TRED-HF - Withdrawal of HF meds in patients with recovered (non-ischemic) dilated cardiomyopathy

Halliday BP, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 2019 Jan 5;393(10166):61-73.

Bottom Line: In patients with recovered dilated cardiomyopathy (DCM), even careful withdrawal of HF medications will result in relapse of DCM (based on clinical signs, imaging or biomarkers) in approximately 4 out of 10 patients within 6 months, compared to no deterioration in this timeframe if these medications are continued.

These medications should be considered “lifelong” medications until we have tools that can reliably predict which patients can stop them without deteriorating.

Context

• In patients who initially have HF with reduced ejection fraction (HFrEF), recovery of ejection fraction >50% portends a more favorable prognosis

  • e.g. In one study, vs patients who had initial HFrEF followed by LVEF recovery to >50%, patients with non-recovered HFrEF had an increased risk of death, transplant or VAD placement (HR 3.4) & CV hospitalization (HR 1.8)

• The 2017 Canadian Cardiovascular Society (CCS) heart failure (HF) guidelines recommend consideration of monitored, sequential discontinuation of HF meds in certain subsets of patients with recovered non-ischemic cardiomyopathy

  • Including: chemotherapy-related, ETOH overuse-related, peripartum, tachycardia-related, or valvular cardiomyopathy

  • If: Asymptomatic (NYHA 1), LVEF and LV volumes normalized, trigger eliminated (e.g. ETOH abstinence, HR controlled, valve repaired/replaced)

• There is limited evidence for pharmacological treatment withdrawal in patients with HFrEF who get EF recovery

  • e.g. in an early observational study of 13 participants with DCM taking metoprolol for >2.5 years who weaned off metoprolol, 54% (7/13) experienced clinical deterioration (4 deaths & 3 patients who worsened by 1 NYHA functional class).

Design: Open-label RCT (pilot trial designed to plan larger trial)

Patients (n=51)

• Included if:

  • 16+ y/o

  • Previous dx of dilated cardiomyopathy (DCM) with LVEF 40% or lower

  • Currently:

    • NYHA functional class 1 (no current HF symptoms)

    • LVEF 50% or higher & left ventricular end diastolic volume indexed (LVEDVi) WNL (based on cardiac MRI, or 3D echo if MRI contraindicated)

    • NT-proBNP <250 ng/L

    • Treatment with 1+ of the following HF meds: Loop diuretic, ACEI, ARB, mineralocorticoid-receptor antagonist (MRA; spironolactone or eplerenone)

• Key exclusion criteria

  • Uncontrolled HTN (>160/100 mmHg in clinic)

  • Mod-severe valvular disease

  • Angina

  • Beta-blocker required for AF/flutter, VT, or SVT

  • GFR <30

  • Pregnant.

• Baseline characteristics (average of both groups unless specified)

  • Median age 55 y/o (IQR 45-64), male (67%)

  • Time since dx (4.9 y), median LVEF at dx 25%

  • Cause: Idiopathic (69%), familial (14%), trigger (excess ETOH, pregnancy, anthracycline, hyperthyroidism or myocarditis; 18%), pathogenic TTN truncation (22%)

  • Time since LVEF >50% (2 y)

  • CV symptom burden (0=none, 185=severe): 10-11

  • Quality of life using Kansas City Cardiomyopathy Questionnaire (KCCQ; 0=worst, 100=best)): 94-97

  • LVEF 60%, LVEDVi 83 mL/m^2, NT-proBNP 72 ng/L

    • Global longitudinal strain median 14% (values <16% considered abnormal)

  • Meds: ACEI/ARB (100%), beta-blocker (88%), MRA (47%), loop diuretic (12%)

Intervention & Comparator

• Intervention: Sequential discontinuation of HF meds over max 4 months, total 6 months follow-up

  • Order of drug dose reduction/discontinuation:

    • (1) Loop diuretic (reduced by 50% q2 weeks until furosemide 40 mg/d-equivalent, then D/Ced)

    • (2) MRA (reduced by 50% until equivalent to spiro 50 mg/d, then D/Ced)

    • (3) Beta-blocker (reduced by 50% until 25% target dose or lower, then D/Ced)

    • (4) ACEI/ARB (reduced by 50% until 25% target dose or lower, then D/Ced)

  • Follow-up schedule:

    • Baseline: Clinic visit, symptom & QoL questionnaire, exercise stress test, cardiac MRI, NT-proBNP

    • q4 weeks: Clinic visit & NT-proBNP

    • @ week 16: Repeat cardiac MRI

    • @ month 6: Same as baseline

• Comparator:

  • Phase 1 (randomized phase) x6 months: Continued all HF meds per baseline

    • @ baseline & month 6: Same as intervention group

    • @ weeks 8 & 16: Clinic visit, NT-proBNP

  • Phase 2: Then, non-randomized crossover to sequential discontinuation of HF meds as per intervention protocol

Results

Primary outcome: DCM relapse in 6-month randomized phase

• Defined as meeting 1+ of:

  • Clinical HF based on signs & symptoms

  • LVEF reduced by >10%, to <50%

  • LVEDVi increased by >10%, to above normal range

  • NT-proBNP doubled, to >400 ng/L

• Discontinuation group 44%, control group 0% (p=0.0001) - “number needed to harm” = 3 (rounded up from 2.3)

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Figure 3 from TRED-HF. Kaplan-Meier curve of time to relapsed DCM comparing discontinuation versus continuation of HF meds

Secondary outcomes:

• Composite safety outcome (CV death, major adverse CV events, unplanned CV hospitalization): 0 in both groups

• (Select) differences in means between groups from baseline to month 6:

  • KCCQ: -5.1 (95% CI -9.9 to -0.4; lower with discontinuation vs continuation of HF meds)

  • LVEF -9.5% (lower with discontinuation vs continuation)

  • LVEDVi +4.7 mL/m^2 (95% CI -1.5 to +11.0, p=0.14)

  • Vitals: HR +15 bpm, BP +7/+7 mmHg

  • Inconclusive: CV symptom burden, exercise time, peak VO2, log-transformed NT-proBNP

Secondary analyses including withdrawals from phase 1 + phase 2

• DCM relapse in control group phase 2: 36%

• Overall DCM relapse rate after HF med discontinuation: 40% (26% relapse <2 months of discontinuation)

Figure 4 from TRED-HF. Venn diagram breakdown of component of primary outcome met (includes all withdrawals from randomized phase + single-arm crossover phase)

Internal validity

• Allocation bias: Low risk

  • Computer-generated random sequence, 1:1 allocation in permuted blocks, stratified by baseline NT-proBNP

  • Centralized allocation via online system

• Performance bias: Low/unclear risk

  • Patients & their clinicians aware of treatment allocation; however, the study employed a standardized protocol to wean & D/C HF meds, as well as standardized monitoring

• Detection bias

  • Low risk of bias for objective outcomes (core lab MDs reading imaging unaware of study group allocation)

  • High risk of bias for QoL outcomes (patients completed the questionnaires aware of treatment allocation)

• Attrition bias: Low risk

  • Loss to follow-up 2% (1 participant in withdrawal group left trial after 7 days)

  • Analyzed intention-to-treat population

Other Considerations

• We can’t yet predict which stable, recovered DCM patients will deteriorate with D/C of HF meds

  • In this trial, predictors of DCM relapse after withdrawal of therapy included: greater age, use of >2 meds, use of MRA, higher NT-proBNP, lower global radial strain on cardiac MRI, & possibly lower peak VO2

    • However, based on univariable analysis only (no adjusting for other variables) & small n of events

  • DCM etiology did not clearly predict risk of deterioration with therapy withdrawal. Some patients with a seemingly reversible cause of DCM (e.g. ETOH use, pregnancy) did have DCM relapse upon D/Cing HF meds. Therefore, presence of a trigger does not indicate that D/Cing HF meds after HF remission will be safe.

DOSE - Diuretic strategies (low vs high dose & IV bolus vs continuous infusion) for acutely decompensated HF

Bottom line: In patients with acutely decompensated HF patients not in cardiogenic shock,

• Higher versus lower doses of loop diuretics did not significantly affect primary efficacy & safety outcomes
  • However, secondary outcomes consistently demonstrated a lower risk of serious adverse events (NNT 9), more rapid resolution of dyspnea & congestion, & greater weight loss (extra -1.2 kg in first 72h), at the cost of an increased risk of AKIN stage 1 AKI (NNH 12)
• Continuous IV administration of loop diuretics does not appear to have any advantage over q12h IV boluses.

Patients (n=300)

• Included
  • Presented for acutely decompensated HF (ADHF) within 24h
    • Diagnosed based on 1+ symptoms (SOB, orthopnea, edema) & 1+ sign (crackles, peripheral edema, ascites, pulmonary vascular congestion on CXR) of HF
  • Hx of chronic HF (any LV ejection fraction [LVEF])
  • Receiving an oral loop diuretic equivalent to furosemide 80-240 mg/d +/- chronic thiazide diuretic
• Excluded
  • SBP <90 mm Hg
  • SCr >265 umol/L
  • Requiring IV vasodilators or inotropes
• Average baseline characteristics
  • Age 66 y
  • Male ~74%
  • Median time from presentation to randomization ~15h
  • Ischemic CM 57%
  • Hospitalized for HF within 1 y ~75%
  • Home dose of furosemide PO ~130 mg/d
  • Clinical characteristics
    • Orthopnea ~90%
    • SBP 120 mm Hg
    • SpO2 96%
    • JVP 8+ cm 91%
    • LVEF 35% (27% with EF 50%+)
    • NT-proBNP ~680-8200 pg/mL
    • Sodium 138
    • SCr 133 umol/L
  • Meds
    • ACEI/ARB ~65%
    • BB ~85%
    • MRA ~27%

Interventions

• Dose comparison
  • High dose: Daily IV dose = 2.5x total home PO dose
  • Low dose: Daily IV dose = total home PO dose
• Administration method comparison
  • Continuous IV infusion
  • IV bolus dose divided as q12h administration
• Assigned treatment continued for up to 72h, after which treatment was open-label at discretion of treating physician
  • At 48h, could either
    • Increase dose by 50%
    • Maintain same strategy
    • D/C IV & switch to open-label PO
• At 48h:
  • Change to PO diuretics: High 31%, low 17% (p<0.001)
  • Need for dose increase
    • High 9%, low 24% (p=0.003)
    • Continuous 11%, bolus 21% (p=0.01)
• Median dose over first 72h
  • High 773 mg, low 358 mg
  • Continuous 480 mg (160 mg/d), bolus 592 mg (~200 mg/d)

Results

At 72h

• Primary efficacy outcome: Global assessment of symptoms (serial 0-100 visual analogue scale measurements tallied using area under the curve [AUC] from baseline to 72h, HIGHER=better)
  • High 4430, low 4171 (p=0.06)
  • Continuous 4373, bolus 4236 (p=0.47)
• Dyspnea AUC (higher=better)
  • High 4668, low 4478 (p=0.04)
  • Continuous 4699, bolus 4456 (p=0.36)
• Free from congestion (JVP <8 cm [<3 cm ASA], no orthopnea & trace/np peripheral edema)
  • High 18, low 11 (p=0.09)
  • Continuous 15%, bolus 14% (p=0.78)
• Wt change (kg)
  • High -3.9, low -2.7 (p=0.01)
  • Continuous -3.6, bolus -3.0 (p=0.20)
• Primary safety outcome: Change in SCr (umol/L) from baseline to 72h
  • High +7.1, low +3.5 (p=0.21)
  • Continuous +6.2, bolus +4.4 (p=0.45)
• SCr increase >26 umol/L
  • High 23%, low 14% (p=0.04)
  • Continuous 19%, bolus 17% (p=0.64)

At 60 days

• Serious adverse event
  • High 38%, low 50% (p=0.03)
  • Continuous 44%, bolus 44% (p=0.92)
• Composite of death, hospitalization or ED visit: 42% overall, no difference between groups

No difference between groups in median length of stay (5 days for all)

Generalizability

• Included a mix of HFrEF & HFpEF patients at high risk of HF hospitalization with moderate to high home doses of loop diuretics, a reasonable proportion of whom were receiving good HF medical therapy
• Outcomes were clinically important and easily measurable and translatable to practice

Internal validity

• Low risk of bias
  • 2x2 factorial randomization using permuted blocks
  • Allocation concealed
  • Double-blind, dummy-dummy design (saline placebos with identical appearance)
  • ITT analysis
  • Threshold for significance p<0.025 for coprimary outcomes (global assessment of wellbeing & change in SCr from baseline to 72h) 

ACCOMPLISH - Amlodipine vs HCTZ added to benazepril in HTN

Jamerson K, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. NEJM 2008;359:2417-28.

Bottom line: 

• When added to an ACE inhibitor, amlodipine reduced the risk of CV events versus HCTZ (NNT 46 over 3 years). Amlodipine produced less dizziness (NNT 20), but far more peripheral edema (NNH 5) than HCTZ.

• Calcium channel blockers are not superior to other thiazides.

 

Patients (n=11,506)

• Included
  • HTN
  • High CV risk, defined as hx of any of the following:
    • Existing CVD: Stroke, ACS/MI, PAD, prior revascularization
    • LVH
    • CKD
    • Diabetes
• Typical study patient
  • Age 68 y
  • Female 40%
  • Prior CVD
    • Stroke 13%
    • MI 24%, unstable angina hospitalization 12%
    • Coronary revascularization 36%
  • Other CV risk factors
    • Smoker 11%
    • LVH 13%
    • eGFR <60 18%, other renal disease 6%
    • Diabetes 60%
    • Dyslipidemia 74%
  • BP 145/80 mm Hg (baseline, treated or untreated)
  • eGFR 79
  • Meds
    • Antiplatelet 65%
    • Statin 68%

Interventions

• All: Benazepril, plus addition of non-ACEI/CCB/thiazide BP-lowering med after maxing out study meds to achieve target BP)
  • Initial: 20 mg daily
  • After 1 month: Increased to 40 mg daily
• Amlodipine
  • Initial: 5 mg daily
  • Increased to max 10 mg daily to achieve BP <140/90 (or <130/80 if diabetes/CKD)
    • 61% receiving this dose @ month 6
• Hydrochlorothiazide (HCTZ)
  • Initial: 12.5 mg daily
  • Increased to max 25 mg daily to achieve BP <140/90 (or <130/80 if diabetes/CKD)
    • 60% received this dose @ month 6

Results @ ~3 years

• Achieved SBP ~132 with amlodipine vs ~133 mm Hg with HCTZ (SBP 0.9 mm Hg lower with amlodipine)
  • Office BP <140/90: 75% vs 72%
• Death: 4.1% vs 4.5%, hazard ratio (HR) 0.90 (0.76-1.07)
• Primary outcome (composite of: CV death, non-fatal MI, stroke, unstable angina hospitalization, coronary revascularization, or resuscitation after sudden cardiac arrest): 9.6% vs 11.8% (NNT 46), HR 0.80 (0.72-0.90)
  • CV death: 1.9% vs 2.3%, HR 0.80 (0.62-1.03)
  • MI: 2.2% vs 2.8%, HR 0.78 (0.62-0.99)
  • Stroke: 1.9% vs 2.3%, HR 0.84 (0.65-1.08)
  • Coronary revascularization: 5.8% vs 6.7%, HR 0.86 (0.74-1.00)
• Study drug discontinuation: 28.8% vs 31.2%
• Specific adverse effects
  • Dizziness: 20.7% vs 25.4% (NNT 22)
  • Hypotension: 2.5% vs 3.6%
  • Peripheral edema: 31.2% vs 13.4% (NNH 5)
  • Hypokalemia: 0.1% vs 0.3%

Generalizability

• Patients in this trial were either "secondary CV prevention" or high-risk "primary CV prevention" patients, so absolute benefit of amlodipine over HCTZ likely lower in a population with lower baseline CV risk
• Interventions
  • HCTZ is arguably the least effective available thiazide diuretic; therefore, this trial cannot be extrapolated to conclude that amlodipine is superior to other thiazides, particularly chlorthalidone or indapamide when added to an ACE inhibitor
  • Non-comparable doses: Amlodipine 5-10 mg represents the "mid to high" dose range for this agent, whereas HCTZ 12.5-25 mg represents the "low to mid" dose range
    • This likely explains the small but significant difference between groups in mean BP & % of patients achieving target BP

Internal validity

• Low risk of allocation, performance & detection bias
  • Central allocation; patients, personnel & outcome adjudicators unaware of allocated treatment
  • However: Given high rate of peripheral edema with amlodipine, likely that a sizable portion of patients and clinicians were unblinded to treatment allocation. The effect of this on risk of performance bias is unclear, but likely minimal
• Low risk of attrition bias
  • Analyzed by intention-to-treat; low loss-to-follow-up (1%) with similar time on treatment in both groups
• Other: Study stopped early due to benefit based on pre-defined stopping rule
  • This is unlikely to have a meaningful impact on the results as primary outcome results based on >1200 events

Other studies

• ALLHAT is the major trial that seems to conflict with ACCOMPLISH:
  • Randomized 33,357 adults (55+ y) with BP 140-180/90-110 + high CV risk (existing atherosclerotic CVD, LVH, T2DM, HDL <0.90 mmol/L, or smoker) to chlorthalidone vs amlodipine vs lisinopril for a mean 4.9 years
  • Achieved SBP: ~134 vs ~135 vs ~136 mm Hg
  • Chlorthalidone vs amlodipine: No difference between any group in primary outcome (fatal coronary event or MI) or individual CV outcomes, except lower lower risk of HF incidence (NNT 40) & HF hospitalization (NNT 53) with chlorthalidone
• A meta-analysis of 7 RCTs comparing diuretics vs CCB (n=51,450), driven largely by ACCOMPLISH & ALLHAT, found no difference in rates of major CV events
• In my opinion, the above studies suggest that HCTZ is inferior to chlorthalidone. No RCT has ever compared effect of HCTZ vs chlorthalidone on CV events, so only low-quality evidence exists evaluating this theory:
  • Indirect comparison by network meta-analysis suggests that HCTZ may indeed be inferior to chlorthalidone for reduction in CV events;
  • Small RCT showed that chlorthalidone produces greater reduction in 24h & nighttime BP (which is more strongly associated with CV events than office BP) vs HCTZ despite similar office BP lowering;
  • A large administrative cohort study found no difference in CV events between chlorthalidone & HCTZ.

SHEP - Targeting systolic BP <160 mm Hg in patients with isolated systolic hypertension

SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991;265:3255-64.

Bottom line: In patients with isolated systolic HTN with SBP ~170, reducing SBP <160 mm Hg with a chlorthalidone-based regimen reduced the risk of CVD (NNT 19), including individual components such as stroke (NNT 46) over 4.5 years. This benefit was countered by an increase in adverse events, including bothersome adverse events (NNH 14), syncope (NNH 112) and electrolyte abnormalities.

 

Patients (n=4736)

• Included: SBP 160-219 mm Hg & DBP <90 mm Hg
• Excluded: Existing "major CV disease"
• Typical study patient
  • Age 72 y
  • Female 57%
  • Previous CVD: Stroke 1.4%, MI 5%
  • BP 170/77 mm Hg

Interventions

• I: Chlorthalidone 12.5-25 mg/d +/- atenolol 25-50 mg/d to achieve BP goal
  • If baseline SBP 160-179 mm Hg: Goal to reduce BP by >20 mm Hg
  • If baseline SBP 180+ mm Hg: Goal SBP <160 mm Hg
• C: Placebo & attempt to reach same BP goals as above

Results @ mean 4.5 years

• Achieved SBP at year 5: 144 vs 155 mm Hg (mean difference 11 mm Hg)
• Receiving BP meds by year 5: 90% vs 44%
• Death: 9.0% vs 10.2%, relative risk (RR) 0.87 (0.73-1.05)
• Efficacy
  • CV disease (CV death, MI, stroke/TIA, coronary revascularization, aneurysm, endarterectomy): 12.2% vs 17.5% (NNT 19), RR 0.68 (0.58-0.79)
    • Total stroke (primary outcome): 4.1% vs 6.3% (NNT 46), RR 0.63 (0.49-0.82)
    • Non-fatal MI or coronary death: 4.4% vs 5.9% (NNT 72), RR 0.73 (0.57-0.94)
  • "LV failure": 2.0% vs 4.3% (NNT 44), RR 0.46 (0.33-0.65)
• Safety
  • Any adverse event: 91.8% vs 86.4% (NNH 19)
  • Any intolerable adverse event: 28.1% vs 20.8% (NNH 14)
  • Key adverse events (not a comprehensive list)
    • Falls: 12.8% vs 10.4% (NNH 42)
    • Loss of consciousness/passing out: 2.2% vs 1.3% (NNH 112)
    • Na <130: 4.1% vs 1.3% (NNH 36)
    • K <3.2: 3.9% vs 0.8% (NNH 33)

Internal validity

• Low risk of allocation, performance, detection & attrition bias
  • Central allocation
  • Double-blind
  • Protocolized, stepped approach to treatment

HOPE-3 (BP lowering)

Lonn EM, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;online

Clinical Question

In patients without CVD with 1+ CV risk factors, does the indiscriminate use of a fixed "medium" dose of candesartan + HCTZ irrespective of BP reduce the risk of CVD?

Bottom Line

In this population of patients without CVD at mostly intermediate risk, a fixed "medium" dose of candesartan + HCTZ did not lower the risk of CVD over ~5 years.

Possible explanations for the results of this study include already-low baseline CV risk and BP and suboptimal BP-lowering agents as intervention (amlodipine chlorthalidone, &/or an ACEI would have been more appropriate based on prior evidence). As a result, this study complements, rather than conflicts with, similar studies such as the well-publicized SPRINT trial.

Design

2x2 factorial, allocation-concealed RCT with "everybody" blinded, low loss-to-follow-up (<1%), and analyzed using the intention-to-treat population.

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Special notes:

• Pre-enrollment run-in phase: Single-blind treatment with both HOPE-3 active treatments (BP- & cholesterol-lowering) x4 weeks. Advanced to randomization if:
  • Took at least 80% of doses
  • Tolerated regimen without unacceptable adverse events
• Power calculation: Based on described assumptions, inclusion of 12,700 participants should rule out relative risk reduction by 22.5% with candesartan/hydrochlorothiazide
• Change to pre-defined outcomes:
  • Single primary outcome changed to 2 co-primary outcomes (done before investigators saw unblinded data)

Patients and Setting

• 21 countries, 228 centers
• April 2007 - November 2010
• Inclusion criteria:
  1. Men 55+ y/o and women 65+ y/o + 1 additional CV risk factor:
     • FHx: Premature CHD in 1o-degree relative (age <55 in men or <65 in women)
     • SHx: Current/recent smoking (regular tobacco within 5 years)
     • O/E: Waist/hip ratio >89 in men and >84 in women
     • Labs:
       • Low HDL (<1.0 mmol/L in men, <1.3 mmol/L in women)
       • Renal dysfunction (microalbuminuria, eGFR <60 mL/min or SCr >124 micromol/L)
       • Dysglycemia (impaired fasting glucose or glucose tolerance test, but not diabetes requiring more than 1 oral antihypoglycemic) Women 60-6
  2. Women 60-64 y/o with 2 additional CV risk factors
  • NOTE: BP not included as a CV risk factor for eligibility, & no minimum BP criteria for enrollment
• Exclusion criteria:
  • PMHx:
    • Manifest atherothrombotic CVD
    • Clear indication or contraindication for statin &/or ACEI/ARB/thiazide, as determined by subject's own local MD
    • Symptomatic hypotension
      • Chronic liver disease or abnormal liver enzymes (i.e. ALT or AST >3x ULN)
      • Severe renal impairment (calculated CrCl <30 mL/min/1.73 m^2 or SCr >264 micromol/L
      • Inflammatory muscle disease or CK >3x ULN
      • Significant psychiatric illness, senility, dementia, ETOH or substance abuse
  • Concurrent meds:
    • Cyclosporine, or a condition likely to result in organ transplant & need for cyclosporine
    • ACEI, ARB, thiazide
    • Statin or fibrate (patients taking other cholesterol-lowering drugs could be enrolled)
  • Enrolled in other drug study
• 14,682 entered run-in phase -> 12,705 (86.5%) enrolled
• Average patient:
  • 65.7 y/o
  • 46% female
  • Race: 29% Chinese, 27% Hispanic, 20% White, 15% South Asian, <2% Black
  • Enrollment CV risk factors:
    • 26% with FHx premature CHD
    • 28% current/recent smoking
    • 87% with elevated waist/hip ratio (mean BMI 27)
    • 36% with low HDL
    • <3% with renal dysfunction
    • 13% with impaired glucose, 6% with diabetes
    • BP 138/82 mm Hg (38% with history of HTN)
    • SCr: 80 micromol/L
    • Lipids: Total cholesterol 5.2 mmol/L, HDL 1.17 mmol/L, LDL 3.29 mmol/L
    • Fasting plasma glucose: 5.3 mmol/L
    • Baseline meds
      • Any BP-lowering drug 22%
        • CCB 15%
        • Beta-blocker 8%
      • ASA 10%

Intervention and Control

• Intervention: Single-tablet combination of candesartan 16 mg + hydrochlorothiazide 12.5 mg PO once daily
  • Adherence: 88% @ 1 year, 84% @ 3 years, 75% @ 5 years, 77% @ end of trial
  • Mean BP decrease from baseline: 10/6 mm Hg
• Control: Matching placebo
  • Adherence: 88% @ 1 year, 83% @ 3 years, 75% @ 5 years, 76% @ end of trial
  • Mean systolic BP decrease from baseline: 4/3 mm Hg
• Co-interventions common to both groups:
  • Randomized to rosuvastatin 10 mg PO daily or placebo
  • Individualized structured lifestyle advice
• Follow-up:
  • Visits q6 weeks x6 months, then q6 months
    • Monitoring parameters: Adherence, safety, trial outcomes
  • BP measurement
    • q visit x1 year, then q1 year
    • Using Omron automated device
    • Average of 2 measurements after 5 min of quiet rest

Outcomes

• @ median follow-up 5.6 years
• Mean BP 6/3 mmHg lower with intervention vs control
• No statistically significant difference in any primary or secondary outcome
• Subgroup analyses:
  • 16+ performed
  • Significant difference in efficacy based on tertile of SBP (<132, 132-143, >143), p for interaction = 0.02 & 0.009, respectively, for each coprimary outcome
    • Benefit if baseline SBP > ~140
    • No effect, or possible harm if baseline SBP <140
  • No difference in effect based on other subgroups (baseline diastolic BP, +/- rosuvastatin, age, baseline CV risk or LDL, etc)

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Outcomes in HOPE-3 BP-lowering trial

Key Considerations

Patients: This trial evaluated a "minimal investigation" preventative philosophy of management. Patient were enrolled based on age and presence of 1+ other CV risk factors; CV risk calculators were not used to determine study eligibility. Individual risk scores have varying impact on CV risk (e.g. a 30-year smoking history increases CV risk substantially more than a fasting plasma glucose of 6.5 mmol/L). In practice, a more nuanced assessment of CV risk incorporating a CV risk calculator, other conditions and medications with impact on CV risk will better capture patients who may benefit from BP lowering.

Intervention: The "neutral results" of this trial may be due to suboptimal BP-lowering therapy. For thiazides, far more robust evidence of lowering CV events exists for chlorthalidone (ALLHAT, SHEP) & indapamide (ADVANCE, HYVET, PROGRESS]) than HCTZ, in addition to greater reductions in 24h BP on ambulatory monitoring. Candesartan has the advantage of not causing an "ACEI cough", but also has a less-robust evidence base than ACE inhibitors such as ramipril (used in the original HOPE trial).

Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD
Summary date: 4 May 2016