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Supplementary digital content 1: Detailed overview of studies reporting proportions of people remaining normotensive for six months or longerAuthor Date CountryStudy designThreshold for hypertension in mmHgSample size and ageEligibility criteriaPrimary outcomes of studyAHT used before withdrawal% people normoten-sive after 6 months% people normotensive after >6 monthsFactors predictive of successful for 6 months or longer withdrawalCASP appraisal - limitations of studiesAlderman et al., 1986; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGRlcm1hbjwvQXV0aG9yPjxZZWFyPjE5ODY8L1llYXI+
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ADDIN EN.CITE.DATA [1]Prospective cohort study with a 1 year follow upUnder 65 years old: BP ≥160/95 mmHg; over 65 years old: BP≥165/95 mmHgn=66; mean age = 55.7 (SD 8.3) years; 27% men;Inclusion: taking AHT at time of screening; mean of 2 or more readings pre-treatment ≥ 160/95 mmHg; use AHT for another 6 months following screening; no contra-indication to AHT withdrawal; possibility to participate in 2 year follow -up; for people under 65 years: 2 BP readings within 6 months <140/85 mmHg, for over 65 years old: two BP readings in 6 months <150/90 mmHg Number of participants remaining below threshold BPAny - At 1 year: 70% (44 out of 63); of those remaining normotensive at year 1, 35 were followed up after 2 years: 51%(18 out of 35); those remaining normotensive at year 2, 35 were followed up after 3 years: 88% (15 out of 17)Although there was no difference in BP between those successfully and unsuccessfully withdrawn at the point of withdrawal, all subsequent mean BP readings of patients remaining normotensive were sig. lower than the mean BP readings of those whose AHT needed to be reinstated; Small sample size; Aylett et al., 1999; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BeWxldHQ8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [2]Longitudinal observational study with a 3 year follow-upDetermined by the patient's practitioner on the basis of individual risk profilesn=196; age range: 40-69 years; sex not reported;Inclusion: people with HT taking AHT; exclusion: poorly controlled (BP>160/90 mmHg); on AHT for less than 2 years; had major cardio- vascular event within last year; indication for AHT in addition to HT; had a previous relapse of HT after stopping AHT Proportion of patients remaining below threshold BPAny52%At 12 months: 38%; at 24 months: 23%; at 36 months: 22%Male sexVery large sample size; sample; demographic characteristics not well reported Beltman et al., 1996; Netherlands PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWx0bWFuPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48
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ADDIN EN.CITE.DATA [3]Observational study following an AHT RCT with 1 year follow upAmbulatory BP of 135/85n=29; mean age= 51 (SE 2); men n=18;Inclusion: completion of RCT (one year of treatment with amlodipine or lisinopril); dias BP<90 mmHg during RCTProportion of patients remaining below threshold BPAmlodipine or lisinopril - Using ambulatory BP with a dias cut-off only: at week 60: 59% (17 out of 29); at week 104: 48% (14 out of 29); using seated office BP with a dias cut-off only: at week 60: 83% (24 out of 29); at week 104: 66% (19 out of 29); - Small sample size; Danielson et al., 1981; Sweden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYW5pZWxzb248L0F1dGhvcj48WWVhcj4xOTgxPC9ZZWFy
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ADDIN EN.CITE.DATA [4]Prospective cohort withdrawal studyBetween 155/95 and 180/110 depending on age and risk factorsn=47; mean age = 42 years (SD 11); men n = 21; Inclusion: essential hypertension state 1 for not less than 1 year; well controlled HT for > 6 monthsNumber of patients remaining normo-tensive without returning to AHTHydrochlorothiazide, beta-blockers or a combi-nation of both 74% (31 out of 42) At 1 year: 55% (22 out of 40); at 2 years: 36% (10 out of 28) -Population not well described; small sample size; Ekbom et al., 1994; Sweden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fa2JvbTwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [5]Observational study with a 5 year follow-up including participants of the wash-out phase of the STOP -Hypertension trialNo level set, restarting AHT depended on GP advicen=333; mean age= 75.2 (SD 3.8; range 70-84); 32% menInclusion: hypertension; between 70 to 84 years oldTime until AHT was re-started Any - At 1 year: 60%; at 5 years: 20%; Monotherapy, low dose and low BP level before withdrawal were significant predictors for successful withdrawal; age, sex, duration of drug treatment before withdrawal and low BP levels before patient received treatment for the first time were not significant predictorsVery large sample size; sample; no pre-set BP threshold; Fernandez et al., 1982; Canada PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZXJuYW5kZXo8L0F1dGhvcj48WWVhcj4xOTgyPC9ZZWFy
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ADDIN EN.CITE.DATA [6]Prospective cohort study: 60 week follow -up for those remaining normotensive after wash-out phase for a cross over study;140/95n=24; mean age = 43.5 (SD 11.6), men n = 17;Inclusion: uncomplicated essential HT; HT diagnosis with 3 supine and 3 erect BP readings of dias BP > 95 mmHg and sys BP > 140 mmHg; exclusion: cardiovascular disease, grade III or IV retinopathy, liver or renal impairment, diabetes, hypokalaemia or any condition that did not justify inclusionBP levels after withdrawal of AHTHydrochlorothiazide and loop diuretic (MK-196) - At 48 weeks: 100%; at 60 weeks: 75% (18 out of 24) - Small sample size; likely to be the same study as Fernandez 1983 though results are different;Fernandez et al., 1983; Canada PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZXJuYW5kZXo8L0F1dGhvcj48WWVhcj4xOTgzPC9ZZWFy
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ADDIN EN.CITE.DATA [7]Prospective cohort study; AHT discontinued for cross-over study and those remaining normotensive followed up for 60 weeks; 140/95n=35; age range : 21-65 years; Inclusion: uncomplicated essential HT; HT diagnosis with 3 supine and 3 erect BP readings of dias BP > 95 mmHg and sys BP > 140 mmHg; exclusion: cardiovascular disease, grade III or IV retinopathy, liver or renal impairment, diabetes, hypokalaemia or any condition that did not justify inclusionNumber of patients remaining normotensive without AHTHydrochlorothiazide and loop diuretic (MK-196) - At 60 weeks: 66% (23 out of 35)Comparison of a wide range of biomarkers that separated those who remained normotensive from those redeveloping hypertension. Those in the normotensive group had lower serum sodium levels, lower mean corpuscular volume, higher serum albumin and higher body weightSmall sample size, in particular for this type of analysis; likely to be the same study as Fernandez 1983 though results are slightly different;Fotherby & Potter, 1994; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3RoZXJieTwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+
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ADDIN EN.CITE.DATA [8]Prospective cohort study with 1 year follow-up160/90 on 2 consecutive visitsn = 74; mean age 76 years (SD 5; range 65-84); 47 % men;Inclusion: fit, hypertensive, on AHT for > 1 year, age ≥ 65; exclusion: symptoms of angina or congestive heart failure, history of myocardial infarction or stroke within preceding 6 months, renal impairment, on other medication sig affecting BP, other diseases that would sig affect survivalProportion of people who remained normotensive at 12 months after withdrawal Any - At 12 months: 25% n=20); of n=64 available at 2 years follow-up, 20% (n= 13) remained normotensiveNo sig difference between those remaining normotensive at 1 year and those restarting AHT in age, sex number of AHT, alcohol or cigarette use, history of vascular disease, treatment duration, LV mass index, clinic or mean 24 h dias BP; less AHT, lower sys BP, ECG voltage and BMI at baseline were sig predictors of remaining normotensiveSmall sample size; study included lifestyle advice (but no further intervention);Freis et al, 1989; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmVpczwvQXV0aG9yPjxZZWFyPjE5ODk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [9]RCT comparing AHT reduction, AHT withdrawal and control group followed up for up to 30 monthsDias BP 85-90 depending on previously or newly diagnosed; no threshold for systolic BPtotal n=606; AHT discontinued n = 137; mean age = 56.9 years; all men;Inclusion: previously diagnosed with a dias BP was <115 mmHg and newly diagnosed patients with a dias BP between 90-95 mmHg; exclusion: malignant HT, haemorrhagic stroke, recent myocardial infarction, history of alcoholism or drug abuse, contraindication to study;Number of participants who maintained control BPHydrochlorothiazide (HCTZ)55% (of those discontinueing low dose of HCTZ)At 18 months: 35%; at 30 months: 23%Patients maintaining BP control had lower BP at baseline Very large sample size; only low dose HCTZ discontinued Hansen et al., 1983; Denmark PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW5zZW48L0F1dGhvcj48WWVhcj4xOTgzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [10]Prospective cohort withdrawal study with 1 year follow upFor inclusion: diastolic BP 105-110 (depending on age); restart of AHT decided by GPn = 169; over 50 years old; sex not reportedInclusion: history of hypertension; Number of participants not back on AHTAny - At 12 months: 25% (n = 43) remained below a dias BP level of 110 mmHg; 23% (n = 39) remained below as dias BP level of 100 mmHg - Large sample size; recruitment and demographics of participants not well reported; Herlitz et al., 1988; Sweden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXJsaXR6PC9BdXRob3I+PFllYXI+MTk4ODwvWWVhcj48
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ADDIN EN.CITE.DATA [11]Cohort withdrawal study170/105n=22; mean age = 56 years; all menInclusion: regular visits to a HT Unit for 7 years; mild to moderate HT with dias BP levels ≥ 100 mmHg at first 3 visits Time after withdrawal until HT returnedBeta blockers, beta blockers and HCTZ, or beta blockers, HCTZ and hydralazine - 50% remained normotensive (slow return group) for a mean of 240 days (range 65-578 days)There was no difference in pre-treatment BP between rapid and slow return to HT groups; there was a difference in number of AHT used with more AHT used in the rapid return groupSmall sample size; only men included;Jennings et al., 1995; Australia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KZW5uaW5nczwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+
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ADDIN EN.CITE.DATA [13]RCT; participants were stratified into an obese and not obese group and randomised into dietary intervention or no intervention and AHT withdrawal or no withdrawal; only AHT withdrawal groups without lifestyle intervention included in review analysisMedication restarted if dias BP 95-99 mmHg on 3 occasions within 3 months, or if 2 diastolic BP readings were in the 100-104 mmHg rage in a one month period, or if at any time diastolic BP rose to 105 mmHg or highern=496; age range: 30-69 years; sex not reported; overweight control group n = 89; not overweight control group n= 70; Inclusion: active controlled participants of the previous Stepped Care HT Detection and follow-up programme; had no sys BP> 180 mmHg; average dias BP < 95 mmHg during past year; average of last 2 dias BP readings was < 95 and neither was > 95 mmHgNumber of people off AHT after 56 weeksAny - Only control groups are reported here as the other groups used lifestyle interventions; follow up at 56 weeks: overweight: for mild HT 52% (19 out of 37); for severe HT (diastolic BP> 105 mmHg) 24% (12 out of 52); not overweight: for mild HT 58% (24 out of 41); for severe HT 28% (8 out of 29)If participants had been diagnosed with severe HT 5-6 years previously, their relative odds of success to withdraw medication were 0.38 compared to those who had not have severe HT. If they were taking 2 drugs at start of study, odds for successful withdrawal were 0.47 compared to those taking one drug; they were taking 3 or more drugs at start of study, odds for successful withdrawal were 0.23 compared to those taking one drug; there was not sig. effect of age, race, sex, smoking status, overweight or study centre on relapse rateVery large sample size; Lernfelt et al; 1990; Sweden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXJuZmVsdDwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+
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ADDIN EN.CITE.DATA [14]Prospective cohort study with 2 year follow-up200/105n=25; age = 70; 10 men (40%)Inclusion: part of the '70 year old people in Gothenburg, Sweden' study; using AHT; exclusion: BP> 175/95 mmHg; cardiovascular disease; EEG abnormalities; increased heart volume; other serious diseasesPercentage of people who completed 2 years follow-up without treatment reinstatedAny85% (17 out of 20);At 2 years: 43% (six out of 14) - Small sample size; Medical Research Council Working Party on mild HT, 1986; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IeXBlcnRlbnNpb248L0F1dGhvcj48WWVhcj4xOTg2PC9Z
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ADDIN EN.CITE.DATA [15]Withdrawal RCT following RCT assessing treatment with propranolol or bendrofluazideDias BP > 90 mmHg Men bendrofluazide (BF) group: 12 months: n=205; 24 months: n=50; propranolol (PP) group: at 12 months n=201; at 24 months: n=55; placebo: at 12 months: n=292; at 24 months: n=59; Women: BF group: 12 months: n=212; 24 months: n=54; PP: at 12 months n=165; at 24 months: n=33; placebo: at 12 months: n=290; at 24 months: n=66;Inclusion: age 35-64 years; diastolic BP 90-109 mmHg; completion of medication trialRates of successful withdrawal of AHT at 3, 12 and 24 monthsBendrofluazide or propranolol - Men: BF group: 12 months: 56.5%; 24 months: 44%; PP group: at 12 months 48.2%; at 24 months: 47.3%; placebo: at 12 months: 51.8%; at 24 months: 42.4%; Women: BF group: 12 months: 56.3%; 24 months: 53.7%; PP group: at 12 months 45.2%; at 24 months: 27.3%; placebo: at 12 months: 52.7%; at 24 months: 40%Following propranolol treatment: in older people BP levels tended to increase less quickly, this effect was not observed following bendrofluazide treatment or in those in the placebo group; after stopping bendrofluazide, sys BP levels rose more quickly in men (but not women) with increased entry levels; this effect was not seen when stopping propranolol; Very large sample size; no sys BP threshold valuesMitchell et al., 1989; Canada PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXRjaGVsbDwvQXV0aG9yPjxZZWFyPjE5ODk8L1llYXI+
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ADDIN EN.CITE.DATA [16]Prospective cohort study with 1 year follow-upDias BP of second and third reading < 120; if average between 105-119, new visit one week later: if BP> 105 mmHg participant withdrawn from studyn=107; mean age= 51 years; 78% menInclusion: 30-70 years old; on AHT of 2 or less units with 1 unit being equivalent to 50 mg of hydrochlorothiazide; under good BP control (dias BP<105 during last 4 visits); no evidence of target organ disease; no contraindication to nadolol; no history of a psychotic disorder, diabetes, asthma or chronic obstructive lung diseaseNumber of participants remaining below threshold BPAny - At 12 months: 36% (38 out of 107)Sex was not predictive of successful withdrawal; lower standing dias.BP at study entry and total months of BP control was predictive of remaining normotensive;No threshold values for sys BP; Myers et al., 1996; Canada PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NeWVyczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [17]Cohort withdrawal study Restart of AHT if mean of 2 ambulatory BP recordings exceeding 160/95; n=98; mean age: 62 years (SD 2; range 21-80); men n = 36;Inclusion: receiving AHT exclusion: target organ damage, secondary HT, cardiac arrhythmias, receiving other medication affecting their BP; if mean ambulatory sys BP ≥160 or dias BP ≥ 95 mmHg; if AHT had been changed in the last 3 monthsProportion of patients remaining off treatment at 1 yearAny - At 1 year: with a 160/95 cut-off 51% (50 out of 98); with a 150/90 cut-off 42% (41 out of 98); with a 140/90 cut-off 21% (21 out of 98)Age, gender, intensity of AHT, and family physician BP readings were not related to successful withdrawal; diastolic BP taken by the research nurse and by ambulatory monitor at baseline was sig. higher in those who returned to drug therapy; Well reported analysis with different cut-off values Nelson et al., 2002; Australia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OZWxzb248L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [18]Prospective cohort study with 12 months follow-up (extended run-in phase of AHT trial)160/90n=503; age range: 65-84 years; sex of total group not reported; Inclusion: treatment with AHT, participant in the 2nd Australian national blood pressure study but BP remaining normotensive in run-in phaseProportion of patients remaining below threshold BPAny - At 12 months: 36% remained normotensive (181 out of 503)Lower systolic BP, younger age, greater waist-hip ratio and use of a single AHT were sig. predictors for remaining normotensive; [not clear which variables were entered into analysis]Very large sample size; Nelson et al., 2003; Australia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OZWxzb248L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [19]Wash-out cohort study preceding RCT160/90 n = 6291; mean age = 71.9; 44.0% men; Inclusion: between 65 and 84 years, receiving AHT; exclusion determined by GP: mostly those with pre-existing cardiovascular complications, difficulty to manage patients, those not willing to participate or those for who GP suggested to continue AHT Patient characteristics of those remaining normotensive after AHT withdrawalAny - n= 1228 remained normotensive (<160/90) for a median of 4 weeks (0-76 weeks, the longest period to return to hypertension was 108 weeks (1 patient)Lower sys and dias BP levels before withdrawal, younger age, being on a single AHT; using the lower threshold of 140/90, the same predictors were identified with exception of younger age Very large sample size; not clear which variables were entered into analysis of factors that predict remaining normotensivePrasad et al, 1997; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmFzYWQ8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [20]Prospective cohort study with 1 year follow-upDaytime ABPM BP > 150/90n= 25; median age = 64 (range 51-82); 17 women, 19 menInclusion: on AHT monotherapy; exclusion: ischaemic heart disease, cerebrovascular disease, peripheral vascular disease, diabetes, renal impairment, secondary HT;Proportion of people who remained normotensive at 52 weeks after withdrawal AnyAt 6 months: 28% (7 out of 25)At 1 year: 24% (6 out of 25)-Small sample size; Preston et al., 2000; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmVzdG9uPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48
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ADDIN EN.CITE.DATA [21]RCT including active treatment and placebo groups with 1 year follow-up of the placebo groupDias BP>95n = 1292; active treatment group: n = 1105; placebo group n = 187; no mean age reported; all men;Inclusion: age > 21 years, reasonable expectation that dias BP would be between 95 and 105 mmHg with placebo; exclusion: secondary HTResponse to placebo at 1 year follow up and effect of race and age on responseNot reported - All placebo at 1 year: 30% (57 out of 187); No difference between treatment and placebo groups regarding resting pulse rate, age or baseline laboratory values (haematocrit, serum electrolyte, cholesterol, triglyceride or 24 h urine sodium or potassium excretion levels)Very large sample size; sample not well described; no sys BP threshold value set;Sasamura et al., 2013; Japan PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXNhbXVyYTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
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ADDIN EN.CITE.DATA [22]RCT comparing withdrawal of 2 AHTs If 1 of 4 criteria were reached: 1) office sys BP > 140 and/or dias BP >90 at 2 consecutive visits; 2) office sys BP>160 and/or dias BP > 100 at 1 visit; 3) mean weekly home sys BP > 140 and/or dias BP> 90 on 2 consecutive visits; 4) mean weekly home sys BP> 160 and/or dias BP> 100 at any 1 weekn=244; Candesartan group n = 124; mean age=51.1 (SD 6) years; men n = 75; nifedipine group n = 120; mean age= 51.3 (SD 5.7) years; men n = 79; Inclusion: age 30-59 with stage 1 HT; family history of HT; no prior pharmacological treatment for > 3 months prior to study; exclusion: secondary HT, plans for pregnancy, diabetes, renal dysfunction, cardiovascular disease, severe liver dysfunction, malignancies or otherwise judged inappropriateSurvival until recurrence of HTCandesartan or nifedipineCandesartan group: 1.8%; nifedipine group: 0%At 12 months: candesartan group: 0.9%; nifedipine group: 0% - Very large sample size; limited generalisability due to inclusion criterion 'family history of HT'; Sieg-Dobrescu et al., 2001; Switzerland PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaWVnLURvYnJlc2N1PC9BdXRob3I+PFllYXI+MjAwMTwv
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ADDIN EN.CITE.DATA [23]Withdrawal RCT with 24 week follow-up140/90Withdrawal group: mean n = 20; mean age = 48 years (SD 14.3); men n = 10; treatment group: n = 20; mean age = 47 years (SD 13.2); men n = 11 Inclusion: receiving AHT for at least previous 6 months, BP < 140/90 mmHg; exclusion: requiring treatment for hypercholesterolemia, diabetes, angina pectoris or congestive heart failure, previous cardiovascular event BP levels after withdrawalAny[at 24 weeks: 35% (7 out of 20)] - - Very small sample size;Schmieder et al., 1997; Germany PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2htaWVkZXI8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFy
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AAAA
ADDIN EN.CITE.DATA [24]Prospective cohort study with 6 months intensive treatment, followed by treatment under the supervision of GP; after 6 years patients were followed up160/95 and 140/90n= 88; at baseline mean age = 42.6 (SD 7.2) yearsCivil servants; those included were male, not receiving AHT prior to the study and had no evidence of secondary HT; only those with BP levels > 160/95 mmHg were includedPercentage of those who have been withdrawn from AHT and predictors for recurrence of HTBeta blockers, calcium entry blockers, angiotensin-converting enzyme inhibitors or clonidine - Follow up was after 6 years: with 160/95 mmHg cut-off: 17% (15 out of 88); with 140/90 mmHg cut-off: 8% (7 out of 88)Lower screening dias BP; lower screening rest sys and dias BP; high cardiac output at rest, low total peripheral resistance at rest; cardiac output and increase in cardiac output during mental stress, increase in heartrate during exercise test were higher in patients who returned to HT; low echocardiographic left ventricular mass and short duration of HT were associated with normotension at follow-up; age, height, initial weight, weight after 6 years, coexistence of other cardiovascular risk factors did not predict successful withdrawalOnly men who had previously not received AHT were includedVan den Bosch et al., 1994; Netherlands PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVuIEJvc2NoPC9BdXRob3I+PFllYXI+MTk5NDwv
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ADDIN EN.CITE.DATA [25]Prospective cohort study with 5 year follow upDias BP: 100n = 25, mean age = 56.2 (range 39-81 years)Inclusion: monotherapy, dias BP <85 mmHg on 3 or more readings, no other reason to continue AHT such as co-morbiditiesNumber of participants remaining below threshold BPAny - At 5 years: 56% (14 out of 25) No difference between groups regarding BP levels at diagnosis or start of withdrawal, or regarding history of HT (years since being diagnosed)Small sample size; sample not well described; no sys BP threshold value set;Van Duijn et al., 2011; Netherlands PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gRHVpam48L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy
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ADDIN EN.CITE.DATA [26]Prospective cohort study with 6 months follow upLow cardiovascular risk and patient's decision to stop or re-start AHTn= 135; age: 25-75 years; Inclusion: no known target organ damage, receiving AHT and/or medication for hypercholesterolaemia; exclusion: cardiovascular disease, taking drugs for other indications than HT or hypercholeserolaemia; Attendance for re-evaluationAny59% (80 out of 135) - Those who used more than 2 oral drugs were more likely to restart medication, other characteristics (sex, age, smoking and family history of cardiovascular risk) were not predictive; Reasons to re-start medication reported in combination with withdrawal of medication for hyperchole-sterolaemia;Veterans Administration Cooperative Study Group on Antihypertensive Agents, 1975; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2VudHM8L0F1dGhvcj48WWVhcj4xOTc1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [27]RCT including continued treatment and withdrawal arm with 72 week follow upDias BP > 129 at one visit or dias BP > 114 at any 2 visits or dias BP > 104 at any 3 visits or dias BP > 94 at any 5 visits or any major cardiovascular complicationsWithdrawal group: n = 60 ; mean age = 52.2 years; treated group: n=26; mean age 52.8 years; all menInclusion: participant of previous AHT trial; dias BP for 2 preceding visits ≤ 90 mmHg; no dias BP > 95 mmHg during any of the 3 preceding visits; average dias BP during preceding 12 months ≤95 mmHgNumber of participants remaining below threshold BPHydrochlorothiazide, reserpine and hydralazine23% (14 out of 60)At 72 weeks: 15% (9 out of 60)Lower BP levels prior to entrance into AHT trial (preceding withdrawal trial); no correlation with age; Small sample size; no sys BP threshold value set;Wahi et al., 1993; India PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhpPC9BdXRob3I+PFllYXI+MTk5MzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [28]Prospective cohort study with a 1 year follow up160/90 at 2 readings or 200/110 at one readingn = 42; mean age = 40.7; (range 22 to 65); 30 men;Inclusion: 15-65 years; no secondary HT; on AHT; had BP on 2 occasions before start of AHT; at least 6 months of AHT; no contraindication to AHT withdrawal; possibility to follow up for a minimum of 1 year; BP averaging less than 140/85mmHg in 6 months before withdrawal and 140/90 mmHg on start of withdrawalNumber of participants remaining below threshold BPAny61.9% (26 out of 42)at 12 months: 42.8% (18 out of 42); at 100 weeks 33% (14 out of 42) Being younger, having milder HT, a shorter period of diagnosed HT and using monotherapy was related to remaining drug free for longerSmall sample size; sample not well described; AHT: antihypertensive treatment; dias: diastolic; HT: hypertension; sys: systolic; sig: significant; References ADDIN EN.REFLIST 1.Alderman, M.H., et al., Antihypertensive drug therapy withdrawal in a general population. Archives of Internal Medicine, 1986. 146(7): p. 1309-11.2.Aylett, M., et al., Stopping drug treatment of hypertension: experience in 18 British general practices. British Journal of General Practice, 1999. 49(449): p. 977-80.3.Beltman, F.W., et al., Predictive value of ambulatory blood pressure shortly after withdrawal of antihypertensive drugs in primary care patients. BMJ, 1996. 313(7054): p. 404-6.4.Danielson, M. and M. Lundback, Withdrawal of antihypertensive drugs in mild hypertension. Acta Medica Scandinavica - Supplementum, 1981. 646: p. 127-31.5.Ekbom, T., et al., A 5-year prospective, observational study of the withdrawal of antihypertensive treatment in elderly people. Journal of Internal Medicine, 1994. 235(6): p. 581-8.6.Fernandez, P.G., A.B. Galway, and B.K. Kim, Prolonged normotension following cessation of therapy in uncomplicated essential hypertension. Clinical & Investigative Medicine - Medecine Clinique et Experimentale, 1982. 5(1): p. 31-7.7.Fernandez, P.G., et al., Separation of essential hypertensive patients based on blood pressure responses after the withdrawal of antihypertensive agents by step-wise discriminant analysis. Current Medical Research and Opinion, 1983. 8(7): p. 509-517.8.Fotherby, M.D. and J.F. Potter, Possibilities for antihypertensive drug therapy withdrawal in the elderly. Journal of Human Hypertension, 1994. 8(11): p. 857-63.9.Freis, E.D., et al., Effects of reduction in drugs or dosage after long-term control of systemic hypertension. American Journal of Cardiology, 1989. 63(11): p. 702-8.10.Hansen, A.G., et al., Withdrawal of antihypertensive drugs in the elderly. Acta Medica Scandinavica - Supplementum, 1983. 676: p. 178-85.11.Herlitz, H., et al., Different patterns of cellular sodium turnover in essential hypertension. Journal of Hypertension - Supplement, 1988. 6(4): p. S213-5.12.Jennings, G.L., et al., Factors influencing the success of withdrawal of antihypertensive drug therapy. Blood Pressure Supplement, 1995. 2: p. 99-107.13.Langford, H.G., et al., Return of hypertension after withdrawal of prolonged antihypertensive therapy, effect of weight loss, sodium reduction, and baseline factors. Transactions of the Association of American Physicians, 1984. 97: p. 190-6.14.Lernfelt, B., et al., Overtreatment of hypertension in the elderly? Journal of Hypertension, 1990. 8(5): p. 483-90.15.Hypertension, M.R.C.W.P.o.M., Course of blood pressure in mild hypertensives after withdrawal of long term antihypertensive treatment. Medical Research Council Working Party on Mild Hypertension. British Medical Journal Clinical Research Ed., 1986. 293(6553): p. 988-92.16.Mitchell, A., et al., The likelihood of remaining normotensive following antihypertensive drug withdrawal. Journal of General Internal Medicine, 1989. 4(3): p. 221-5.17.Myers, M.G., et al., Overtreatment of hypertension in the community? American Journal of Hypertension, 1996. 9(5): p. 419-25.18.Nelson, M.R., et al., Predictors of normotension on withdrawal of antihypertensive drugs in elderly patients: prospective study in second Australian national blood pressure study cohort. BMJ, 2002. 325(7368): p. 815.19.Nelson, M.R., et al., Short-term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in the second Australian National Blood Pressure Study (ANBP2). American Journal of Hypertension, 2003. 16(1): p. 39-45.20.Prasad, N., et al., Safe withdrawal of monotherapy for hypertension is poorly effective and not likely to reduce health-care costs. Journal of Hypertension, 1997. 15(12 Pt 1): p. 1519-26.21.Preston, R.A., et al., Placebo-associated blood pressure response and adverse effects in the treatment of hypertension: observations from a Department of Veterans Affairs Cooperative Study. Archives of Internal Medicine, 2000. 160(10): p. 1449-54.22.Sasamura, H., et al., Feasibility of regression of hypertension using contemporary antihypertensive agents. American Journal of Hypertension, 2013. 26(12): p. 1381-1388.23.Sieg-Dobrescu, D., et al., The return of increased blood pressure after discontinuation of antihypertensive treatment is associated with an impaired post-ischemic skin blood flow response. Journal of Hypertension, 2001. 19(8): p. 1387-92.24.Schmieder, R.E., et al., Discontinuation of antihypertensive therapy: prevalence of relapses and predictors of successful withdrawal in a hypertensive community. Cardiology, 1997. 88(3): p. 277-84.25.van den Bosch, W.J., et al., Withdrawal of antihypertensive drugs in selected patients. Lancet, 1994. 343(8906): p. 1157.26.van Duijn, H.J., et al., Revised guidelines for cardiovascular risk management - time to stop medication? A practice-based intervention study. British Journal of General Practice, 2011. 61(587): p. e347-52.27.Agents, V.A.C.S.G.o.A., Return of elevated blood pressure after withdrawal of antihypertensive drugs. Circulation, 1975. 51(6): p. 1107-13.28.Wahi, S., S. Sagar, and B.K. Sharma, Is a hypertensive always a hypertensive? Journal of the Association of Physicians of India, 1993. 41(4): p. 198-9.Supplementary digital content 2: Studies reporting adverse events or changes potentially leading to adverse events following withdrawal of AHTAuthor Date CountryStudy designThreshold for hypertension in mmHgSample size and ageEligibility criteriaStudy outcomesAHT used before withdrawalChanges following withdrawalStudy limitationsAmes & Hill, 1982; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbWVzPC9BdXRob3I+PFllYXI+MTk4MjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [1] Prospective cohort study with 4-21 weeks follow upDias BP>90n = 35; mean age = 53 (SD 9); 25 men, 10 womenInclusion: on conventional AHTChanges of glycohemoglobin and indices of lipid metabolism following withdrawal of AHTAnyTotal serum cholesterol sig. decreased after withdrawal of diuretics and combination therapy; triglyceride decreased sig after discontinuation of combination therapy but not diuretics; the ratio of total cholesterol to HDL cholesterol sig decreased after discontinuation of diuretics but not of combination therapy; glycohemoglobin was sig. lower after discontinuation of combination therapy but not of diuretics; one participant developed headache after withdrawal of chlorthalidone. Small sample size; Andersen et al., 2003; Denmark PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNlbjwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+
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ADDIN EN.CITE.DATA [2]RCT for treatment of people with diabetes with irbesartan; 1 month withdrawal period after trial165/95n= 91 for those withdrawing after trial; placebo: n = 48; mean age = 57 (SD 9); men n = 35; irbesartan 150mg: n = 42; mean age = 57 (SD 9); men n = 33; irbesartan 300mg: n = 43; mean age = 55 (SD 9); men n = 31; Inclusion: people with HT, type 2 diabetes and microalbuminuriaChange of mean BP levels after withdrawal of AHT; excretion rate of urinary albuminIrbesartan BP levels were unchanged at follow up in placebo group but had sig increased in irbesartan groups; following withdrawal, urinary albumin excretion rate did not change sig. in the placebo group or irbesartan 300mg group but sig increased in irbesartan 150mg group (by 68%); Small sample sizes;Andersen et al., 2008; Iceland (same study as Andersen et al., 2009, different outcomes reported) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNlbjwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+
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ADDIN EN.CITE.DATA [3]Withdrawal RCT following AHT RCT with 1 month withdrawal period after trial - Following re- randomisation before drug withdrawal: aliskiren withdrawal group: n= 163; aliskiren treatment group n = 170; ramipril withdrawal group n = 177; ramipril treatment group = 165; mean age: aliskiren group = 54.2 (SD 11.2); ramipril group = 53.0 (SD 10.1), 58.3% men in aliskiren group; 71% men in Ramipril groupInclusion : age 18+; dias BP 90-110; exclusion: BP> 180/110; secondary hypertension; diabetes; history of cerebrovascular or cardiovascular disease; any condition that may affect the evaluation of efficacy or safety data or alter the absorption, distribution , metabolism or excretion of study drugs;Efficacy, safety and tolerability of aliskiren and ramipril; Aliskiren and ramiprilFollowing withdrawal, BP increased more rapidly in ramipril group compared to aliskiren group; incidents of adverse events during withdrawal were similar in those who stopped and continued aliskiren. Those who stopped ramipril or continued had higher rates of AE than those in the aliskiren group but there was no significant difference between continuing and stopping ramipril treatment; 3 SAEs occurred but none were considered related to study medication; changes in biochemistry and haematology parameters during withdrawal were small with no clinically meaningful differences between groups Large sample size; same study as Anderson et al., 2009;Andersen et al., 2009; Iceland PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNlbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA [4]Withdrawal RCT following AHT RCT with 1 month withdrawal period after trial - Following re- randomisation before drug withdrawal: aliskiren withdrawal group: n= 163; aliskiren treatment group n = 170; ramipril withdrawal group n = 177; ramipril treatment group = 165; mean age: aliskiren group = 54.2 (SD 11.2); ramipril group = 53.0 (SD 10.1), 58.3% men in aliskiren group; 71% men in Ramipril groupInclusion : age 18+; dias BP 90-110; exclusion: BP> 180/110; secondary hypertension; diabetes; history of cerebrovascular or cardiovascular disease; any condition that may affect the evaluation of efficacy or safety data or alter the absorption, distribution , metabolism or excretion of study drugs;Change in BP levels after withdrawal; plasma renin activity (PRA) and plasma renin concentration (PRC)Aliskiren and ramiprilBP reductions persisted for longer after withdrawing aliskiren compared to ramipril; most increase occurred 1 week after stopping ramipril, while BP increased more gradually after stopping aliskiren; PRC decreased within 2 weeks after withdrawing AHT to pre-treatment levels; PRA levels were increased in those withdrawing from aliskiren but decreased rapidly in those who had stopped ramipril; geometric mean valuses for urinary albumin creatinine ratio did not change significantlyLarge sample size; same study as Anderson et al., 2008;Bishu et al., 2006; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXNodTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [5]Prospective cohort study with a max of 5 week withdrawal period150/90 using ABPMn = 41; mean age = 56.2 years (SD 14.1); men n = 19 (46%);Inclusion: age 18+; diagnosed with end stage renal disease; treated with haemodialysis (HD) for at least 3 months and hypertension; exclusion: atrial fibrillation, BMI ≥ 40; history of missing one or more HD in the previous month; known drug abuse; severe chronic obstructive airway disease; stroke or myocardial infarction within the previous 6 monthsProportion of chronic HD patients remain normotensive when AHT was withdrawnAnyEchocardiograms after the withdrawal period showed that the mean left ventricular mass index in those who remained normotensive was sig lower compared to those who remained hypertensive; sig less people who remained normotensive had left ventricular hypertrophy compared to those who were hypertensive at the end of the withdrawal periodSmall sample size; Bruce et al., 1979; USA ADDIN EN.CITE <EndNote><Cite><Author>Bruce</Author><Year>1979</Year><RecNum>1158</RecNum><DisplayText>[6]</DisplayText><record><rec-number>1158</rec-number><foreign-keys><key app="EN" db-id="x5wrse29rw90sue5atw5r02sswzzfavtdtfw" timestamp="1430484139">1158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bruce, D. L.</author><author>Croley, T. F.</author><author>Lee, J. S.</author></authors></contributors><titles><title>Preoperative clonidine withdrawal syndrome</title><secondary-title>Anesthesiology</secondary-title><alt-title>Anesthesiology</alt-title></titles><periodical><full-title>Anesthesiology</full-title><abbr-1>Anesthesiology</abbr-1></periodical><alt-periodical><full-title>Anesthesiology</full-title><abbr-1>Anesthesiology</abbr-1></alt-periodical><pages>90-2</pages><volume>51</volume><number>1</number><keywords><keyword>Antihypertensive Agents</keyword><keyword>*Clonidine</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Preoperative Care</keyword><keyword>*Substance Withdrawal Syndrome/et [Etiology]</keyword><keyword>Syndrome</keyword><keyword>0 (Antihypertensive Agents)</keyword><keyword>MN3L5RMN02 (Clonidine)</keyword></keywords><dates><year>1979</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0003-3022</isbn><accession-num>453602</accession-num><work-type>Case Reports</work-type><urls><related-urls><url> Technologies</remote-database-provider><language>English</language></record></Cite></EndNote>[6]Report of 2 case studiesn/an=2; age 54 and 52; both men;Not reportedEffects of clonidine withdrawalClonidine Rebound hypertension after 12h following abrupt withdrawal; Case studiesByyny et al., 1996; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CeXlueTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [7]RCT followed by 24h withdrawal n/an=100; mean age = 54.3 (SD9.8) years; 60 menInclusion: mild to moderate HT (dias BP 95-120 mmHg); age 21-72 years; within 30% of body weight; exclusion: black people; active medical problems that might affect the treatment of their HT; no drug treatment that might affect BPSafety of LosartanLosartan and EnalaprilBP returned slowly towards baseline in all treatment groups after 24 hours; no clinically important patterns in mean changes in pulse rate for any of the treatment group (not statistically tested)Sample includes men only; short withdrawal follow-up period; Caruana et al., 1985; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJ1YW5hPC9BdXRob3I+PFllYXI+MTk4NTwvWWVhcj48
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ADDIN EN.CITE.DATA [8]Prospective cohort study with a 24 h withdrawal period following treatment with pinacidiln/an=9; age and sex not reported;Inclusion: patient at a hypertension clinicDuration of action and useful dose-range of pinacidilPinacidilNo evidence of rebound HTVery small sample size; demo-graphic character-istics not reported; short withdrawal follow-up period;Cooper et al., 1988; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db29wZXI8L0F1dGhvcj48WWVhcj4xOTg4PC9ZZWFyPjxS
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AAA=
ADDIN EN.CITE.DATA [9]Comparison of previously treated and untreated patients with HT following a 2 week withdrawal periodn/an =11710; age range: 18-97; 45.3% male; previously treated n= 7210 (61.6%); previously not treated n=4500 (38.4%)Inclusion: diagnosed with HTEffect of therapy withdrawalAnyA sig increase was found in frequency of headache following withdrawal in all AHT medication groups, except in previously untreated patients and in those on a calcium antagonistVery large sample size; type of statistical test not reported De Cesaris et al., 1993; Italy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBDZXNhcmlzPC9BdXRob3I+PFllYXI+MTk5MzwvWWVh
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ADDIN EN.CITE.DATA [10]4 week prospective withdrawal study following a 10 months RCT comparing lisinopril and metoprolol 150/90Total n = 44; lisinopril group n=22; mean age = 47.2 (SD 10); 11 men; metoprolol group n = 22; mean age = 46.1 (SD 9.4); 12 men;Inclusion: mild to moderate essential hypertension as documented on three outpatient visitsEffects of lisinopril and metoprololLisinopril and metoprololLisinopril group: sig increase in brachial artery diameter and compliance and a decrease in vascular resistance and pulse wave velocity persisted after 4 weeks of withdrawal (values similar to those during treatment); Metoprolol group: no change in forearm hemodynamics;Small sample size;Ekbom et al., 1994; Sweden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fa2JvbTwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [11]Observational study with a 5 year follow-up including participants of the wash-out phase of the STOP -Hypertension trialNo level set, restarting AHT depended on GP advicen=333; mean age= 75.2 (SD 3.8; range 70-84); 32% menInclusion: hypertension; between 70 to 84 years oldTime until AHT was re-started AnyNo sig. difference between groups in total death hazard; those withdrawing had a sig. lower risk of cardiovascular events compared to those remaining in the treatment arms of the STOP-Hypertension trialVery large sample size; sample Eldridge et al., 1984; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGRyaWRnZTwvQXV0aG9yPjxZZWFyPjE5ODQ8L1llYXI+
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ADDIN EN.CITE.DATA [12]One week prospective withdrawal study following a 24 months RCT comparing hydrochlorothiazise (HCTZ) and guanabenzn/aTotal n = 45; age range: 28 to 75; 20 menInclusion: essential HT; exclusion: clinically significant cardiac, hepatic, renal or endocrinologic impairmentsEndocrinologic effects of HCTZ and GuanabenzHCTZ and GuanabenzNo changes in levels of growth hormones, prolactin or insulin following withdrawal of HCTZ or guanabenz; no changes in glucagon levels following guanabenz withdrawal; glucagon levels sig decreased following HCTZ withdrawal;Small sample size;Fotherby & Potter, 1994a; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3RoZXJieTwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+
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ADDIN EN.CITE.DATA [13]Prospective cohort study with a 1 year follow up175/100n = 47; median age= 76 years, (range 68-82); Inclusion: ≥ 65 years; BP <175/100 mmHg; on AHT for more than one year; currently attending hypertension clinic; exclusion: MI or stroke within the last 6 months; angina or known major illness, diabetes and other diseases to affect BPOrthostatic HTThiazide diuretics, calcium antagonists and beta-adrenoceptor antagonistsFollowing withdrawal from AHT, numbers of people having orthostatic HT sig. fell from 11 (23%) to 4 (11%) by 12 monthsSmall sample size; participant characteristics not well reported;Freis et al, 1989; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmVpczwvQXV0aG9yPjxZZWFyPjE5ODk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [14]RCT comparing AHT reduction, AHT withdrawal and control group after baseline phase of receiving different doses of hydrochlorothiazide (HCTZ) followed up for up to 30 monthsDiastolic BP 85-90 depending on previously or newly diagnosed; no threshold for systolic BPtotal n=606; AHT discontinued n = 137; mean age = 56.9 years; all men;Inclusion: previously diagnosed with a dias BP was <115 mmHg and newly diagnosed patients with a dias BP between 90-95 mmHg; exclusion: malignant HT, haemorrhagic stroke, recent myocardial infarction, history of alcoholism or drug abuse, contraindication to study;Number of participants who maintained control BP; changes in blood chemistry (glucose, potassium, cholesterol, triglycerides, uric acid and alkaline phosphatase)HCTZNo sig. changes in glucose and triglycerides levels; sig. increase in serum potassium and alkaline phosphatase levels and a sig. decrease in serum uric acid at 6 months in withdrawal group;Very large sample size; only low dose HCTZ discontinued included men only; Gerlis & Wright, 1980; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZXJsaXM8L0F1dGhvcj48WWVhcj4xOTgwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [15]Prospective cohort study of 12 months tiamenidine treatment with a 36 h follow-up after withdrawal of AHTn/an = 10; mean age = 47 years; men n = 3;Inclusion: essential HT; pre-treatment resting BP > 150/100 mmHg; Effects of abrupt withdrawal; outcomes incl. rebound HT and biochemistries to assess catecholamine activity (urea, electrolytes, uric acid, haemoglobin, urinary sodium and metanephine levels)TiamenidineSlight but non-sig. raise of pulse rate following withdrawal; no consistent evidence of excess catecholamine activity; evidence of systolic but not diastolic rebound HT following abrupt withdrawal; Very small sample size; short withdrawal follow-up period; Goldberg et al., 1977; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2xkYmVyZzwvQXV0aG9yPjxZZWFyPjE5Nzc8L1llYXI+
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ADDIN EN.CITE.DATA [16]Prospective cohort study with 3 day follow-upn/an = 26; age range: 31 - 68; men n =15; Inclusion: single drug AHTImmediate effects of withdrawal on heart rate AnyAHTs were categorised into 4 groups: clonidine, postganglionic neurone-blocking drugs, methyldopa and beta blockers; clonidine withdrawal: sig. increase in heart rate with intense ectopic activity; postganglionic neurone-blocking drug withdrawal: similar but less pronounced reaction with increased ventricular ectopic activity; no alarming reactions after withdrawal of metyldopa or beta blockers; Small sample size; short withdrawal follow-up period;Hajjar et al, 2013; US PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWpqYXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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AAA=
ADDIN EN.CITE.DATA [17]Prospective cohort study with a 3-4 week follow-upn/an = 53; mean age = 71 (SD 7) years; 44% men; Inclusion: currently receiving AHTSafety of short term AHT withdrawalAnyIn 2% of readings BP exceeded 180/100 mmHg but not in 2 consecutive readings; none of the participants reported headaches, dizziness, visual changes or focal weakness during withdrawal phase; Small sample size; Hansen et al., 1995 Denmark PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW5zZW48L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [18]Prospective cohort study with a 1 month follow-upn/an = 42; mean age = 40 (SD 7); men n = 26; Inclusion: patients who are on AHT and insulin dependent with diabetic nephropathyBP, GFR and albuminuriaAnyBP, GFR and albuminuria were all sig increased after 1 month withdrawal(although 20-25% of participants had unchanged BP, GFR and or albuminuria)Small sample size; Hansen et al., 1997; Denmark PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW5zZW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [19]Prospective cohort study with a 1 month follow-upn/an = 40; mean age = 61 (SD 7); men n = 29;Inclusion: GFR> 25 ml · min-1 · 1.73m-2; receiving AHT for > 1 year; age between 18 and 75 years; not insulin dependentBP, GFR and albuminuriaAnyBP and albuminuria levels sig increased after 4 weeks of withdrawal. There was no sig change in GFR. 10-17% of participants had a decrease in BP and/or albuminuriaSmall sample size; Hansson & H?kfelt, 1981; Sweden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW5zc29uPC9BdXRob3I+PFllYXI+MTk4MTwvWWVhcj48
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ADDIN EN.CITE.DATA [20]Withdrawal phases (3 days) in cross-over study assessing effects of tiamenidine or clonidinen/aSample size and age not reported; all men; Inclusion: primary essential moderate HT, between 20 and 65 years old, male; exclusion: concomitant renal, cardiovascular or cerebrovascular complications or severe intercurrent illness, receiving sedatives, tranquillisers, antidepressants, cardiac glycosides or diuretics BP, weight change, plasma noradrenaline, plasma adrenaline, urinary catecholamines and plasma renin activityTiamenidine or clonidineBP, plasma noradrenaline, plasma adrenaline, urinary catecholamines and plasma renin activity levels after withdrawal overshot baseline levels; no sig. change in weight; Sample size and demographics not reported; only men included; short withdrawal follow-up period; Ikeda et al., 1997; USA; PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ja2VkYTwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [21]One week cross-sectional withdrawal study following 12 weeks of AHT RCTn/an = 366; mean age 54 (range 26-78); 64% menInclusion: mild to moderate HT, at least 21 years old; exclusion: no medical problems that might affect treatment of HT, no drugs that might affect BP, pregnant or lactating females; medical conditions that might put patient at undue risk, adversely affect participation in trial or compromise quality of data obtainedEfficacy and safety of AHTLosartanNo evidence of rebound HTLarge sample size; Jennings et al., 1984; Australia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KZW5uaW5nczwvQXV0aG9yPjxZZWFyPjE5ODQ8L1llYXI+
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ADDIN EN.CITE.DATA [22]Prospective cohort study with a up to 20 week follow-up n/an = 11; mean age = 51.5 (SD 3.4); men n = 5;Inclusion: Uncomplicated essential hypertension which has been treated for at least 1 year; BP < 160/90 mmHg at last visitBP levels after withdrawal, total peripheral resistance index (TPRI) , plasma renin activity, noradrenaline and adrenaline, 24h urinary aldosterone and electrolyte excretionAnyFollowing withdrawal the non-autonomic TPRI raised sig. to a normal level; plasma renin activity rose following withdrawal of diuretics but remained constant thereafter; noradrenaline, adrenaline, 24h urinary aldosterone and electrolyte levels as expected after drug withdrawal; Very small sample size; Kirch & Distler, 1978; Germany PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXJjaDwvQXV0aG9yPjxZZWFyPjE5Nzg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [23]Double blind crossover study with 2 week withdrawal periodn/an = 21; mean age = 48.5 years (range 18-63); men n = 12; Inclusion: essential HT; exclusion: any form of secondary HT;Effectiveness and side effects of N- amidino-2- acetamide hydrochloride and clonidine N-amidino-2- acetamide hydrochloride and clonidineTwo days after abruptly stopping AHT rebound HT was determined following clonidine treatment onlySmall sample size; recruitment and selection not well reported; Lacourciere et al., 1998; Canada PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYWNvdXJjaWVyZTwvQXV0aG9yPjxZZWFyPjE5OTg8L1ll
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ADDIN EN.CITE.DATA [24]AHT RCT followed by a 2 week wash-out periodn/an = 278; mean age = 53.4 (SD 9.5) years; 67% men;Inclusion: mild to moderate HT; age between 21 and 70 years; exclusion: secondary HT; cardiac, pulmonary, renal, neurologic, hepatic, hematologic or metabolic disease, hypersensitivity to angiotensin II antagonists or using drugs acting on BP; women with childbearing potentialEffects of 4 doses of tasosartanTasosartanNo rebound HT after withdrawal of AHTVery large sample size; well reported study;Lernfelt et al; 1990; Sweden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXJuZmVsdDwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+
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ADDIN EN.CITE.DATA [25]Prospective cohort study with 2 year follow-up200/105n=25; age = 70; 10 men (40%)Inclusion: part of the '70 year old people in Gothenburg, Sweden' study; using AHT; exclusion: BP> 175/95 mmHg; cardiovascular disease; EEG abnormalities; increased heart volume; other serious diseasesBP, heart rate, left ventricular (LV) morphology, LV diastolic function, LV ejection phase indices, LV wall stress, ECGAnyNo sig. change in LV morphology and LV diastolic function; sig. decrease in fractional shortening and ejection fraction; slight but sig. increase in end-systolic wall stress; four participants showed signs of cardiovascular disorders after withdrawal but the authors were unable to determine if this was a consequence of the withdrawal study;Small sample size; Ljungman et al., 1988; Sweden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ManVuZ21hbjwvQXV0aG9yPjxZZWFyPjE5ODg8L1llYXI+
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AD==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ManVuZ21hbjwvQXV0aG9yPjxZZWFyPjE5ODg8L1llYXI+
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AD==
ADDIN EN.CITE.DATA [26]Cross sectional cohort study with 7 years of AHT and subsequent withdrawal170/105n = 120; mean age = 49; all menInclusion: 49 years old, male; exclusion: previous AHT, malignant or secondary HT;Renal function (GFR, renal plasma flow, renal blood flow, renal vascular resistance)Metoprolol, hydrochlorothiazide and hydralazineBP levels returned to HT after a median time of 10 weeks; no sig changes in renal function after AHT withdrawal except for increase in renal vascular resistanceLarge sample size; only men Middeke et al., 1990; Germany PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWRkZWtlPC9BdXRob3I+PFllYXI+MTk5MDwvWWVhcj48
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ADDIN EN.CITE.DATA [27]RCT with subsequent withdrawal study for 4 weeksn/an = 40; age not reported; all maleInclusion: essential hypertensionCholesterol, high and low density lipoproteins, triglycerides in serumDiuretics: hydrochlorothiazide (in n = 23) and beta blocker: atenolol ( in n = 17)No sig change in heart rate in diuretic group but sig increase in heart rate in beta blocker group following withdrawal; after discontinuation of diuretics sig decrease in total cholesterol and low density lipoproteins, but no sig change in high density lipoproteins or triglycerides; following withdrawal of beta blockers sig decrease of low density lipoproteins and triglycerides but sig increase of high density lipoproteinsSmall sample size; recruitment and selection not well reported; Miller et al., 1994; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsZXI8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [28]Open label trial with quinapril followed by a 4 week withdrawal RCT including a placebo and a quinapril treatment groups for moderate renal impairment and chronic renal failuren/aModerate renal impairment (MRI) group: placebo: n=10; mean age= 42 (SD 3.5); men n = 5; quinapril: n = 10; mean age= 48 (SD 3.6); men n= 8; chronic renal failure (CRF) group: placebo: n=13; mean age = 55 (SD 3.7); men n= 10; quinapril: n= 15; mean age = 53 (SD 3.5), men n = 5;Inclusion: moderate renal impairment or chronic renal failureBP levels after withdrawal of AHT; change in creatinine clearance; mean urinary protein; blood urea nitrogenQuinaprilSig increase of mean sitting BP in placebo compared to quinapril groups (MRI and CRF); no sig difference in creatinine clearance between groups; sig greater increase of mean urinary protein in placebo compared to quinapril group in patients with CRF but in patients with MRI only borderline sig; mean blood urea nitrogen decreased sig in placebo compared with quinapil group in CRF group but not in MRI group; Very small sample sizes; Muiesan et al., 2000; Italy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdWllc2FuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48
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ADDIN EN.CITE.DATA [29]Prospective cohort study with treatment and 4 week withdrawal phasen/an = 68; mean age = 47 (SD 9) years; age range: 22-62; men n = 50;Inclusion: uncomplicated HT, prior to study untreated; exclusion: coronary and/or vascular heart disease, heart failureChanges in left ventricular (LV) performanceAngiotensin converting enzyme inhibitors, calcium antagonists or a combination of bothNo sig changes in LV mass index, relative wall thickness, endocardial or midwall fractional shortening and LV diastolic diameter following withdrawal; Small sample size; Myers et al., 1996; Canada PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NeWVyczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [30]Cohort withdrawal study with regular BP monitoring at 1,2,4,8 weeks and then 6-8 weeks intervals (incl. ambulatory monitoring) Mean of two ambulatory BP recordings exceeding 160/95 for restart of medication; 150/90 and 140/90 cut-offs were also considered for % remaining normotensive at 1 yearn=98; mean age: 62 years (SD 2; range 21-80); men n = 36;Inclusion: receiving AHT exclusion: target organ damage, secondary HT, cardiac arrhythmias, receiving other medication affecting their BP; if mean ambulatory sys BP ≥160 or dias BP ≥ 95 mmHg; if AHT had been changed in the last 3 monthsProportion of patients remaining off treatment at 1 yearAnyWithdrawal of AHT had not effect on left ventricular mass Nami et al., 1983; Italy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYW1pPC9BdXRob3I+PFllYXI+MTk4MzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [31]AHT RCT followed by a 6 day withdrawal periodn/aClonidine group: n = 10; mean age = 60.8 (SD 914); men n= 5;Inclusion: stable mild to moderate HT who had not been refractory to previous single drug therapy; supine dias BP 95-120 mmHg after placebo run-in period exclusion: target organ damage, diabetes, liver or renal diseases; pregnant women, people with alcohol problems; BP, heart rate, urinary catecholamines, cyclic nuceotidesClonidine or guanfacine (not reported as out-dated)Clonidine group: BP levels and pulse rate returned to pre-treatment levels within 2 days and sometimes went sig. above them in the following days (no stat. test results reported); Urinary catecholamine and urinary cyclic nucleotides levels returned to baseline values and to higher (but not sig higher) levels the following days; side effects of withdrawal of clonidine included headache ( in 9 out of 10 pp), palpitations (5/10), dizziness (2/10), sweating (2/10) and facial flushing (1/10);Very small sample size; recruitment not reported; short withdrawal follow-up period; Panza et al., 1993; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYW56YTwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [32]Case-control AHT study with a 2 weeks withdrawal periodn/aHT group: n = 15; mean age = 54.1 (SD 12) years; men n = 11; control group (without history of HT) n= 15; mean age = 52.3 (SD 7) years; men n= 10Inclusion HT group: history of chronically elevated BP (≥145/95 mmHg); no apparent underlying cause of HT; normotensive when on AHT; exclusion: BP remained elevated despite AHT; control group: matched cases without HTResponse of vasculature following withdrawalAnyDuring withdrawal, increase in blood flow and decrease in vascular resistance with acetylcholine were sig lower in withdrawal group compared to control group (no history of HT); no sig differences between forearm blood flow and vascular resistance response to sodium nitroprusside between groups during withdrawal; heart rate was similar during treatment and withdrawal phasesVery small sample size; well reported study;Pedersen, 1976; Denmark PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZWRlcnNlbjwvQXV0aG9yPjxZZWFyPjE5NzY8L1llYXI+
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ADDIN EN.CITE.DATA [33]Crossover comparison of metoprolol and hydrocholothiazide with a 8 week placebo period between the two treatmentsn/an = 20; mean age = 44 (range 29-63 years); men n = 10;Inclusion: mild arterial essential HT; exclusion: chronic bronchitis, bronchial asthma, cardiac failure, diabetes mellitusBP level and heart rateMetoprolol and hydrochlorothiazideFive out of 20 patients had subjective symptoms following withdrawal of metoprolol: general malaise, palpitations and headacheSmall sample size; recruitment not reported; Pedrinelli et al., 2000; Italy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZWRyaW5lbGxpPC9BdXRob3I+PFllYXI+MjAwMDwvWWVh
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ADDIN EN.CITE.DATA [34]Two week cohort withdrawal study following AHT RCTn/an = 28; age range: 33-77 years; all menInclusion: mild essential HT; exclusion: secondary HTSkin blood flow (laser doppler flowmetry), leg weightAmlodipine, enalapril, and enalapril and amlodipine combinedResting and dependent skin flow as well as leg weight increased during treatment with amlodipine and amlodipine and enalapril combination (not enalapril alone) and recovered during withdrawal; Small sample size; study includes men only; Perlini et al., 2001; Italy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXJsaW5pPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48
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ADDIN EN.CITE.DATA [35]One month cohort withdrawal study following AHT RCTn/an = 152; age and sex not reported;Inclusion: essential HT, age range 20-65 years, dias BP between 95-115 after 4 weeks without AHT, left ventricular hypertrophy (LVH); exclusion: history or signs of cardiovascular complications or major target organ damage, major cardiovascular or non- cardiovascular disease besides HT, pregnancy, lactation, contraindications to study drugs, conditions that would prevent data collection, atrial fibrillation, using >2 AHTLVHLisinopril or lininopril and hydrochlorothiazideDuring withdrawal after AHT RCT, only one third of treatment induced LVH regression was reversed; Circumferential end-systolic stress returned to pre-treatment values after AHT withdrawal; improvement in midwall fractional shortening persisted after withdrawal period; BP levels returned to pre-treatment levels following withdrawal; relative wall thickness was reduced by AHT and did not change after withdrawal; Large sample size; demographic characteristics not reported;Petretta et al., 1996; Italy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXRyZXR0YTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+
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Tm90ZT4AAAA=
ADDIN EN.CITE.DATA [36]Prospective cohort study with 1 month withdrawaln/an = 30; mean age = 48 (SD 8); men n= 18Inclusion: uncomplicated essential HT, LVH; Exclusion: age > 70 years, diagnosis of angina, myocardial infarction, vascular heart disease, heart failure, atrial fibrillation, diabetes mellitus, renal failure, obesity, poor exercise capacity as a result of a lung disease, musculoskeletal problems, decreased left ventricular systolic function , abnormal or doubtful thallium stress tests resultsCardiac autonomic controlLisinopril Following withdrawal, BP rose to pre-treatment baseline levels; left ventricular mass index did not change after withdrawal; the increase of night-time high frequency power of heart period variability due to treatment remained detectable after withdrawal; in people with LVM normalisation, day and night-time high-frequency powers increased; in people with LVM reduction without normalisation power spectral measures of heart period variability were sig lower than in those with LVM normalisation. Small sample size; recruitment not reported; Pl?nitz, 1984; Germany PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QbGFuaXR6PC9BdXRob3I+PFllYXI+MTk4NDwvWWVhcj48
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ADDIN EN.CITE.DATA [37]Three day withdrawal study following 4 weeks of a AHT RCT cross-over studyn/aMoxonidine followed by clonidine group: n = 10; mean age= 41 (SD 5.8) years; men n= 7; clonidine followed by moxonidine group: n = 10; mean age 39 (SD 7.5) years, men n = 6Inclusion: uncomplicated essential HT; exclusion: additional ailmentsBP levels and withdrawal reactionsMoxonidine and clonidineAfter abrupt discontinuation of clonidine therapy, there was a more rapid rise in BP than after stop of moxonidine therapy; There was no indication of overshoot in either treatment group; no subjective withdrawal symptoms such as anxiety, insomnia, sweating, headache or tachycardia were observed after abrupt stop of either drug.Very small sample size; short withdrawal follow-up period Pool et al., 1998; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb29sPC9BdXRob3I+PFllYXI+MTk5ODwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [38]One week withdrawal study following 8 weeks of AHT RCTn/an = 570; mean age = 54.2 years (SD 10.3); 67% men; Inclusion: age 18 years or older; well established history of mild to moderate HT, women sterile or post- menopausal; exclusion: diseases that would present safety hazards or concomitant medications that might interfere with the assessment of the safety or efficacy of irbesartanEfficacy, safety, pharmacokinetics and pharmacodynamicsIrbesartan No indication of rebound HTVery large sample size; Prasad et al, 1997; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmFzYWQ8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [40]RCT including active treatment and placebo groups with 1 year follow-up of the placebo groupDias BP>95n = 1292; active treatment group: n = 1105; placebo group n = 187; no mean age reported; all men;Inclusion: age > 21 years, reasonable expectation that dias BP would be between 95 and 105 mmHg with placebo; exclusion: secondary HTResponse to placebo at 1 year follow up and effect of race and age on responseNot reportedHeadache and joint pain was sig more often reported in the placebo group compared to the treatment group and sleepiness was sig more often reported in the active treatment group compared to the placebo group. There was no difference in fatigue, weakness, nightmares, vivid dreams, sleep disturbance, stomach cramps, diarrhoea, constipation, vertigo, dizziness, nausea, muscle cramps, impotence, loss of libido, cold extremities, palpitations, chest pain, change in taste or dry mouthVery large sample size; sample not well described;;Saul et al., 2013; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXVsPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [41]One month withdrawal study following AHT RCTn/aCarvedilol and lisinopril group: n = 23, mean age = 52 (SD 13) years, men n = 17; Carvedilol group n = 24, age = 53 (SD 10) years, men n = 17; Lisinopril group n = 21, age = 53 (SD 10) years, men n = 16; Placebo group n = 23, age = 51 (SD 13) years, men n = 15;BP prehypertensive or hypertensive (≥ 130/85 mmHg), not taking AHT, additional risk factor; exclusion: previous cardiovascular events, current pregnancy or lactation, use of AHT or other cardiac medication, other serious medical conditions;Cardiovascular healthCarvedilol, lisinopril and a combination of bothAll changes due to AHT were reversed following withdrawal (sig decrease of BP levels, small borderline sig improvement of disease score for cardiovascular health (scores for small and large artery elasticity, resting BP, exercise BP, retinal analysis, electrocardiography, carotid intimal media thickness, LVM, microalbuminuria, N-terminal pro B-type natriuretic peptide) and metabolic parameters;Small sample size; sig. of changes of individual parameters not reported; Schmieder et al., 1985; Germany PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2htaWVkZXI8L0F1dGhvcj48WWVhcj4xOTg1PC9ZZWFy
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ADDIN EN.CITE.DATA [42]Prospective cohort study with a 5 months follow up159/94n= 47; mean age= 43.5 (SD 6 years); all menInclusion: essential hypertension, AHT monotherapy for 6 monthsBP levels after withdrawalOxprenolol and nitrendipineSig higher standing dias BP levels in people withdrawn from nitrendipine compared to those withdrawn from oxprenolol; at 2 weeks sig higher heart rate in erect position in those previously on oxprenolol compared to those on nitrendipine; at later measurements these differences disappearedSmall sample size; study includes men only; Schneider et al., 2012; Germany PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2huZWlkZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy
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ADDIN EN.CITE.DATA [43]Four to five days withdrawal study following AHT RCTn/an = 34; mean age = 54 years (SD 9; range 28-71); men n= 27 Inclusion: mean BP > 140/90 mmHg or treated arterial HT; exclusion: clinically sig liver or kidney disease, atrial fibrillation, atrioventricular blockade grade II or higher and current treatment with aliskirenRenal perfusion (measured by MRI)AliskirenFollowing withdrawal, sys and dias BP levels did not change; increase in renal perfusion, and decrease in angiotensin II and aldosterone levels due to Aliskiren was reversed following withdrawal; no changes following withdrawal in urinary angiotensinogen levels; plasma renin activity remained reduced following withdrawal; Small sample size; short follow-up; recruitment not reported; Sieg-Dobrescu et al., 2001; Switzerland PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaWVnLURvYnJlc2N1PC9BdXRob3I+PFllYXI+MjAwMTwv
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ADDIN EN.CITE.DATA [44]Withdrawal RCT with 24 week follow-up140/90Discontinuation group: mean n = 20; mean age = 48 years (SD 14.3); men n = 10; treatment continuation group: n = 20; mean age = 47 years (SD 13.2); men n = 11 Inclusion: receiving AHT for at least previous 6 months, BP < 140/90 mmHg; exclusion: requiring treatment for hypercholesterolemia, diabetes, angina pectoris or congestive heart failure, previous cardiovascular event BP levels after withdrawalAnyPost-ischemic skin blood flow responses decreased sig in those who were successfully withdrawn from AHT compared to those continuing or re-starting AHT who showed no change in blood flow responses; Very small sample size;Smith et al., 1986; UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWl0aDwvQXV0aG9yPjxZZWFyPjE5ODY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [46]One month withdrawal study following AHT cohort studyn/an = 11; mean age = 49 years (SD 1.6); men n = 9; Inclusion: mild to moderate essential HT, left ventricular hypertrophy; exclusion: coronary artery disease, diabetes mellitus, renal insufficiency, heart failure, prior myocardial infarction, secondary HT;Cardiovascular function and structure Oxazoline (rilmenidine)No sig differences between treatment and withdrawal period were found in left ventricular mass index, interventricular septum and posterior wall thickness; improvements of left ventricular diastolic function observed during treatment returned to baseline following washout; effects on forearm circulation (pulse wave velocity) and brachial artery compliance did not change after withdrawal of oxazoline; reduction in forearm vascular resistance during AHT returned to baseline after withdrawal; plasma atrial natriuretic factor levels sig decreased following AHT withdrawalVery small sample size;Van Duijn et al., 2011; Netherlands PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gRHVpam48L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy
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ADDIN EN.CITE.DATA [47]Prospective cohort study with 6 months follow upLow cardiovascular risk and patient's decision to stop or re-start AHTn= 135; age: 25-75 years; Inclusion: no known target organ damage, receiving AHT and/or medication for hypercholesterolaemia; exclusion: cardiovascular disease, taking drugs for other indications than HT or hypercholeserolaemia; Attendance for re-evaluationAnyReasons for re-starting medication were headaches (n=12), ankle oedema (n=2), not feeling well n=9), high BP and/or high cholesterol (n=32). However, in 21 of 32 patients who restarted medication because of high BP or high cholesterol the cardiovascular mortality risk would not have been high enough to advise restarting medication according to Dutch guidelines; Reasons to re-start medication reported in combination with withdrawal of medication for hypercholesterolaemiaVeterans Administration Cooperative Study Group on Antihypertensive Agents, 1975; USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2VudHM8L0F1dGhvcj48WWVhcj4xOTc1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [48]RCT including continued treatment and withdrawal arm with a 72 week follow upDias BP > 129 at one visit or dias BP > 114 at any 2 visits or dias BP > 104 at any 3 visits or dias BP > 94 at any 5 visits or any major cardiovascular complicationsWithdrawal group: n = 60 ; mean age = 52.2 years; treated group: n=26; mean age 52.8 years; all menInclusion: participant of previous AHT trial; dias BP for 2 preceding visits ≤ 90 mmHg; no dias BP > 95 mmHg during any of the 3 preceding visits; average dias BP during preceding 12 months ≤95 mmHgNumber of participants remaining below threshold BPHydrochlorothiazide, reserpine and hydralazineSerum uric acid fell sig in withdrawal but not treatment group; serum potassium rose sig in withdrawal but not treatment group; Serum creatinine did not change sig in either group; Small sample size; high dias BP threshold value; no sys BP threshold value set;Wahi et al., 1993; India PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhpPC9BdXRob3I+PFllYXI+MTk5MzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (2-4).Renin inhibitorsFollowing withdrawal of aliskiren, plasma renin activity remained reduced for up to one month PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNlbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA (5, 6) Angiotensin converting enzyme inhibitorsImprovements in forearm haemodynamics due to treatment with ACE inhibitors (significnat increase in brachial artery diameter and compliance, as well as a decrease in vascular resistance and pulse wave velocity) persisted at four weeks after withdrawal (values similar to those during treatment; PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBDZXNhcmlzPC9BdXRob3I+PFllYXI+MTk5MzwvWWVh
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ADDIN EN.CITE.DATA (9). However, withdrawal led to an increase of mean urinary protein, which was significant in people with CRF. In the CRF group, mean blood urea nitrogen significantly decreased following withdrawal in people who received placebos but did not decrease in people who had been treated with ACE inhibitors. For people with mild renal impairment, there was no significant difference. Two cohort studies investigated left ventricular changes due to withdrawal of ACE inhibitors. Both studies showed that left ventricular mass did not change significantly one month after withdrawal of ACE inhibitors PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXRyZXR0YTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+
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ADDIN EN.CITE.DATA (12). A small cross-sectional study stopping beta blockers indicated a significant decrease in low density lipoproteins and triglycerides, and a significant increase in high density lipoproteins after 4 weeks of withdrawal PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWRkZWtlPC9BdXRob3I+PFllYXI+MTk5MDwvWWVhcj48
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWRkZWtlPC9BdXRob3I+PFllYXI+MTk5MDwvWWVhcj48
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ADDIN EN.CITE.DATA (13). Following withdrawal of metoprolol, no significant changes occurred in forearm haemodynamics (brachial artery circulation, vascular resistance, pulse wave velocity) at four weeks after withdrawal PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBDZXNhcmlzPC9BdXRob3I+PFllYXI+MTk5MzwvWWVh
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AD==
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AD==
ADDIN EN.CITE.DATA (7). Following the withdrawal of clonidine, pulse rate increased significantly to pre-treatment levels within two days and occasionally significantly above that during the following four days PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYW1pPC9BdXRob3I+PFllYXI+MTk4MzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (16). In addition, withdrawal from clonidine and postganglionic neurone-blocking drugs led to intense increased ectopic activity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2xkYmVyZzwvQXV0aG9yPjxZZWFyPjE5Nzc8L1llYXI+
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2xkYmVyZzwvQXV0aG9yPjxZZWFyPjE5Nzc8L1llYXI+
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ADDIN EN.CITE.DATA (15). While a cross-over study reported that plasma renin activity levels overshot baseline levels following withdrawal of either Clonidine or Thiamenidine at three days after withdrawal PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW5zc29uPC9BdXRob3I+PFllYXI+MTk4MTwvWWVhcj48
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ADDIN EN.CITE.DATA (12). However, Pl?nitz et al. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QbGFuaXR6PC9BdXRob3I+PFllYXI+MTk4NDwvWWVhcj48
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QbGFuaXR6PC9BdXRob3I+PFllYXI+MTk4NDwvWWVhcj48
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ADDIN EN.CITE.DATA (20) found no evidence for rebound hypertension after three days following abrupt withdrawal of moxonidine or clonidine. DiureticsTwo small cohort studies and one cross sectional study indicated that stopping diuretics did not lead to a significant change in levels of growth hormones, prolactin, insulin, high density lipoproteins, triglycerides or glycohemoglobin when measured between one and 21 weeks after withdrawal PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbWVzPC9BdXRob3I+PFllYXI+MTk4MjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (11, 13, 21). The effects of thiazide diuretic withdrawal were investigated in a cohort study with a four week follow up assessment, which showed no significant change in heart rate following the withdrawal PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWRkZWtlPC9BdXRob3I+PFllYXI+MTk5MDwvWWVhcj48
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ADDIN EN.CITE.DATA (13). No studies evaluated pulse rate or haemodynamics.After withdrawal of hydrochlorothiazide, serum potassium levels had significantly increased and serum uric acid had significantly decreased when measured up to 30 months later PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmVpczwvQXV0aG9yPjxZZWFyPjE5ODk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (22, 23). No change in serum creatinine was found 72 weeks after withdrawal PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2VudHM8L0F1dGhvcj48WWVhcj4xOTc1PC9ZZWFyPjxS
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2VudHM8L0F1dGhvcj48WWVhcj4xOTc1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (23). The findings of a very small study (n=11; PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KZW5uaW5nczwvQXV0aG9yPjxZZWFyPjE5ODQ8L1llYXI+
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ADDIN EN.CITE.DATA (25). No studies evaluated pulse rate or haemodynamics following withdrawal of calcium antagonists. A cohort study with a very short follow-up at 24 h after Felodipine withdrawal did not show any change in plasma renin activity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWl0aDwvQXV0aG9yPjxZZWFyPjE5ODY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (25).VasodilatorsOnly one small cohort study with a follow-up assessment at 24 hours investigated rebound hypertension after abrupt withdrawal of pinacidil but the results showed no evidence of rebound hypertension PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJ1YW5hPC9BdXRob3I+PFllYXI+MTk4NTwvWWVhcj48
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ADDIN EN.CITE.DATA (27). These parameters remained significantly lower after withdrawal compared to the baseline assessment before Rilmenidine treatment. LV ejection fraction did not significantly change throughout the study. LV diastolic function, which had significantly improved during treatment, returned to baseline values following withdrawal of AHT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmltYXJjbzwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+
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ADDIN EN.CITE.DATA (19). Mixed or undefined AHTFollowing withdrawal of AHT combination therapy, a small cohort study showed a significant decrease in total cholesterol, triglycerides and glycohemoglobin but no significant change in the ratio of total cholesterol to high density lipoprotein cholesterol when measured between 4 to 21 weeks after stopping AHT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbWVzPC9BdXRob3I+PFllYXI+MTk4MjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (21). In addition, a Dutch cohort study demonstrated that high cholesterol was a reason for the patient to re-start AHT even when the cardiovascular mortality risk was not considered high enough to advise AHT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gRHVpam48L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy
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ADDIN EN.CITE.DATA (29). The percentage of people diagnosed with orthostatic hypotension significantly decreased from 23% prior to withdrawal to 11% at one year follow-up after AHT cessation. Pulse rate was investigated in a cohort study with a 24 hour follow-up assessment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CeXlueTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CeXlueTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (31). Both study indicated no significant changes after withdrawal of AHT. Blood flow in response to acetylcholine has been demonstrated to be significantly higher at two weeks after AHT withdrawal than in normotensive people, but there was no significant difference in blood flow in response to nitroprusside between normotensive people and those withdrawn from AHT at two weeks PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYW56YTwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (31). At 20 weeks after withdrawal, the total peripheral resistance index had raised significantly to values found in normal individuals PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KZW5uaW5nczwvQXV0aG9yPjxZZWFyPjE5ODQ8L1llYXI+
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ADDIN EN.CITE.DATA (34) reported that no deterioration of renal function was observed atone year after withdrawal of AHT. Two studies investigated the effects of AHT withdrawal in people with diabetic nephropathy who were insulin dependent PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW5zZW48L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxS
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW5zZW48L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxS
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ZXl3b3JkPjxrZXl3b3JkPjAgKEFudGloeXBlcnRlbnNpdmUgQWdlbnRzKTwva2V5d29yZD48L2tl
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PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDA4NS0yNTM4PC9pc2JuPjxhY2Nlc3Npb24tbnVt
Pjc2NDM1NDI8L2FjY2Vzc2lvbi1udW0+PHdvcmstdHlwZT5DbGluaWNhbCBUcmlhbCYjeEQ7UmFu
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K3dpdGhkcmF3YWwrb2YrbG9uZy10ZXJtK2FudGloeXBlcnRlbnNpdmUrdHJlYXRtZW50K2luK2Rp
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IFRlY2hub2xvZ2llczwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5FbmdsaXNo
PC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgAAAA==
ADDIN EN.CITE.DATA (35) or not insulin dependent PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW5zZW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (36). In those insulin dependent, stopping AHT led to a significant increase in glomerular filtration rate (GFR) and albuminuria in 75-80% of participants at one month. In those who were not insulin dependent there was no significant change in GFR and albuminuria decreased significantly.The majority of studies reported that there was no significant change in LV mass PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXJuZmVsdDwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+
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ADDIN EN.CITE.DATA (42). One study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXJuZmVsdDwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+
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ADDIN EN.CITE.DATA (37) showed a slight but significant decrease of LV ejection phase indices at two years after withdrawal but this was deemed as minor clinical change as 13 out of 14 patients stayed within normal range. Two further studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdWllc2FuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48
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ADDIN EN.CITE.DATA (37)and showed a small but significant increase after one year of withdrawal but, again, the change was deemed as a minor clinical increase as the values remained within normal limits. Furthermore, in haemodialysis patients, those remaining normotensive after AHT withdrawal at 5 weeks had developed significantly less often LV hypertrophy (50%) compared to those who had re-developed hypertension (91%). ADDIN EN.REFLIST 1.Andersen S, Brochner-Mortensen J, Parving HH, Irbesartan in Patients With Type D, Microalbuminuria Study G. Kidney function during and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria. Diabetes Care. 2003;26(12):3296-302.2.Ikeda LS, Harm SC, Arcuri KE, Goldberg AI, Sweet CS. Comparative antihypertensive effects of losartan 50 mg and losartan 50 mg titrated to 100 mg in patients with essential hypertension. Blood Press. 1997;6(1):35-43.3.Lacourciere Y, Pool JL, Svetkey L, Gradman AH, Larochelle P, de Champlain J, et al. A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of tasosartan in patients with essential hypertension. Tasosartan Investigator's Group. Am J Hypertens. 1998;11(4 Pt 1):454-61.4.Pool JL, Guthrie RM, Littlejohn TW, 3rd, Raskin P, Shephard AM, Weber MA, et al. Dose-related antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension. Am J Hypertens. 1998;11(4 Pt 1):462-70.5.Andersen K, Weinberger MH, Constance CM, Ali MA, Jin J, Prescott MF, et al. Comparative effects of aliskiren-based and ramipril-based therapy on the renin system during long-term (6 months) treatment and withdrawal in patients with hypertension. J Renin Angiotensin Aldosterone Syst. 2009;10(3):157-67.6.Schneider MP, Janka R, Ziegler T, Raff U, Ritt M, Ott C, et al. 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Eur J Clin Pharmacol. 1984;27(2):147-52.21.Ames RP, Hill P. Improvement of glucose tolerance and lowering of glycohemoglobin and serum lipid concentrations after discontinuation of antihypertensive drug therapy. Circulation. 1982;65(5):899-904.22.Freis ED, Thomas JR, Fisher SG, Hamburger R, Borreson RE, Mezey KC, et al. Effects of reduction in drugs or dosage after long-term control of systemic hypertension. Am J Cardiol. 1989;63(11):702-8.23.Agents VACSGoA. Return of elevated blood pressure after withdrawal of antihypertensive drugs. Circulation. 1975;51(6):1107-13.24.Jennings GL, Korner PI, Laufer E, Esler MD, Burton D, Bruce A. How hypertension redevelops after cessation of long-term therapy. J Hypertens Suppl. 1984;2(3):S217-9.25.Smith SA, Mace PJ, Littler WA. Felodipine, blood pressure, and cardiovascular reflexes in hypertensive humans. Hypertension. 1986;8(12):1172-8.26.Caruana MP, Al-Khawaja I, Royston P, Raftery EB. The effects of long-acting pinacidil on intra-arterial blood pressure. Br J Clin Pharmacol. 1985;20(2):140-3.27.Trimarco B, Rosiello G, Sarno D, Lorino G, Rubattu S, DeLuca N, et al. Effects of one-year treatment with rilmenidine on systemic hypertension-induced left ventricular hypertrophy in hypertensive patients. Am J Cardiol. 1994;74(13):36A-42A.28.van Duijn HJ, Belo JN, Blom JW, Velberg ID, Assendelft WJ. Revised guidelines for cardiovascular risk management - time to stop medication? A practice-based intervention study. Br J Gen Pract. 2011;61(587):e347-52.29.Fotherby MD, Potter JF. Orthostatic hypotension and anti-hypertensive therapy in the elderly. Postgrad Med J. 1994;70(830):878-81.30.Byyny RL, Merrill DD, Bradstreet TE, Sweet CS. An inpatient trial of the safety and efficacy of losartan compared with placebo and enalapril in patients with essential hypertension. Cardiovasc Drugs Ther. 1996;10(3):313-9.31.Panza JA, Quyyumi AA, Callahan TS, Epstein SE. Effect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol. 1993;21(5):1145-51.32.Sieg-Dobrescu D, Burnier M, Hayoz D, Brunner HR, Waeber B. The return of increased blood pressure after discontinuation of antihypertensive treatment is associated with an impaired post-ischemic skin blood flow response. J Hypertens. 2001;19(8):1387-92.33.Ljungman S, Aurell M, Hartford M, Wikstrand J, Berglund G. Renal function before and after withdrawal of long term antihypertensive treatment in primary hypertension. Drugs. 1988;35 Suppl 5:55-8.34.Wahi S, Sagar S, Sharma BK. Is a hypertensive always a hypertensive? J Assoc Physicians India. 1993;41(4):198-9.35.Hansen HP, Rossing P, Tarnow L, Nielsen FS, Jensen BR, Parving HH. Increased glomerular filtration rate after withdrawal of long-term antihypertensive treatment in diabetic nephropathy. Kidney Int. 1995;47(6):1726-31.36.Hansen HP, Nielsen FS, Rossing P, Jacobsen P, Jensen BR, Parving HH. Kidney function after withdrawal of long-term antihypertensive treatment in diabetic nephropathy. Kidney Int Suppl. 1997;63:S49-53.37.Lernfelt B, Landahl S, Svanborg A, Wikstrand J. Overtreatment of hypertension in the elderly? J Hypertens. 1990;8(5):483-90.38.Muiesan ML, Salvetti M, Monteduro C, Rizzoni D, Corbellini C, Castellano M, et al. Changes in midwall systolic performance and cardiac hypertrophy reduction in hypertensive patients. J Hypertens. 2000;18(11):1651-6.39.Myers MG, Reeves RA, Oh PI, Joyner CD. Overtreatment of hypertension in the community? Am J Hypertens. 1996;9(5):419-25.40.Prasad N, Davey PG, Watson AD, Peebles L, MacDonald TM. Safe withdrawal of monotherapy for hypertension is poorly effective and not likely to reduce health-care costs. J Hypertens. 1997;15(12 Pt 1):1519-26.41.Perlini S, Muiesan ML, Cuspidi C, Sampieri L, Trimarco B, Aurigemma GP, et al. Midwall mechanics are improved after regression of hypertensive left ventricular hypertrophy and normalization of chamber geometry. Circulation. 2001;103(5):678-83.42.Bishu K, Gricz KM, Chewaka S, Agarwal R. Appropriateness of antihypertensive drug therapy in hemodialysis patients. Clin J Am Soc Nephrol. 2006;1(4):820-4. ................
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