Randomized, double-blind, placebo-controlled trial to compare the effect, three months of follow-on pulse pressure and vascular function of isosorbide mononitrate extended release, associated with antihypertensive treatment in patients over 65 years refractory isolated systolic hypertension

INTERVENTION: Trade Name: CARDIONIL 20 mg cápsulas de liberación prolongada Pharmaceutical Form: Capsule INN or Proposed INN: 5‐mononitrato de isosorbida (D.C.I.), 20 mg Current Sponsor code: CARDIONIL 20 mg cápsulas de liberación prolongada Other descriptive name: ISOSORBIDE MONONITRATE Concentration unit: mg milligram(s) Concentration type: range Concentration number: 40‐60 Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: Refractory isolated systolic hypertension Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14] PRIMARY OUTCOME: Main Objective: To compare the effect on clinic pulse pressure of extended release isosorbide mononitrate vs placebo, added to the usual treatment of patients over 65 with refractory ISH, after 3 months of treatment. Primary end point(s): ‐ Difference between PP final visit and PP baseline visit: mmHg (office) Secondary Objective: 1.‐ To quantify the effect on vascular function (estimated by central BP, augmentation index and pulse wave velocity) of extended release isosorbide mononitrate vs placebo, after 3 months of treatment.; 2.‐ To compare the effect of the addition of extended releasese isosorbide mononitrate on previous parameters, depending on whether HT is truly refractory (mean 24 hour BP >130/80 mmHg) or pseudorefractory (?130/80 mmHg); 3.‐ To evaluate the safety profile of the strategy based on the addition of extended release isosorbide mononitrate, by the appearance of adverse effects (with particular attention to headache and orthostatic hypotension).; 4.‐ To quantify the percentage of patients that reach a clinic sistolyc blood pressure <140mmHg in both treatments groups Timepoint(s) of evaluation of this end point: The primary efficacy assessment will be the difference between PP in the last visit compared to PP in the screening visit, and it will be demonstrated significantly differences compared to placebo. SECONDARY OUTCOME: Secondary end point(s): ‐ Difference between SBP( Systolic Blood Pressure)baseline visit and SBP final visit: mmHg (office) ; ‐ Difference between DBP(Diastolic Blood Pressure) baseline visit and DBP final visit: mmHg (office) ; ‐ Difference between PP(Pulse Pressure) baseline visit and PP final visit: mmHg (24 hours mean at ABPM,Ambulatory Blood Pressure Monitoring) ; ‐ Difference between SBP baseline visit and SBP final visit: mmHg (24 hours mean at ABPM) ; ‐ Difference between DBP baseline visit and DBP final visit: mmHg (24 hours mean at ABPM) ; ‐ Difference between PWV baseline(Pulse Wave Velocity) visit and PWV final visit ; ‐ Difference between Central SBP baseline visit and central SBP final visit ; ‐ Difference between Central PP baseline visit and central PP final visit ; ‐ Difference between AI baseline visit and AI final visit ; ‐ Percentage of subjects with SBP<140mmHg at office at the study end ; ‐ Percentage of responders subjects: decrease on SBP (baseline‐final) >10 mmHg at office ; ‐ Percentage of subjects with adverse effects and type of adverse effect at 6 and 12 weeks after intervention ; ‐ Percentage of subjects that must abandon the study due to adverse effects. ? Patients with refractory ISH defined as SBP ?140 mmHg and DBP <90 mmHg, despite treatment with three drugs as maximum doses, one of them diuretic, during at least one month before the start ? Good adherence to treatment, defined as a good response to all questions of Morisky‐Green?s test. ? SBP between 140 y 179 mmHg ? Ability to understand study procedures and to comply with them for the entire length of the study. ? Life expectancy greater than 1 year ; ‐ Percentage of patients with orthostatic hypotension (a decrease on SBP >20mmHg and/or DBP >10mmHg after one minute of standing) at each one of the visits Timepoint(s) of evaluation of this end point: All of secondary objectives will be measured as the difference between the last visit compared to the inclusion visit. INCLUSION CRITERIA: ? Patients aged 65 or over of both genders, belong to some primary care or Hypertension?s Unit of Hospital La Princesa, who will be given their written informed consent to participate in the study. ? Signing the informed consent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 154