matching placebo once daily. There was no true placebo group as 56 percent of the patients in the placebo group were receiving blood pressure–lowering therapy at the end of the two years of follow‐up.
Berglund 1981	Drug‐drug comparison of bendrofluazide 2.5 mg versus propanolol 160 mg, with no placebo or untreated control group.
CASTEL 1994	Drug‐drug comparison with no placebo or untreated control group. Control group included non‐specific antihypertensive therapy.
Coope 1986	Randomized trial in 884 patients aged 60 to 79 years with hypertension. It could not be used to evaluate thiazides or beta‐blockers as first‐line therapy because 67% of patients received bendrofluazide and 70% received atenolol. Five percent were not on any treatment throughout the study. In the control group 2% were put on antihypertensive therapy because of rise in BP above 280/120 mmHg; seven percent were put on diuretics due to ventricular failure.
DIABHYCAR 2004	This was a randomized, double‐blind, parallel group trial comparing ramipril (1.25 mg/day) with placebo (on top of usual treatment) for cardiovascular and renal outcomes for at least three years in 4937 patients with type 2 diabetes and high urinary albumin excretion. 56% patients had hypertension at baseline. There was no true placebo control group.
DREAM 2006	This was a double‐blind, randomized clinical trial in 5269 participants without cardiovascular disease but with impaired fasting glucose levels (after an 8‐hour fast) or impaired glucose tolerance. Patients were randomized to ramipril (up to 15 mg per day) or placebo (and rosiglitazone or placebo) and followed for a median of 3 years. 43.7% patients at baseline had a history of hypertension. Not all patients had hypertension at baseline.
EUROPA 2003	This was a randomized 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). The mean follow‐up was 4.2 years. There was no true placebo group.
Fuchs 2011	Randomized, double‐blind, clinical trial, controlled by placebo in patients 30 to 70 years of age with pre‐hypertension
GENERIC 2010	A single‐centre randomized double‐blind placebo‐controlled parallel trial comparing the effects of moexipril and placebo on insulin sensitivity and 24‐hour blood pressure control in post‐menopausal women with essential hypertension. Excluded because it was only 8 weeks in duration.
GENRES 2007	GENRES was a prospective randomized 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. It was not 52 weeks duration of drug therapy.
GLANT 1995	Employed alternate allocation (i.e. not random allocation). Drug‐drug comparison of delapril 30 to 120 mg versus several dihydropyridine calcium channel blockers with no placebo or untreated control group.
HAPPHY 1987	Drug‐drug comparison of bendrofluazide 5 mg or HCTZ 50 mg versus atenolol 100 mg or metroprolol 200 mg with no placebo or untreated control group.
HDFP 1984	Treated group included various lifestyle measures in addition to antihypertensive drug therapy. Control group was usual care and not necessarily untreated controls.
Hood 2007	A placebo‐controlled, double‐blind, randomized cross‐over trial. Patients then received 10 cycles of double‐blind treatment comprising spironolactone 50 mg to 100 mg, amiloride 20 mg to 40 mg, bendroflumethiazide 2.5 mg to 5 mg at the 2 doses shown, losartan 100 mg, and placebo. Order of drugs and doses were randomized, except that the higher doses of diuretic and the 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	A total 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 were randomized to double‐blind treatment with 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. Participants were not selected on the basis of history of either hypertension or hyperlipidemia, and the trial did not mandate strict blood pressure or lipid levels for entry. Persons with a history of hypertension could be enrolled if the blood pressure was adequately controlled (in the assessment of the recruiting physician) with lifestyle or drugs other than an angiotensin receptor blocker, ACE inhibitor, or thiazides. Only 38% patients had hypertension at baseline and 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
HOT 1995	Evaluated the effects of achieving pre‐specified levels of diastolic blood pressure control with all patients receiving antihypertensive treatment.
IDM 2001	Other antihypertensive drugs were prescribed to 56% of the placebo group
IDNT 2003	This was a randomized double‐blind, placebo‐controlled trial with a median follow‐up of 2.6 years in 1715 adults with type 2 diabetic nephropathy and hypertension treated with irbesartan, amlodipine, or placebo. The distribution of non‐study drugs used to achieve the target blood pressure was similar in the three groups (Table 2). The placebo group received an average of 3.3 non‐study drugs, and the other two groups received an average of 3.0 drugs. There was no true placebo control group.
IMAGINE 2008	This was a double‐blind, placebo‐controlled study of 2553 patients after CABG who were randomly assigned to quinapril, target dose 40 mg/d, or placebo, who were followed for a maximum of 43 months. Blood pressure entry criteria were not required. 47% had hypertension at baseline and baseline SBP/DBP was 122/70 mmHg. Before CABG, 91% of subjects were taking aspirin, 65% were taking a statin, 79% were taking a beta‐blocker, 23% were taking an ACE inhibitor or angiotensin receptor blocker, and 37% were taking a calcium channel blocker. After randomization, over the entire study period, the use of antiplatelet agents averaged 95%, whereas lipid‐lowering drug use averaged 85% (statins 83%), and beta‐blocker use averaged 63%. Among patients randomized to placebo, 5% were taking an ACE inhibitor at 1 year, 8% at 2 years, and 11% at 3 years.
Imai 2011	A RCT in 577 patients treated with antihypertensive therapy (73.5% (N  =  424) received concomitant ACE inhibitors), were given either once‐daily olmesartan (10 mg 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	No placebo or untreated control group
IPPPSH 1985	Thiazide was given to over 67% of patients in both the treated and control group.
Kondo 2003	In this study patients with a history of coronary intervention and no significant coronary stenosis on follow‐up angiography 6 months after intervention were randomly assigned into 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‐2 1994	Head‐to‐head comparison of different drug therapies (nicardipine vs trichlormethiazide) without a placebo or untreated control group.
Lewis 1993	This was a randomized controlled trial in 207, comparing captopril with placebo in patients with insulin dependent diabetes mellitus in whom urinary protein excretion was > 500 mg/day and serum creatinine concentration was < 2.5 mg/dL regardless of previous blood pressure status or a previous need for antihypertensive medication. 75.5% patients were hypertensive at baseline. Median follow‐up of 1.7 years. Patients receiving calcium channel blockers or ACE inhibitors were eligible provided their blood pressure could be maintained with BP goals required by the trial. There was no true placebo group and not all patients had hypertension at baseline.
Lewis 2001	The placebo group received an average of 3.3 antihypertensive drugs per patient during the study.
MacMahon 2000	This was a double‐blind placebo‐controlled randomized trial in patients aged 75 years or younger, if they had a hospital diagnosis (within five years of enrolment) of any of the following: acute myocardial infarction (MI), angina with coronary disease confirmed by angiography or exercise electrocardiogram, transient ischemic attack (TIA) or intermittent claudication. Patients were excluded for several reasons, one of them was a diastolic blood pressure (BP) > 100 mmHg, a systolic BP > 160 mmHg, or SBP < 100 mmHg during the pre‐randomization run‐in period. Patients (N = 617) were randomized to ramipril 5 mg or 10 mg daily or placebo for a duration of 4 years. The primary outcomes were carotid atherosclerosis, assessed by B‐mode (brightness mode) ultrasound, and left ventricular mass, assessed by M‐mode (Motion mode) echocardiography. At baseline 42% patients were on beta‐blockers and 25% were on calcium antagonists. The percentage of patients at baseline with hypertension was not reported. The average BP at entry was 133/79 mm Hg.
MAPHY 1988	Represents a subgroup of the patients included in the HAPPHY trial. Excluded as drug‐drug comparison of bendrofluazide 5 mg or HCTZ 50 mg versus atenolol 100 mg or metroprolol 200 mg with no placebo or untreated control group.
Materson 1997	Randomized double‐blind placebo‐controlled study of 1292 male veterans with DBP of 95 mmHg to 109 mmHg. After placebo washout, patients randomized to placebo or one of the six drugs ‐ HCTZ 12.5 mg to 50 mg/day; atenolol 25 mg to 100 mg/day; captopril 25 mg to 100 mg/day; clonidine 0.2 mg to 0.6 mg/day; a sustained preparation of diltiazem 120 mg to 360 mg/day or prazosin 4 mg to 20 mg/day for a period of 1 year. Morbidity and mortality outcomes were not reported for different drug classes. Blood pressure control and incidence of termination of treatment were the main outcomes.
MIDAS 1996	Drug‐drug comparison of HCTZ 25 mg versus isradipine 5 mg with no placebo or untreated control group.
Morgan 1980	Allocation to groups was not random, it was based on week of presentation at the clinic.
NAVIGATOR 2010	Randomized double‐blind placebo‐controlled study 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, to achieve and maintain a 5% weight loss, reduce intake of saturated and total dietary fat, and increase physical activity to 150 minutes weekly. 77.5% patients were hypertensive at baseline. Patients with cardiovascular disease were treated more intensively at baseline than were those who had risk factors only: 21.5% received an ACE inhibitor, compared with 2.7% of those with risk factors only; 75.8% received antiplatelet treatment, compared with 24.2% of those with risk factors only; 61.7% received a beta‐blocker, compared with 32.2% of those with risk factors only; and 64.1% received lipid‐modifying therapy, compared with 30.2% of those with risk factors only. The use of diuretics and calcium‐channel blockers was similar in the two 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 true placebo group.
NICOLE 2003	The NICOLE study (NIsoldipine in COronary artery disease in LEuven) was a single centre, randomized, double‐blind, placebo‐controlled trial with coronary angiography at baseline, six months, and three years of follow‐up. 826 patients who had undergone successful coronary angioplasty were randomized to nisoldipine 40 mg once daily or placebo. Hypertension at baseline reported in 41.7% patients in Nisoldipine group and in 39.4% patients in placebo group. Data were not reported separately in patients with hypertension.
NORDIL 2000	No placebo or untreated control group
PEACE 2004	This was a randomized, double‐blind, placebo‐controlled trial 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% 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.
Pool 2007	This study was a 8‐week, multicentre, randomized, 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. Did not meet the minimum inclusion criteria of 52‐week duration.
PRoFESS 2008	This was a multicenter trial in 20,332 patients who recently had an ischemic stroke and were randomly assigned to receive telmisartan (80 mg daily) and placebo for a mean follow‐up of 2.5 years. 74% 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 true placebo control group in this study.
PROGRESS 2001	Less than 50% of patients had elevated blood pressure and about 50% of patients were receiving other antihypertensive therapy at baseline and throughout the trial.
QUIET 2001	Most patients did not have elevated blood pressure. 25% of patients were receiving a beta‐blocker.
REIN 1997	This was a prospective double‐blind trial in 352 patients classified according to baseline proteinuria (stratum 1: 1 to 3 g/24 h; stratum 2: ≥ 3 g/24 h), and randomly assigned to ramipril or placebo plus conventional antihypertensive therapy targeted at achieving diastolic blood pressure under 90 mmHg. There was no true placebo control group.
RENAAL 2001	This was a double‐blind randomized controlled trial (N = 1513) comparing losartan (50 mg to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium channel antagonists, diuretics, alpha‐blockers, beta‐blockers, and centrally acting agents), for a mean of 3.4 years. 93% patients had hypertension at baseline.There was no true placebo control group.
ROAD 2007	This was a prospective, randomized, open, blinded endpoint (PROBE) study with median follow‐up of 3.7 years in patients with chronic renal insufficiency. A total of 360 patients were randomly assigned to four 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 mg/d to 40 mg/d), a conventional dosage of losartan (50 mg/d), or individual up titration of losartan (median 100 mg/d; range 50 mg/d to 200 mg/d). Up titration was performed to optimal antiproteinuric and tolerated dosages, and then these dosages were maintained. After 4 weeks of therapy with the study drugs, patients who continued to show inadequate BP control (i.e. SBP of 130 mmHg, DBP of 80 mmHg, or both) had an additional antihypertensive agent (diuretic, calcium channel blocker, centrally acting agent, or combination of these medications, excluding ACE inhibitors and ARB) added to their treatment regimen. There was no true placebo or no treatment control group.
ROADMAP 2011	This was a double‐blind placebo‐controlled randomized trial in 4447 patients with type 2 diabetes comparing olmesartan 40 mg once daily or placebo for a median duration of 3.2 years. The study enrolled patients with type 2 diabetes, among whom there was a wide range of blood pressure values, including some that were in the normal range. 82% 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 mm Hg. There was no true placebo or no treatment control group.
SCAST 2015	SCAST was a randomized placebo‐controlled, double‐masked trial of the angiotensin receptor blocker candesartan in 2029 patients presenting within 30 hours of acute ischemic or hemorrhagic stroke and with systolic blood pressure ≥140 mmHg. Patients were treated with candesartan or placebo for seven days, with doses increasing from 4 mg to 16 mg once daily during the first three days, and were followed for six months. Minimum duration of 1 year criteria was not met.
SCAT 2000	This was a double‐blinded randomized controlled, 2 x 2 factorial, angiographic trial evaluating the effects of cholesterol lowering and angiotensin‐converting enzyme inhibition on coronary atherosclerosis in normo‐cholesterolemic patients. There were a total of 460 patients: 230 received simvastatin, and 230, a simvastatin placebo, and 229 received enalapril and 231, an enalapril placebo (some subjects 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.
Schmieder 2012	This was a double‐blind randomized placebo‐controlled study. After a 2‐ to 4‐week placebo run‐in, 1124 patients were randomized 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 titrated to 10 mg from week 18, for patients whose BP remained uncontrolled. This study was not a placebo or no treatment controlled study of 52 weeks duration.
SCOPE 2003	SCOPE was a study of 4964 patients aged 70 to 89 years, with systolic blood pressure 160 to 179 mmHg, diastolic blood pressure 90 to 99 mmHg, or both, 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 true placebo or no treatment control group.
SHELL 1995	No placebo or untreated control group
Sprackling 1981	123 elderly subjects were randomly allocated to simple observation or to treatment with methyldopa. Methyldopa was used at an initial dose of 250 mg twice daily, which was subsequently adjusted as necessary to bring the standing diastolic pressure towards the target of 90 mmHg. Excluded because alpha‐methyldopa was not one of the first‐line drug classes specified for this review.
STONE 1996	A single‐blind trial in 1632 subjects, 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 randomized allocation.
STOP 1991	STOP was a prospective, double‐blind randomized controlled trial, set up to compare the effects of active antihypertensive therapy (three beta‐blockers and one diuretic) and placebo on the frequency of fatal and nonfatal stroke and myocardial infarction, and other cardiovascular death in hypertensive Swedish men and women aged 70 to 84 years. Could not be used to represent first‐line thiazide or first‐line beta blocker as 67% received a beta blocker and > 70 % received a thiazide.
STOP‐2 1993	Head‐to‐head comparison of different drug therapies without a placebo or untreated control group.
Strandberg 1991	Treatment group had multiple interventions. Control group was usual treatment, not untreated control.
SYST‐CHINA 1993	Allocation to treatment and control groups not randomized (alternate allocation was employed).
TOMHS 1993	TOMHS was a 4 year double‐blind randomized controlled trial comparing six treatments for long‐term care of people with mild hypertension aged 45 to 69 years. All randomized participants received intensive nutritional‐hygienic intervention aimed at weight loss with a fat modified diet, lowering dietary sodium and alcohol intake, and increasing leisure‐time physical activity. 902 men and women with mild hypertension (average blood pressure 140/91 mmHg) were randomized to receive nutritional‐hygienic intervention plus one of six treatments: (1) placebo; (2) diuretic (chlorthalidone); (3) beta‐blocker (acebutolol); (4) alpha 1 antagonist (doxazosin mesylate); (5) calcium antagonist (amlodipine maleate); or (6) angiotensin‐converting enzyme inhibitor (enalapril maleate). The primary outcomes of TOMHS were changes in BP. Morbidity and mortality events were not reported separately for the different drug treatments. Corresponding author was contacted and refused to provide the data.
TRANSCEND 2008	5926 patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end‐organ damage were randomized to receive telmisartan 80 mg/day (N = 2954) or placebo (N = 2972). Many of these patients were receiving concomitant proven therapies. 76.4% 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; beta‐blockers: 1492 (56.6%) vs 1561 (59.0%), P = 0.081; alpha‐blockers: 140 (5.3%) vs 197 (7.5%), P = 0.002). There was no true placebo or no treatment control group.
VACS 1982	Drug‐drug comparison of HCTZ 50 mg versus propanolol 80 mg with no placebo or untreated control group.
VHAS 1997	Drug‐drug comparison of chlorthalidone 25 mg versus verapamil 240 mg with no placebo or untreated control group.
White 1995	No placebo group and patients were not randomly allocated to moexipril or moexipril plus hydrochlorothiazide.

HCTZ = hydrochlorothiazide; DBP = diastolic blood pressure; SBP = systolic blood pressure; M‐mode echocardiography =Motion mode; CABG = Coronary Artery Bypass Grafting; ACE inhibitor = Angiotensin Converting enzyme inhibitor; ARB = Angiotensin Receptor Blocker