are inferior in benefit compared with other classes. · There is evidence from a large meta-analysis (Wald 2009) that the BP reduction from each class of drug combined with one from another class is approximately additive. The meta-analysis also shows that combining given doses of two classes of drugs is approximately five times more effective than doubling the dose of one drug. · There is good evidence from a large meta-analysis and subsequent validated RCTs that low-dose combination perindopril-indapamide therapy is more effective in controlling hypertension than sequential monotherapy or the stepped-care approach (Kang 2004, Mourad 2004 and 2007, Patel 2007). · There is some evidence that fixed-dose combination therapies may be associated with higher rates of compliance and persistence with therapy in addition to better control of blood pressure. · A Cochrane review and meta-analysis (Heran 2008 - CD003823) showed that there were no clinically meaningful BP-lowering differences between the different ACE inhibitors. Another metaanalysis by the same group (Heran 2008 - CD003822) also suggests that no one ARB is superior or inferior to others. · The ONTARGET trial (ONTARGET Investigators 2008) provides evidence that ARBs are not 14 inferior to ACE inhibitors and that combining both classes does not lead to better outcomes but does lead to more harms. · There is evidence that the use of beta-blockers (atenolol in 75% of the studies) as a first-line therapy for hypertension had a weak effect on reducing cardiovascular disease and stroke, and no effect on reducing CHD compared to placebo. When compared to other active antihypertensive therapies, it had a trend for worse outcomes and discontinuation of therapy due to side effects. · There is some evidence that, compared to other antihypertensive drugs, atenolol used as a firstline monotherapy had a similar effect in lowering BP but was associated with higher mortality and stroke (Carlberg 2004, Lindholm 2005). This could be due to the fact that in most atenolol trials the drug was given in a once-daily dose. According to several investigators, atenolol needs to be taken more frequently, based on its pharmacodynamic and pharmacokinetic properties. Atenolol has a half-life of 6–9 hours and is usually given once daily, while carvedilol and metoprolol have half-lives of 6–10 hours and 3–7 hours respectively, and are given in at least twice-daily doses (Neutel 1990, Sarafidis 2008). · There is evidence that calcium channel blockers slightly decrease the risk of all-cause mortality and stroke versus other treatments, but increase the risk of heart failure. · There is insufficient evidence to determine the comparative effectiveness and safety of chlorthalidone and HCTZ in patients with hypertension. The published evidence from observational studies and meta-analyses with indirect comparisons was conflicting. · Dhalla and colleagues’ observational study (2013) suggests that chlorthalidone may be associated with higher incidence of electrolyte abnormalities in older adults. · There is evidence from meta-analyses (Heran 2009, Chen 2010) quantifying the dose-related SBP- and DBP-lowering efficacy of the different antihypertensive agents that: o For ACE inhibitors, a dose of one-eighth or one-fourth of maximum recommended dose achieved a BP-lowering effect 60–70% of that attained by the maximum manufacturerrecommended dose (one-half of the maximum dose achieved BP lowering 90% of the maximum dose). o For ARBs, a dose of one-eighth or one-fourth of maximum recommended dose achieved a BP-lowering effect 60–70% of that attained by the maximum manufacturer-recommended dose. o For beta-blockers, the addition of one-fourth the recommended dose to a thiazide or calcium channel blocker was associated with BP reduction (2.9/1.4 mm Hg). Adding 1x starting dose was associated with BP reduction of 6/4 mm Hg. Antihypertensive therapy in the elderly The HYVET trial (Beckett 2008) provides good evidence that antihypertensive treatment of generally healthy elderly patients is safe and effective in reducing blood pressure, total mortality, and cardiovascular events. The results of a large meta-analysis (Blood Pressure Lowering Treatment Trialists' Collaboration 2008) show that reduction of BP with various drugs is independent of the patient's age or the drug regimen used, and supports the early and aggressive management of hypertension irrespective of age. There is fair evidence that beta-blockers, atenolol in particular, may be associated with a higher rate of stroke compared to other antihypertensive agents, especially among older patients (Carlberg 2004, Lindholm 2005, Khan 2006). Chronotherapy (timing of medication) for hypertension · There is fair evidence from prospective studies (Ayala 2013, Hermida 2010, Hermida 2011 [J Am Coll Cardiol], Hermida 2011 [J Am Soc Nephrol], Fan 2010) that the asleep BP mean is a better predictor of CVD risk than either the awake or 24-hour BP mean. · There is fair evidence from a number of prospective studies conducted mainly in Spain (Ayala 2013, Hermida 2010, Hermida 2011 [J Am Soc Nephrol], Hermida 2013) that bedtime administration of antihypertensive medications may lead to better BP control and reduce CVD risk 15 among the populations studied, which were predominantly male Spanish, Caucasian, and