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This review discusses the triple\u2010therapy combination of an angiotensin receptor blocker (<jats:styled-content style=\"fixed-case\">ARB<\/jats:styled-content>) or direct renin antagonist (<jats:styled-content style=\"fixed-case\">DRI<\/jats:styled-content>) with a calcium channel blocker (<jats:styled-content style=\"fixed-case\">CCB<\/jats:styled-content>) and a diuretic, with a focus on mechanisms of action. Multiple physiologic pathways contribute to hypertension. Combining antihypertensive agents not only better targets the underlying pathways, but also helps blunt compensatory responses that may be triggered by single\u2010agent therapy.<jats:styled-content style=\"fixed-case\">DRI<\/jats:styled-content>s and<jats:styled-content style=\"fixed-case\">ARB<\/jats:styled-content>s target the renin\u2013angiotensin\u2013aldosterone system (<jats:styled-content style=\"fixed-case\">RAAS<\/jats:styled-content>) at the initial and final steps, respectively, and both classes lower<jats:styled-content style=\"fixed-case\">BP<\/jats:styled-content>by reducing the effects of angiotensin\u20102; however,<jats:styled-content style=\"fixed-case\">ARB<\/jats:styled-content>s may trigger a compensatory increase in renin activity. Dihydropyridine<jats:styled-content style=\"fixed-case\">CCB<\/jats:styled-content>s target<jats:styled-content style=\"fixed-case\">L<\/jats:styled-content>\u2010type calcium channels and lower<jats:styled-content style=\"fixed-case\">BP<\/jats:styled-content>through potent vasodilation, but can trigger compensatory activation of the sympathetic nervous system (<jats:styled-content style=\"fixed-case\">SNS<\/jats:styled-content>) and<jats:styled-content style=\"fixed-case\">RAAS<\/jats:styled-content>. Thiazide diuretics lower<jats:styled-content style=\"fixed-case\">BP<\/jats:styled-content>initially through sodium depletion and plasma volume reduction, followed by total peripheral resistance reduction, but can also trigger compensatory activation of the<jats:styled-content style=\"fixed-case\">SNS<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">RAAS<\/jats:styled-content>. The combination of an agent targeting the<jats:styled-content style=\"fixed-case\">RAAS<\/jats:styled-content>with a<jats:styled-content style=\"fixed-case\">CCB<\/jats:styled-content>and diuretic is rational, and triple combinations of valsartan\/amlodipine\/hydrochlorothiazide, olmesartan\/amlodipine\/hydrochlorothiazide, and aliskiren\/amlodipine\/hydrochlorothiazide have demonstrated greater effectiveness compared with their respective dual\u2010component combinations. In addition, single\u2010pill, fixed\u2010dose combinations can address barriers to<jats:styled-content style=\"fixed-case\">BP<\/jats:styled-content>control including clinical inertia and poor adherence. Fixed\u2010dose antihypertensive combination products capitalize on complementary mechanisms of action and have been shown to result in improved<jats:styled-content style=\"fixed-case\">BP<\/jats:styled-content>control.<\/jats:p>","DOI":"10.1111\/1755-5922.12015","type":"journal-article","created":{"date-parts":[[2012,11,2]],"date-time":"2012-11-02T15:21:12Z","timestamp":1351869672000},"page":"251-258","source":"Crossref","is-referenced-by-count":38,"title":["Hypertension Management: Rationale for Triple Therapy Based on Mechanisms of Action"],"prefix":"10.1111","volume":"31","author":[{"given":"Joel M.","family":"Neutel","sequence":"first","affiliation":[{"name":"Orange County Research Center Tustin CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H. 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