Hypertension Clinical Trials

Issues of Concern

AASK (The 2002 African American Study of Kidney Disease and Hypertension)

In African American patients with a known history of hypertension and chronic kidney disease, intensive blood pressure control (targeting MAP <92 mmHg) did not slow the progression of kidney disease compared to conservative blood pressure control (targeting MAP 102 to 107 mmHg). The use of Angiotensin-converting enzyme inhibitors slowed the rate of GFR decline.[1]

Key Points

1. African American patients are six times more likely to develop hypertension-related chronic kidney disease and end-stage renal disease when compared to White-race patients.
2. The AASK study included African Americans with hypertension and chronic kidney disease without a clear secondary cause for CKD. 
3. Median follow-up was for four years and noted no difference in the progression of CKD by BP target. But the ACE inhibitor was associated with fewer CKD events or death. 
4. AASK study played a role in solidifying the recommendations for using ACE inhibitors or ARBs among patients with CKD.

Design

1. Multicenter, randomized, 2x3 factorial, controlled trial with N=1,094 African-American patients, of which 540 patients were included in the intensive BP control group and 554 in the conservative BP control group. Initial BP medications used were calcium channel blockers in 217, beta-blockers in 441, and ACE-I in 436 patients.
2. Median follow-up: About four years
3. Primary outcomes: Rate of change in eGFR and progression of CKD or all-cause mortality

Inclusion Criteria

• African-American
• Age 18-70
• Diastolic blood pressure ≥95 mm Hg
• Hypertensive renal disease
• eGFR 20-65 mL/min/1.73 m^2

Exclusion Criteria

• Diabetes
• Urine protein: creatinine ratio > 2.5
• Malignant hypertension in the prior six months
• Heart failure
• Serious comorbidities

Interventions

1.  Patients were randomized to either the intensive BP control group (target MAP ≤92 mmHg) or the standard BP control group (target MAP 102 to 107 mmHg)
2.  Patients were also randomized to initial drug therapy:

• ACE-inhibitor - Ramipril 2.5 to 10 mg/day
• Beta-blocker - Metoprolol succinate 50-200 mg/day
• CCB - Amlodipine 5 to 10 mg/day

      3. Initial drugs were up-titrated to the highest doses before adding a second antihypertensive. 

      4. The following medications were used for additional control of BP - furosemide, doxazosin, clonidine, and hydralazine or minoxidil.

Outcomes  

Primary Outcomes

• Rate of change in eGFR (total slope)
• Lower BP vs. usual BP: -0.25 mL/min/1.73 m^2/year (P=0.24)

Progression of CKD (defined as the reduction in eGFR by ≥50% or drop by 25 mL/min/1.73 m^2, or ESRD)  or all-cause mortality

• Lower BP vs. usual BP: 2% RR (95% CI -22 to 21; P=0.85)
• ACE-inhibitor vs. beta-blocker: 22% RR (95% CI 1 to 38; P=0.04)
• CCB vs. beta-blocker: 20% RR (95% CI -10 to 41; P=0.17)
• ACE-inhibitor vs. CCB: 38% RR (95% CI 14 to 56; P=0.004)

Secondary Outcomes

Progression of CKD

• Lower BP vs. usual BP: -2% RR (95% CI -31 to 20; P=0.87)
• ACE-inhibitor vs. beta-blocker: 22% RR (95% CI -2 to 41; P=0.07)
• ACE-inhibitor vs. CCB: 40% RR (95% CI 14 to 59; P=0.006

ESRD or All-cause Mortality

• Lower BP vs. usual BP: 12% RR (95% CI -13 to 32; P=0.31)

ACCOMPLISH (2008 Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension trial)

Among patients with hypertension at high risk for cardiovascular complications, benazepril/amlodipine decreases the rate of cardiovascular events compared to benazepril/hydrochlorothiazide.[2]

Key Points

1. One major criticism of the trial was the choice of a short-acting diuretic hydrochlorothiazide rather than a long-acting chlorthalidone. Due to its short half-life, HCTZ may not be able to control the BP adequately over a 24hr period, and the office measurements may not have represented actual measurements in 24 hours. 
2. A 2010 follow-up study from the ACCOMPLISH authors measured blood pressure continuously in 573 patients on the HCTZ formulation and found no significant difference in pressures throughout 24 hours. 

Design

1. Multicenter, randomized, industry-sponsored, controlled trial.
2. N=11,506, and 5,744 of them, were given benazepril/amlodipine, and the remaining got benazepril/hydrochlorothiazide.
3. Mean follow-up of 2.5 years and the trial was stopped early due to a significant primary outcome. 
4. Primary outcome: Cardiovascular mortality, nonfatal myocardial infarction, nonfatal cerebrovascular accident, Unstable Angina, resuscitation after cardiac arrest, or coronary revascularization.

Inclusion Criteria

• Systolic blood pressure ≥ 160 mmHg or on antihypertensive medications.
• Age 55 to 59 years and ≥ 2 of the following or ≥ 60 years and ≥ 1 of the following in their medical history: Acute coronary syndrome, coronary revascularization, cerebrovascular accident, chronic kidney disease, peripheral arterial disease, left ventricular hypertrophy, diabetes mellitus type II.

Exclusion Criteria

• Angina in the prior three months
• Symptomatic heart failure or left ventricular ejection fraction <40%
• Acute coronary syndrome or revascularization in the prior month
• Cerebrovascular disease or transient ischemic attack in the previous three months
• Severe or refractory hypertension  

Interventions 

1. Patients were randomized to groups of benazepril/amlodipine 20 mg/5 mg or benazepril/Hydrochlorothiazide 20 mg/12.5 mg daily.
2. The benazepril component was increased to 40 mg after one month
3. Increase of amlodipine to 10 mg or hydrochlorothiazide to 25 mg to reach target BP <140/90 or <130/80 among patients with diabetes mellitus 
4. Additional antihypertensives were allowed except for calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or thiazide.
5. Loop diuretics taken once daily were permitted for volume management.

Outcomes 

Primary Outcome

• CV mortality, nonfatal MI, nonfatal CVA, UA, resuscitation after cardiac arrest, or coronary revascularization: 9.6% vs. 11.8% (HR 0.80; 95% CI 0.72-0.90; P<0.001)

Secondary Outcomes

• Fatal MI or non-fatal MI : 2.2% vs. 2.8% (HR 0.78; 95% CI 0.62-0.99; P=0.04)
• Any cardiac event: 8.6% vs. 10.3% (HR 0.83; 95% CI 0.73-0.93; P=0.002)
• CV mortality, nonfatal MI, or nonfatal CVA: 5.0% vs. 6.3% (HR 0.79; 95% CI 0.67-0.92; P=0.002)
• Unstable angina: 0.8% vs. 1.0% (HR 0.75; 95% CI 0.74-1.10; P=0.14)
• Cardiac arrest resuscitation: 0.2% vs. 0.1% (HR 1.75; 95% CI 0.73-4.17; P=0.20) 
• Fatal CVA or non-fatal CVA: 1.9% vs. 2.3% (HR 0.84; 95% CI 0.65-1.08; P=0.17) 
• Coronary revascularization: 5.8% vs. 6.7% (HR 0.86; 0.74-1.00; P=0.04) 
• All-cause mortality: 4.1% vs. 4.5% (HR 0.90; 95% CI 0.76-1.07; P=0.24)  

ACCORD BP (The 2010 Action to Control Cardiovascular Risk in Diabetes-Blood Pressure trial) 

In patients with Type II diabetes mellitus at high risk for cardiovascular events, targeting systolic blood pressure <120 mmHg did not reduce rates of nonfatal MI, nonfatal stroke, or cardiovascular mortality compared to a target SBP <140 mmHg.[3]

Key Points 

1. The study had a median follow-up of 4.7 years and did not notice any significant difference in nonfatal myocardial infarction, nonfatal stroke, or cardiovascular mortality between the intensive vs. standard therapy group.
2. Among the outcomes, one statistically significant outcome was a minimal reduction in stroke risk with intensive BP control (0.32%/yr vs. 0.53%/yr), with a P value of 0.01, but the number needed to treat was 476 patients per year. 
3. The intensive therapy group had a significantly higher rate of serious adverse events attributed to antihypertensive medications as well as hypo and hyperkalemia and renal failure with eGFR < 30 ml/min/1.73m^2
4. One criticism was that the patients may have been in the advanced stages of the disease process and may have missed the opportunity to benefit (mean age 62, 34% had cardiovascular events before trial, and average 10 yrs of diabetes mellitus type 2)

Design 

1. Multicenter, randomized, controlled, open-label trial with N=4,733, of which 2,362 were in the Intensive BP control group (SBP<120 mmHg) and the remaining in the standard BP control group (SBP<140 mmHg)
2. Mean follow-up: 4.7 years
3. Primary outcome: nonfatal myocardial infarction, nonfatal stroke, or cardiovascular mortality

Inclusion Criteria

• Type 2 diabetes mellitus with a hemoglobin A1c ≥7.5%
• Age ≥40 years with cardiovascular disease
• Age ≥55 years with evidence of substantial Atherosclerosis, albuminuria, Left ventricular hypertrophy, or with ≥2 cardiovascular risk factors like dyslipidemia, hypertension, smoking, and obesity.

Exclusion Criteria 

• BMI >45 kg/m^2
• Creatinine >1.5 mg/dL 
• Any serious illness 

Interventions 

1. Open-label randomization to either the Intensive BP control group with a Goal SBP <120 mmHg or to the Standard BP control with a Goal SBP <140 mmHg
2. BP was controlled with conventional therapies per standard protocol.  

Outcomes 

Primary Outcome

•  Nonfatal myocardial infarction, nonfatal stroke, or Cardiovascular mortality: 1.87%/yr vs. 2.09%/yr (HR 0.88; 95% CI 0.73-1.06; P=0.20)

Secondary Outcomes

• Non-fatal myocardial infarction: 1.13%/yr vs. 1.28%/yr (HR 0.87; 95% CI 0.68-1.10; P=0.25) 
• Stroke

1. Any: 0.32%/yr vs. 0.53%/yr (HR 0.59; 95% CI 0.39-0.89; P=0.01; NNT 476/yr)
2. Nonfatal: 0.30%/yr vs. 0.47%/yr (HR 0.63; 95% CI 0.41-0.96; P=0.03; NNT 588/yr)

• All-cause mortality : 1.28%/yr vs. 1.19%/yr (HR 1.07; 95% CI 0.85-1.35; P=0.55) 
• Cardiovascular mortality : 0.52%/yr vs. 0.49%/yr (HR 1.06; 95% CI 0.74-1.52; P=0.74) 

Adverse Events

1. Attributed to BP medications: 3.3% vs. 1.27% (P<0.001; NNH 49)
2. Hypotension: 0.7% vs. 0.04% (P<0.001; NNH 152)
3. Bradycardia or arrhythmia: 0.5% vs. 0.13% (P=0.02; NNH 270)
4. Hyperkalemia: 0.4% vs. 0.04% (P=0.01; NNH 278)
5. Laboratory abnormalities

• Potassium <3.2 mmol/L: 2.1% vs. 1.1% (P=0.01; NNH 100)
• eGFR <30 mL/min/1.73 m^2: 4.2% vs. 2.2% (P<0.001; NNH 50)

ALLHAT (The 2002 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) 

In patients with hypertension, amlodipine, chlorthalidone, and lisinopril were studied and showed similar results regarding fatal CAD and nonfatal MI.[4]

Key points 

1. This study sought to determine which of four antihypertensives (chlorthalidone, amlodipine, lisinopril, and doxazosin)are superior in nonfatal myocardial infarction and fatal coronary artery disease.
2. Doxazosin was the fourth arm but was discontinued prematurely as it increased the risk of heart failure compared to chlorthalidone. 
3. Amlodipine and chlorthalidone performed similarly in reducing the overall incidence of CAD, but chlorthalidone decreased the incidence of heart failure (P<0.001). Compared to lisinopril, chlorthalidone reduced overall CAD, stroke, heart failure, and angina.
4. Based on the above results, thiazides became widely used as first-line agents for essential hypertension.

Design  

      a.Multicenter, double-blinded, parallel-group, randomized controlled trial 

      b.N=42,418

• Chlorthalidone (n=15,255)
• Amlodipine (n=9,048)
• Lisinopril (n=9,054)
• Doxazosin (n=9,061)

       c.Mean follow-up: 4.9 years

Inclusion Criteria 

• Age equal to 55 years or above
• Stage I or II HTN with ≥1 additional cardiovascular risk factor:

(stage I HTN is 130-139/80-89, and stage II HTN is ≥140/≥90 mm Hg)

• Previous (> 6 months) MI or stroke
• Left ventricular hypertrophy on EKG or echo
• Type 2 diabetes mellitus 
• Current cigarette smoking
• HDL <35 mg/dL
• Documentation of other atherosclerotic cardiovascular diseases 

Exclusion Criteria 

• History of symptomatic heart failure 
• LVEF <35%

Interventions 

1. Participants were randomly assigned to amlodipine, chlorthalidone, or lisinopril. The doxazosin arm, which was the fourth arm, was terminated prematurely due to an increased risk of heart failure, compared to chlorthalidone noted during an interim analysis. 
2. Participants were allowed to continue their prior antihypertensive regimen until they received a randomized study drug. Once they started the assigned study drug, their previous antihypertensives were stopped.

• Goal BP was < 140/90 mmHg

       Step 1: assigned study drug was titrated as follows 

• 12.5 to 25 mg/d for chlorthalidone
• 10 to 40 mg/d for lisinopril
• 2.5 to 10 mg/d for amlodipine

       Step 2: addition of open-label agents (atenolol, clonidine, or reserpine)

• 25 to 100 mg/d of atenolol
• 0.05 to 0.2 mg/d of reserpine
• 0.1 to 0.3 mg twice daily dose of clonidine

        Step 3: the addition of 25 to 100 mg twice daily dose of hydralazine if needed

Outcomes 

Primary Outcome

• Fatal coronary artery disease or nonfatal MI at six years follow-up: 11.5% vs. 11.3% vs. 11.4% (P=Not significant)

Secondary Outcomes

All-cause mortality:17.3% vs. 16.8% vs. 17.2% (P=Not significant)

• Combined coronary artery disease (composite of coronary revascularization or angina with hospitalization):19.9% vs. 19.9% vs. 20.8% (P=Not significant)
• Stroke: 5.6% vs. 5.4% vs. 6.3%

1. Amlodipine vs. chlorthalidone: RR 0.93 (95% CI 0.82-1.06; P=0.28)
2. Lisinopril vs. chlorthalidone: RR 1.15 (95% CI 1.02-1.30; P=0.02)

• Coronary artery disease, stroke, treated angina without hospitalization, Heart failure, or Peripheral artery disease: 30.9% vs. 32% vs. 33.3%

1. Amlodipine vs. chlorthalidone: RR 1.04 (95% CI 0.99-1.09; P=0.12)
2. Lisinopril vs. chlorthalidone: RR 1.10 (95% CI 1.05-1.16; P<0.001)

Additional Outcomes

• Heart failure:7.7% vs. 10.2% vs. 8.7%

1. Amlodipine vs. chlorthalidone: RR 1.38 (95% CI 1.24-1.52; P<0.001) 
2. Lisinopril vs. chlorthalidone: RR 1.19 (95% CI 1.07-1.31; P<0.001) 

• Angina 12.1% vs. 12.6% vs. 13.6%

1. Amlodipine vs. chlorthalidone: RR 1.02 (95% CI 0.94-1.10; P=0.67)
2. Lisinopril vs. chlorthalidone: RR 1.11 (95% CI 1.03-1.20; P=0.01)

•       Coronary revascularization: 9.2% vs. 10.0% vs. 10.2%

1. Amlodipine vs. chlorthalidone: RR 1.09 (95% CI 1.00-1.20; P=0.06)
2. Lisinopril vs. chlorthalidone: RR 1.10 (95% CI 1.00-1.21; P=0.05)

Adverse Events

1. Angioedema: 0.1% vs. <0.1% vs. 0.4% (P<0.001)
2. Hypokalemia: 8.5% vs. 1.9% vs. 0.8% (P<0.001)

DASH (The 1997 Dietary Approaches to Stop Hypertension Trial) 

In patients with a systolic blood pressure of less than 160 mmHg and diastolic blood pressure of 80 to 90 mmHg, a DASH diet rich in fruits and vegetables and low in saturated fats significantly reduced BP.[5]

Key Points 

1. Reducing sodium chloride intake and alcohol consumption was recommended for all patients involved in the trial.
2. The diet rich in fruits and vegetables reduced BP by 2.8/1.1 mmHg over control, while the combination diet reduced BP by 5.5/3.0 mmHg over control. 
3. The effects on BP reduction were seen within two weeks of starting the diet.
4. The combination diet reduced BP by 11.4 / 5.5 mmHg in hypertensive patients (similar to the results from drug monotherapy for stage I HTN) and by 3.5 / 2.1 mmHg in non-hypertensive patients suggesting that it is an effective non-pharmacological approach to help prevent HTN. 
5. Not designed to assess the long-term effects of the diet on BP or cardiovascular events

Design 

1. Multicenter, non-blind, parallel-group, randomized, controlled trial
2. N=459, of which 154 patients were given a diet rich in fruits and vegetables and 151 patients were given a DASH diet, which is the combination of a diet rich in fruits and vegetables and low in saturated and total fat. A control diet was given to the remaining 154 patients.
3. Primary outcome: Change in resting diastolic BP.

Inclusion Criteria 

• Age ≥22 years
• mean SBP less than 160 mmHg
• mean DBP 80 to 95 mmHg

Exclusion Criteria 

• Use of medications that affect BP
• Poorly controlled diabetes mellitus 
• A cardiovascular event within the prior six months
• Chronic kidney disease
• Chronic diseases that may interfere with study participation
• Pregnancy or lactation
• BMI >35 kg/m^2
• Unwilling to stop vitamins, mineral supplements, or antacids containing Mg or Ca
• >14 alcoholic drinks/per wk

Interventions 

1. All patients had a screening for three visits where BP measurements were recorded, and a questionnaire about physical activity was given. Then patients were given three weeks of a control diet, BP measurements were recorded, 24-hour urine samples were collected, and questionnaires were given to assess for symptoms. 
2. Then each patient was given eight weeks of assigned diet; BP measurements were recorded, 24hr urine samples were collected, along with symptoms and physical activity recall questionnaires.
3. The following diets were given. 

• Control diet : 3g Na; K, Mg, Ca levels at 25th percentile US consumption; fiber and macronutrients at mean US consumption
• 1-2 servings of fruit, two servings of vegetable, 5 to 6 servings of fat, oils, salad dressing, four servings of snacks/sweets
• Fruits & vegetable diet : 3g Na; K, Mg at 75th percentile US consumption; high fiber, more fruits & vegetables
• Five servings of fruit, 3 to 4 servings of vegetables, 5-6 servings of fat, oils, salad dressing, 1-2 servings of snacks/sweets
• Combination diet: 3g Na; K, Mg, Ca at 75th percentile US consumption; high fiber, more fruits & vegetables; low-fat dairy; low in saturated and total fats
• Five servings of fruit, 4 to 5 servings of vegetables, two servings of low-fat dairy, 2 to 3 servings of fat, oils, and salad dressing, <1 serving of snacks/sweets
• ≤3 caffeinated beverages and ≤2 alcoholic beverages per day

Outcomes  

Primary Outcome

Changes in resting DBP

1. Combination vs. control: -3.0 mmHg (97.5% CI -4.3 to -1.6; P<0.001)
2. Combination vs. fruits & vegetables: -1.9 mmHg (97.5% CI -3.3 to -0.6; P=0.002)
3. Fruits & vegetables vs. control: -1.1 mmHg (97.5% CI -2.4 to 0.3; P=0.07)

Secondary Outcomes

• Changes in resting SBP

1. Combination vs. control: -5.5 mmHg (97.5% CI -7.4 to -3.7; P<0.001)
2. Combination vs. fruits & vegetables: -2.7 mmHg (97.5% CI -4.6 to -0.9; P=0.001)
3. Fruits & vegetables vs. control: -2.8 mmHg (97.5% CI -4.7 to -0.9; P<0.001)

•  Changes in ambulatory DBP

1. Combination vs. control: -2.7 mmHg (P<0.001)
2. Fruits & vegetables vs. control: -2.1 mmHg (P=0.002) 

• Changes in ambulatory SBP

1. Combination vs. control: -4.5 mmHg (P<0.001)
2. Fruits & vegetables vs. control: -3.1 mmHg (P=0.001)

HYVET (The 2008 Hypertension in the Very Elderly Trial) 

Among very elderly patients (greater than or equal to 80 years) with hypertension, treatment with a diuretic with or without ACE-I is associated with a trend towards reduced rates of fatal and nonfatal stroke (which is the primary outcome) and a significant reduction in rates of secondary outcomes including fatal stroke, heart failure, cardiovascular events.[6]  

Key Points 

1. This trial was done in 2008, and the goal BP was <150/90, predominantly on patients from Eastern Europe and China (limiting the generalizability of the outcomes)  
2. This trial was stopped early due to a 21% reduction in all-cause mortality in the active group.   
3. The primary outcome is the reduced rates of fatal or nonfatal stroke (excluding transient ischemic attack), but it was not statistically significant (P=0.06), possibly because the study was stopped early.   

Design 

A double-blind, randomized, placebo-controlled trial with N=3845, of which 1933 got active treatment. The median follow-up was 1.8 years.  

Inclusion Criteria 

• Age (greater than or equal to 80 years)  
• Mean sitting BP on two separate occasions one month apart, 160-199/90-109 mmHg  

Exclusion Criteria 

• Secondary hypertension and accelerated hypertension  
• Clinical congestive heart failure and on treatment with a diuretic or ACE-I already.  
• Gout and hypo or hyperkalemia   
• Creatinine above 1.69  
• Dementia, nursing home residents, and terminally ill patients   

Interventions 

1. The patients on antihypertensives at baseline had their medications stopped and got a placebo for two months before being randomized to a group.   
2. Active treatment algorithm: Indapamide SR 1.5 mg daily, then: indapamide SR 1.5 mg daily plus perindopril 2 mg orally each day, then: Indapamide SR 1.5 mg daily plus perindopril 4 mg by orally each day  

Outcomes 

Primary Outcome

• Fatal or nonfatal stroke in person-years (P-Y): 12.4 vs. 17.7/1000 P-Y. (HR 0.70; 95% CI 0.49-1.01; P=0.06)  

Secondary Outcome 

• Fatal stroke: 6.5 vs. 10.7/1000 P-Y (HR 0.61; 95% CI 0.38-0.99; P=0.046) 
• All-cause mortality: 47.2 vs. 59.6/1000 P-Y (HR 0.79; 95% CI 0.65-0.95; P=0.02)  
• Cardiovascular mortality: 23.9 vs. 30.7/1000 P-Y (HR 0.77; 95% CI 0.60-1.01; P=0.06)  
• Congestive heart failure mortality: 1.5 vs. 3.0/1000 P-Y (HR 0.48; 95% CI 0.18-1.28; P=0.14)  
• Myocardial infarction: 2.2 vs. 3.1/1000 P-Y (HR 0.72; 95% CI 0.30-1.70; P=0.45)  

ONTARGET (The 2008 Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial)

In patients with cardiovascular disease or diabetes mellitus with complications, telmisartan is as efficacious as ramipril in preventing death, MI, and stroke. The combination of telmisartan plus ramipril had no increase in benefit but was associated with more adverse effects.[7]

Key Points 

1. The primary outcome of cardiovascular mortality, myocardial infarction, stroke, or heart failure hospitalization was similar in both ramipril and telmisartan groups. 
2. A combination of telmisartan and ramipril, however, showed an increased rate of nephropathy. 
3. The combination group achieved about 2 to 3 mmHg reduction in SBP but did not help with the primary or the secondary outcomes.

Design 

1. Multi-centered, double-blind, non-inferiority, randomized control trial
2. N=25,620, of which 8,576 patients were in the Ramipril group, 8,542 in the telmisartan group, and 8,502 in the combination group
3. Median follow-up: 56 months
4. Primary outcome: Cardiovascular mortality, myocardial infarction, stroke, or Heart failure hospitalization

Inclusion Criteria 

Age ≥55 with any of the following:

• Coronary artery disease - is defined by any of the following:
• Prior Myocardial infarction, > 2 days post uncomplicated MI
• Stable/unstable angina >30 days with documented multivessel CAD
• Multivessel CABG surgery > 4 years or recurrent angina after surgery
• Peripheral artery disease - is defined by any of the following:
• Limb bypass surgery or angioplasty
• Limb or foot amputation
• Intermittent claudication with ABI <0.80 on ≥1 side
• Significant peripheral artery stenosis (>50%) documented by angiography or non-invasive testing
• Cerebrovascular disease - Defined by any of the following:
• Prior stroke
• TIA >7 days and <1 year
• High-risk diabetes - Defined by evidence of end-organ damage

 Exclusion Criteria 

• Hypersensitivity/intolerance to ACE inhibitors or ARBs
• Heart failure
• Hemodynamically significant valvular or outflow tract obstruction
• Complex congenital heart disease
• Syncopal episodes of unknown etiology <3 months
• Planned cardiac surgery/PCA in the next three months
• Uncontrolled HTN on therapy defined by BP >160/100 mmHg
• Heart transplant
• Subarachnoid hemorrhage-related stroke
• Significant renal artery disease
• Liver disease
• Uncorrected volume or sodium depletion
• Primary hyperaldosteronism
• Use of another experimental drug
• Unable to provide written informed consent
• Serious illness

Interventions 

       1. Single-blind run-in period

• Ramipril 2.5 mg once daily x 3 days
• Ramipril 2.5 mg + telmisartan 40 mg daily x 7 days
• Ramipril 5 mg + telmisartan 40 mg for 11 to 18 days

      2. Then, 11.7% were excluded before randomization.

        Randomization to a group:

• Ramipril - Ramipril 5 mg orally daily for two weeks, then 10 mg orally each day
• Telmisartan - Telmisartan 80 mg orally each day
• Combination - Ramipril 5 mg orally daily for two weeks, then 10 mg orally daily plus a stable dose of telmisartan 80 mg orally daily

Outcomes 

Primary Outcome 

• Cardiovascular mortality, MI, stroke, or heart failure hospitalization:16.5% vs. 16.7% vs. 16.3% (RR 1.01; 95% CI 0.94-1.09 | RR 0.99; 95% CI 0.92-1.07)
• Telmisartan noninferior to ramipril (P=0.004)

Secondary Outcomes

• CV mortality, MI, or stroke
• Telmisartan non-inferior to ramipril (P=0.001): 14.1% vs. 13.9% vs. 14.1% (RR 0.99; 95% CI 0.91-1.07 | RR 1.00; 95% CI 0.93-1.09)
• Renal impairment (based on clinician's judgment): 10.2% vs. 10.6% vs. 13.5% (RR 1.04; 95% CI 0.96-1.14 | RR 1.33; 95% CI 1.22-1.44; P<0.001; NNH 30)
• Requiring HD: 0.6% vs. 0.6% vs. 0.8% (RR 1.09; 95% CI 0.74-1.61 | RR 1.37; 95% CI 0.94-1.98)

SPRINT (The 2015 Systolic Blood Pressure Intervention Trial) 

In patients with high risk for cardiovascular disease but without a known history of stroke or diabetes, intensive BP control (target SBP below 120 mmHg) improved cardiovascular outcomes and overall survival compared to standard therapy of treating to target SBP 135 to 139 mmHg.[8]  

Key Points 

1. SPRINT (2015) significantly impacted hypertension management, and the ACC/AHA guidelines that followed in 2017 recommended lowering the threshold of hypertension treatment from 140/90 to 130/80 mm Hg. In addition, the recommendation was to start antihypertensives at 130 mm Hg, especially among those with risk factors like chronic kidney disease, congestive heart failure, coronary artery disease, and diabetes mellitus.   
2. The primary concern about intensive BP control in the SPRINT study regarded the cognitive decline from theoretical hypoperfusion of the brain. Still, a sub-study called SPRINT MIND showed lower cognitive impairment in the intensive BP group. And a secondary analysis of SPRINT found a lower incidence of Orthostatic hypotension with intensive BP control.

Design 

1. A multicenter, open-label, randomized controlled trial  
2. A total of 9,361 non-diabetic patients above or equal to age 50 without a prior history of stroke but at elevated risk for cardiovascular events.   
3. Randomized to intensive BP control group (target SBP <120 mmHg) or to standard therapy group (target SBP 135-139 mmHg)  
4. The diastolic pressure goal in both groups is less than 90 mmHg 
5. Medications were actively withdrawn in the standard treatment group if systolic blood pressure was below 130 to 135 mmHg, even in asymptomatic patients.  
6. In both groups, medications were altered or discontinued if patients developed adverse effects. 
7. Primary outcomes include: 

• Myocardial infarction. 
• Acute coronary syndrome without myocardial infarction. 
• Stroke. 
• Acute heart failure. 
• Cardiovascular death.   
• h.Follow-up for five years was planned, but the trial was stopped after three years as an interim analysis showed the superiority of intensive therapy over standard therapy.   

Inclusion criteria 

Age ≥50 years  

SBP (mmHg) in a range of 130 to 180 mmHg, with most of them on at least one antihypertensive medication in addition to one or more of the following Cardiovascular risk factors-  

• Clinical cardiovascular diseases like prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, carotid endarterectomy or carotid stenting, and revascularized peripheral arterial disease   
• Acute coronary syndrome with or without EKG changes and ischemic changes on stress test and other cardiac imaging  
• ≥50% stenosis of carotid and coronary arteries   
• Abdominal aortic aneurysm ≥5 cm  
• Subclinical cardiovascular disease:  
• Carotid artery calcium score of greater than 400 in prior 2 years.  
• Ankle-brachial index ≤0.90 in prior 2 years, or  
• Left ventricular hypertrophy on EKG, echocardiogram, or other imaging in prior 2 years  
• Chronic kidney disease: eGFR 20-59 mL/min/1.73 m^2  
• Framingham estimated 10-year CVD risk ≥15%  
• Age ≥75 years  

  Exclusion Criteria 

• Diabetes mellitus   
• Stroke  
• Not on disease-appropriate antihypertensives (e.g., beta blocker and recent Myocardial infarction)  
• Secondary hypertension  
• standing SBP <110  
• Proteinuria with either protein to creatinine ratio of ≥ 1 g or albumin-to-creatinine ratio of ≥ 600 mg/g creatinine 
• Urine dipstick ≥ 2+ protein if the above ratios are not available  
• Polycystic kidney disease, glomerulonephritis, or advanced kidney disease with eGFR < 20 mL/min/1.73 m^2  
• Symptomatic heart failure  
• Life-limiting illness  
• Poor adherence  
• Organ transplant  
• Unintentional weight loss >10% in the prior 6 months  
• Pregnancy  
• Nursing home patients 

  Interventions 

1. Patients were randomized in an open-label fashion to either intensive or standard therapy groups as below.  
2. In the Intensive group - the target SBP is < 120 mm Hg  
3. In the Standard group - the target SBP is 135-139 mm Hg  
4. Antihypertensives were encouraged per standard practice, thiazide diuretics as first-line agents, Loop diuretics for chronic kidney disease, and Beta-blockers for coronary artery disease  

Outcomes

Primary Outcome  

• Intensive therapy significantly reduced the first occurrence of an acute coronary syndrome, stroke, acute heart failure, and cardiovascular death: 5.2% vs. 6.8% (HR 0.75; 95% CI 0.64-0.89; P<0.001)  

Secondary Outcomes  

• Reduction in all-cause mortality:3.3% vs. 4.5% (HR 0.73; 95% CI 0.60-0.90; P=0.003)  
• Composite of primary outcome or all-cause mortality: 7.1% vs. 9.0% (HR 0.78; 95% CI 0.67-0.90; P<0.001; NNT 53)  
• Heart failure: 1.3% vs. 2.1% (HR 0.62; 95% CI 0.45-0.84; P=0.002; NNT 125) 
• Cardiovascular mortality: 0.8% vs. 1.4% (HR 0.57; 95% CI 0.38-0.85; P=0.005; NNT 167) 

Adverse Effects

The intensive therapy arm was associated with more non-orthostatic hypotension, syncope, electrolyte abnormalities, and Acute kidney injury, but mostly it is mild to moderate.

Clinical Significance

The above clinical trials about hypertension helped solidify the recommendations and formed the latest ACC/AHA guidelines. The DASH diet (1997) has been permanently incorporated into the non-pharmacological management of hypertension. Thiazides became widely used as first-line agents for essential hypertension based on the ALLHAT(2002) trial results. 

Similarly, the AASK study done in 2002 emphasized using Angiotensin-converting enzyme inhibitors or Angiotensin receptor blockers among patients with Chronic kidney disease. The Accomplish study, which followed in 2008, proved that using the Ace-inhibitors/calcium channel blocker combination helped to decrease cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. And the HYVET study strengthened the above results by stating that using a diuretic with or without ACE-I decreased all-cause mortality even in patients above 80 years of age. 

While the ACCORD BP study done in 2010 showed that intensive BP control (SBP below 120 mmHg) did not show any improvement in the above outcomes, the SPRINT study (2015) showed that in patients at high risk for cardiovascular disease, intensive BP control (target SBP below 120 mmHg) improved cardiovascular outcomes and overall survival compared to standard therapy of treating to target SBP 135 to 139 mmHg.

Nursing, Allied Health, and Interprofessional Team Interventions

Most of the above studies are randomized controlled trials to study the efficacy of various antihypertensive medications.