Optimal Blood Pressure and Cholesterol Targets for Preventing Recurrent Stroke in Hypertensives "ESH-CHL-SHOT"

Recruiting

Phase 4 Results N/A

Trial Description

Stroke is one of the major causes not only of mortality, but of disease burden worldwide, because of residual disability and cognitive decline. Although blood pressure lowering has been clearly shown to be the most effective means for primary and secondary prevention of stroke, the systolic blood pressure (SBP) levels to achieve by treatment in order to optimize prevention results are unknown, and whether SBP levels lower than those usually recommended are accompanied by further or reduced benefits is undecided yet. Likewise, while low-density lipoprotein cholesterol (LDL-C) lowering by statins has been shown to be associated with primary and secondary stroke prevention, whether more intense lowering is or is not of further benefit is unknown. The Stroke in Hypertension Optimal Treatment Trial (ESH-CHL-SHOT) is a factorial 3 x 2 arm, multicenter, randomized clinical trial designed to test the hypothesis that in elderly patients at high risk of recurrent stroke (previous recent stroke or TIA) antihypertensive treatment programs aimed at reducing SBP to the usually recommended values (< 145 to 135 mmHg), to a lower goal (< 135 to 125 mmHg) or to even lower values (< 125 mmHg) will result in progressively greater reductions in recurrent stroke, incidence of cardiovascular outcomes and cognitive decline. Parallely, the preventive efficacy of more and less intense LDL-C reductions will be tested on the same outcomes.

Detailed Description

ESH-CHL-SHOT will randomize about 7500 participants aged > or = 65 years with SBP > or = 140 mmHg or antihypertensive therapy, who have presented a stroke or TIA, within 1 to 6 months before randomization.
The trial will investigate
1. the effects of randomization to antihypertensive treatment of different intensities, aiming at three different SBP targets. SBP targets are < 145 to 135, < 135 to 125, < 125 mmHg, with approximate mean inter-target differences of 8 mmHg;
2. the effects of randomization to lipid lowering treatment of different intensity, aiming at two different LDL-C targets. Targets are 2.8 to 1.8 mmol/l (110 to 70 mg/dl) and < 1.8 mmol/l;
3. possible interactions between antihypertensive and lipid-lowering treatments. The primary hypothesis is that recurrent stroke rates will be 25% lower in the lowest vs intermediate SBP target group, 25% lower in the intermediate vs higher SBP target group, and 20% lower in the lower vs higher LDL-C target group. Sample size has been calculated to provide a 80% power with a significance of 5% after corrections for repetitive measurements on the assumption that stroke incidence will be 4% per year in the highest SBP target group. Participants will be recruited at approximately 250 clinics in Europe (2500 patients) and China (5000 patients) over a 2-year period, and will be followed up for an average of 4 years or until 925 recurrent strokes occur.
Arms and assigned intervention
1. Antihypertensive treatment design and assigned treatment
Participants will be randomly allocated to one of three different sitting SBP targets:
1. < 145 to 135 mmHg
2. < 135 to 125 mmHg
3. < 125 mmHg to be possibly achieved within 3 months and subsequently maintained within the target window.
Investigators are free to choose the drugs (among those approved in each country) to be administered to individual patients. It is expected that patients already on antihypertensive therapy and with SBP at randomization not too far from target will be maintained on current therapy with suitable adjustments. Other patients (untreated or with SBP far from target) may follow a suggested treatment algorithm of progressive increase in number of compounds or doses. During follow-up visits drugs and/or doses will be modified if necessary to maintain patients within randomized target window.
2. Lipid-lowering treatment design and assigned treatment
Participants will be randomly allocated to one of two different LDL-C targets:
A) 2.8 to 1.8 mmol/l (110 to 70 mg/dl) B) < 1.8 mmol/l (< 70 mg/dl) to be possibly achieved within 3 months and subsequently maintained within the target window.
Investigators are free to choose the statin (among those approved in each country) to be administered to individual patients. The initial statin dose should be chosen by the investigator according to LDL-C at randomization and the LDL-C target. The initial dose can be increased (to the maximum dose allowed in each country) or decreased until the LDL-C target is achieved possibly within 3 months, and further adjusted up or down at 6-month intervals in order to maintain LDL-C within the randomized target window.

Conditions

Interventions

  • All approved antihypertensive drugs; rosuvastatin Drug
    Other Names: Calcium channel blockers; Angiotensin converting enzyme inhibitors; Angiotensin receptor blockers; Thiazide diuretics; Beta-blockers; Alpha-blockers; Aldosterone antagonists; Statins
    Intervention Desc: All drugs to be used at doses capable of bringing SBP and LDL-C to targets; only doses approved in each country.
    ARM 1: Kind: Experimental
    Label: SBP < 145-135 mmHg
    Description: Highest SBP target. Control arm
    ARM 2: Kind: Experimental
    Label: SBP < 135-125 mmHg
    Description: Intermediate SBP target. .
    ARM 3: Kind: Experimental
    Label: SBP < 125 mmHg
    Description: Lowest SBP target
    ARM 4: Kind: Experimental
    Label: LDL-C 2.8 - 1.8 mmol/l
    Description: Higher LDL-C target. Control arm
    ARM 5: Kind: Experimental
    Label: LDL-C < 1.8 mmol/l
    Description: lower LDL-C target.
  • All approved antihypertensive drugs; all approved statins Drug
    Other Names: Calcium channel blockers; Angiotensin converting enzyme inhibitors; Angiotensin receptor blockers; Thiazide diuretics; Beta-blockers; Alpha-blockers; Aldosterone antagonists; Simvastatin; Pravastatin; Fluvastatin; Atorvastatin; Rosuvastatin
    Intervention Desc: All drugs to be used at doses capable of bringing SBP and LDL-C to targets; only doses approved in each country.
    ARM 1: Kind: Experimental
    Label: SBP < 145-135 mmHg
    Description: Highest SBP target. Control arm
    ARM 2: Kind: Experimental
    Label: SBP < 135-125 mmHg
    Description: Intermediate SBP target. .
    ARM 3: Kind: Experimental
    Label: SBP < 125 mmHg
    Description: Lowest SBP target
    ARM 4: Kind: Experimental
    Label: LDL-C 2.8 - 1.8 mmol/l
    Description: Higher LDL-C target. Control arm
    ARM 5: Kind: Experimental
    Label: LDL-C < 1.8 mmol/l
    Description: lower LDL-C target.
    ARM 6: Kind: Experimental
    Label: SBP < 145-135 mmHg and LDL-C 2.8 - 1.8 mmol/l
    Description: Highest SBP target. Higher LDL-C target. Control arm
    ARM 7: Kind: Experimental
    Label: SBP < 135-125 mmHg and LDL-C 2.8 - 1.8 mmol/l
    Description: Intermediate SBP target. Higher LDL-C target .
    ARM 8: Kind: Experimental
    Label: SBP < 125 mmHg and LDL-C 2.8 - 1.8 mmol/l
    Description: Lowest SBP target. Higher LDL-C target
    ARM 9: Kind: Experimental
    Label: SBP < 145-135 mmHg and LDL-C < 1.8 mmol/l
    Description: Highest SBP target. Lower LDL-C target.
    ARM 10: Kind: Experimental
    Label: SBP < 135-125 mmHg and LDL-C < 1.8 mmol/l
    Description: Intermediate SBP target. Lower LDL-C target.
    ARM 11: Kind: Experimental
    Label: SBP < 125 mmHg and LDL-C < 1.8 mmol/l
    Description: Lowest SBP target. Lower LDL-C target.

Trial Design

  • Allocation: Randomized
  • Masking: Open Label
  • Purpose: Prevention
  • Endpoint: Efficacy Study
  • Intervention: Factorial Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Recurrent stroke five years No
Secondary Major cardiovascular (CV) events five years No
Secondary Cognitive impairment and dementia five years No

Sponsors