Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension

To test whether the current custom of initiating treatment for hypertension with a single drug is less effective in the short-term than initial combination therapy, and results in the eventual need for comparatively more antihypertensive drug therapy.

To determine if patients randomised to more aggressive (combination therapy) treatment for the initial treatment of hypertension have better blood pressure control compared to those randomised to less aggressive (monotherapy) treatment despite subsequent add-on treatment being similar in each group. This will test the hypothesis that monotherapy patients 'never catch up' with combination therapy patients.

1. To determine if this 'never catch-up' phenomenon of improved BP control persists for at least one year.
2. To understand the underlying mechanism of improved BP control; specifically:

   1. To determine if it is due to haemodynamic compensation, such as increased sodium retention and volume expansion.
   2. To determine if it is due to increased peripheral resistance.
3. To understand the predictors of BP control i.e. age, baseline renin status, sodium status and plasma volume.
4. To validate the National Institute for Clinical Excellence / British Hypertension Society joint guideline ACD algorithm by comparing BP control in the monotherapy crossover arm of phase 1 and to correlate this with age (≤ 55 or \> 55y), and baseline characteristics such as renin.
5. To determine the safety and tolerability of a strategy of prescribing combination therapy as the initial step versus monotherapy as the initial step.

Eligibility Criteria:
Patients must meet ALL inclusion criteria

1. Aged 18-79
2. Male subjects or female subjects taking adequate contraception such as the oral contraceptive pill, an intra uterine device or who are surgically sterilised or postmenopausal Females
3. BP ≥150 mmHg (systolic) OR ≥ 95 mmHg (diastolic). Patients may be included if the PI anticipates BP criteria for inclusion will be met at randomisation
4. Either never-treated or received a maximum of one antihypertensive drug class in the previous year

Patients will be excluded for ANY ONE of the following reasons

1. Clinic SBP \> 200 mmHg or DBP \> 120 mmHg, with PI discretion to override if home BP measurements are lower
2. Secondary or accelerated phase hypertension
3. eGFR \< 45 mls/min
4. Contra-indication or previous intolerance to any trial therapy
5. Failure to record required home BP readings during placebo run-in.
6. Significant co-morbidity (investigator opinion but to include alcoholism, terminal illness, documented non-attendance at clinics etc)
7. Diabetes type 1
8. Plasma K+ outside normal range on two successive measurements during screening
9. Requirement for treatment with ≥2 drugs (which can be a CCB and/or {ACEi OR ARB OR direct renin inhibitor OR β-blocker}) in order to reduce blood pressure to ≤180/120 mmHg
10. Requirement for diuretic therapy (other than for hypertension)
11. Requirement for ACE inhibitor (or ARB) therapy (other than for hypertension)
12. Absolute contra-indications to any of the study drugs (listed on their data-sheet)
13. Current therapy for cancer
14. Anticipation of change in medical status during course of trial (e.g. planned surgical intervention requiring \>2 weeks convalescence , actual or planned pregnancy)
15. Inability to give informed consent
16. Participation in a clinical study involving an investigational drug or device within 4 weeks of screening.
17. Any concomitant condition that, in the opinion of the investigator, may adversely affect the safety and/or efficacy of the study drug or severely limit the subject's lifespan or ability to complete the study (eg, alcohol or drug abuse, disabling or terminal illness, mental disorders).
18. Treatment with any of the following prohibited medications:

    1. Oral corticosteroids within 3 months of screening. Treatment with systemic corticosteroids is also prohibited during study participation.

       Chronic stable or unstable use of non-steroidal anti-inflammatory drugs (NSAIDs) other than acetylsalicylic acid is prohibited. Chronic use is defined as \>3 consecutive or nonconsecutive days of treatment per week. In addition, the intermittent use of NSAIDs is strongly discouraged throughout the duration of this study. If intermittent treatment is required, NSAIDs must not be used for more than a total of 2 days. For all subjects requiring analgesic or anti-pyretic agents, the use of paracetamol is recommended during study participation.
    2. The use of short-acting oral nitrates (eg, sublingual nitroglycerin) is permitted; however, subjects should not take short-acting oral nitrates within 4 hours of screening or any subsequent study visit.
    3. The use of long-acting oral nitrates (eg, Isordil) is permitted; however, the dose must be stable for at least 2 weeks prior to screening and randomisation.
    4. The use of sympathomimetic decongestants is permitted; however, not within 1 day prior to any clinic visit/BP assessment.
    5. The use of theophylline is permitted; however, the dose must be stable for at least 4 weeks prior to screening and throughout study participation.
    6. The use of phosphodiesterase (PDE) type V inhibitors is permitted; however, subjects must refrain from taking these medications within 1 day of screening or any subsequent study visit.
    7. The use of alpha-blockers is not permitted - with the exception of afluzosin and tamsulosin for prostatic symptoms