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

SPRINT - Targeting a systolic BP <120 vs <140

The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. NEJM 2015;373:2103-16.

Bottom line:

• In patients with initial SBP 130-180 mm Hg, targeting SBP <120 vs 135-139 mm Hg reduces the risk of death (NNT 84), CV events (NNT 63; primarily from fewer CV deaths & new cases of HF) over 3.3 years.

• Targeting this lower target results in prescribing of 1 additional BP med & an increase in a number of adverse events related to BP meds, including syncope (NNH 91), AKI (NNH 56) & electrolyte abnormalities (NNH 100) versus the "standard" target.

 

Patients (n=9361)

• Included
  • Age >50 y
  • SBP 130-180 mm Hg (upper limit lower with higher # of BP meds pre-enrolment)
  • High CV risk, defined as 1 or more of:
    • Age 75+ y
    • Clinical CVD other than stroke (prior ACS, PCI, CABG, carotid endarterectomy, carotid stenting, PAD with revascularization, stenosis >50% of coronary, carotid or lower-extremity artery, AAA 5+ cm with or without repair)
    • Subclinical CVD (CAC >400 units, ABI <0.9, LVH) in past 2 years
    • Framingham risk score 15% or more over 10 y
    • CKD (stable eGFR 20-59 in past 6 months)
• Key exclusion
  • Prior stroke
  • Diabetes
  • Symptomatic HF with EF <35%
  • CV event or procedure, or hospitalization for unstable angina within 3 months
  • SBP <110 mm Hg after 1 min of standing 
  • Indication for specific BP med that pt is not taking
  • Renal
    • ESRD or eGFR <20
    • Proteinuria defined as: 24h urinary protein excretion >1 g, 24h urinary albumin excretion 600+ mg, spot urine PCR 1+ g/g, spot urine ACR 600+ mg/g, urine dipstick 2+ protein
    • PCKD
    • Glomerulonephritis
  • Any organ transplant
• Typical study patient
  • Age 67.9 y (75+ 28%)
  • Female 36%
  • CV risk criterion met
    • Clinical CVD 17%
    • Subclinical CVD 5%
    • FRS 15%+ 61%
    • Race: Black 30%, Hispanic 10%, white 58%, other 2%
    • BP 140/78 mm Hg
    • eGFR 72
    • Mean FRS 20%
    • Meds
      • Mean # of BP meds 1.8
      • ASA 51%
      • Statin 44%

Interventions

• BP med adjustments based on automated office BP (AOBP) using Omron device based on average of 3 measurements while sitting after 5 min of quiet rest
• I: Intensive therapy (target SBP <120 mm Hg, with secondary target of DBP <90 mm Hg)
  • At randomization, started on combo of 2-3 BP meds including a thiazide, ACEI or ARB, & CCB (or other agents for compelling indication, e.g. beta-blocker post-MI)
  • Mean AOBP SBP during follow-up: 121.5 mm Hg
  • Mean # of BP meds during follow-up: 2.8
• C: Standard therapy (target SBP 135-139 mm Hg, with secondary target of DBP <90 mm Hg)
  • At randomization, converted to SPRINT formulary
  • If SBP <130 x1 visit or <135 x2 visits, BP meds changed to increase SBP back into 135-140 range
  • Mean AOBP SBP during follow-up: 134.6 mm Hg
  • Mean # of BP meds during follow-up: 1.8
• Agents used in each class as part of SPRINT formulary: Thiazide (chlorthalidone 12.5-25 mg), ACEI (lisinopril 5-40 mg), ARB (azilsartan 40-80 mg, losartan 25-100 mg), beta-blocker (atenolol 25-100 mg, metoprolol tartrate 50-100 mg), CCB (amlodipine 2.5-10 mg, diltiazem 120-540 mg), other classes
• The control group required a very tight SBP range (135-139 mm Hg), which may have resulted in frequent medication adjustments & resulting visits to maintain this target (these data have not yet been reported)

Results @ median follow-up 3.3 years

• BP meds used at last visit (full list included in study's supplemental appendix)
  • Thiazide 55% vs 33%
  • ACEI or ARB 77% vs 55%
  • Beta-blocker 41% vs 31%
  • CCB 57% vs 35%
• Mean AOBP SBP difference at year 1: ~15 mm Hg
• Death: 3.3% vs 4.5% (NNT 84), hazard ratio (HR) 0.73 (95% confidence interval 0.60-0.90)
• Serious adverse event: 38.3% vs 37.1%, p=0.25
• Primary outcome (composite of CV death, ACS, stroke, acute decompensated HF): 5.2% vs 6.8% (NNT 63), HR 0.75 (0.64-0.89)
  • CV death: 0.8% vs 1.4%, HR 0.57 (0.38-0.85)
  • HF: 1.3% vs 2.1%, HR 0.62 (0.45-0.84)
  • MI: 2.1% vs 2.5%, HR 0.83 (0.64-1.09)
  • Stroke: 1.3% vs 1.5%, HR 0.89 (0.63-1.25)
• Renal event
  • Prior CKD (eGFR decreased >50%, development of ESRD requiring long-term dialysis or kidney transplant): 1.1% in both groups
  • No prior CKD (eGFR decreased >30% to <60 mL/min/1.73 m2): 3.8% vs 1.1% (NNH 37), HR 3.49 (2.44-5.10)
  • Subgroup analyses demonstrated no significant subgroup differences
• Events leading to ED visit, hospitalization, death, or resulting in persistent disability:
  • Injurious fall: 7.1% in both groups
  • Syncope: 3.5% vs 2.4% (NNH 91)
  • Hypotension: 3.4% vs 2.0% (NNH 72)
  • Bradycardia: 2.2% vs 1.8%
  • Electrolyte abnormality 3.8% vs 2.8% (NNH 100)
  • AKI: 4.4% vs 2.6% (NNH 56)
• Orthostatic hypotension with dizziness: 1.3% vs 1.5% (asymptomatic: 16.6% vs 18.3%)

Generalizability

• Population caveats
  • Specifically excluded patients with diabetes & stroke due to ongoing BP-target trials at time of SPRINT design (ACCORD-BP for diabetes & SPS3 for lacunar stroke)
    • Therefore, results of SPRINT not directly applicable to patients with diabetes or stroke, but must consider SPRINT in interpretation of both ACCORD-BP & SPS3
  • Excluded patients with symptomatic HFrEF; these patients should be treated to achieve maximally-tolerated doses of HFrEF-modifying drugs as previously reviewed
  • >75% of SPRINT patients had no CVD at baseline (primary prevention), so the absolute risk reduction reported in SPRINT mainly applies to this "lower risk" population, & absolute benefits are likely greater for patients at higher baseline CV risk
• Intervention caveats
  • The SPRINT treatment protocols encouraged use of interventions with greatest evidence base, i.e. thiazides recommended as 1st-line, & chlorthalidone (not hydrochlorothiazide) included on formulary
    • Absolute benefit of intensive BP control may therefore vary based on agents used in practice. Clinicians should strive to use these proven agents

Internal validity

• Low risk of allocation, attrition, & selective outcome reporting biases
  • Random sequence generation & allocation concealment
  • Loss-to-follow-up minimal (~3%), analyzed by intention-to-treat
  • Reported (or in process of gathering & publishing) all clinically-important outcomes of interest
• Unclear risk of performance & detection bias
  • Outcome adjudicator blinded, but patients and clinicians aware of allocated treatment group. Overall, likely low-risk due to protocolized intervention for each group & clearly-defined outcome definitions with objective criteria
• Early truncation unlikely to introduce significant bias due to large number of primary outcome events (>500) & valid, pre-defined stopping rules

Additional publications of SPRINT

• Clinicians are reasonably cautious with BP lowering in very elderly patients, particularly in those who are frail. The SPRINT investigators explored the efficacy and safety of intensive SBP lowering in the 28% of patients in SPRINT 75+ years old at baseline
  • In these 2636 patients with a mean age of 80 y, results were largely consistent with those seen in the overall SPRINT population, with greater absolute benefits due to age-related increases in baseline risk:
    • Efficacy: Reduced primary outcome (NNT 27), death (NNT 41), and HF
    • Safety: No increase in serious adverse events (HR 0.99, 0.89-1.11), injurious falls; non-statistically significant increases in syncope (NNH 167), symptomatic orthostatic hypotension (NNH 167), electrolyte abnormalities and AKI
  • Among those aged 75+ years, efficacy outcomes did not differ based on frailty status or gait speed 
  • A further analysis of patients 75+ years old in SPRINT found that intensive versus standard BP lowering had no impact on gait speed or progression to mobility limitation
    • In other words, intensive BP lowering in SPRINT did not inadvertently result in an increase in frailty or disability due to hypotension-related falls, fractures, gait instability or lightheadedness

Other studies

• ACCORD BP (low target SBP in diabetes):
  • Open-label RCT of 4733 type 2 diabetics with baseline SBP 130-180 mm Hg, A1c 7.5% or more & high CV risk (40+ y with CVD or 55+ y with atherosclerosis, albuminuria, LVH, or 2+ other CV risk factors) randomized to target SBP <120 or <140 mm Hg
  • Mean achieved SBP 119 vs 133 mm Hg (mean difference 14 mm Hg) using a mean of 3.4 & 2.1 BP meds, respectively
  • At mean 5 y, no statistically significant difference in death (HR 1.07, 0.85-1.35) or primary outcome (CV death, MI, stroke; HR 0.88, 0.73-1.06), but statistically significant reduction in stroke (NNT 91; HR 0.59, 0.39-0.89)
  • Subgroup analysis by assignment to intensive vs standard glycemic control (stratified at baseline) suggested that target SBP <120 mm Hg beneficial on primary outcome in patients assigned to standard glycemic control (p=0.08 for interaction)
  • Bottom line of ACCORD BP: Does not rule out clinically important benefit of lower SBP target (especially considering interaction with harmful intensive glycemic control of ACCORD)
• SPS3 (low target SBP post-stroke):
  • Open-label RCT of 3020 patients with symptomatic lacunar stroke within past 6 months randomized to target SBP <130 or 130-149 mm Hg
  • Mean achieved SBP 127 vs 138 mm Hg (mean difference 11 mm Hg) using mean 2.4 vs 1.8 BP meds, respectively
  • At mean 3.7 y, no statistically significant difference in stroke (HR 0.81, 0.64-1.03), MI/vascular death (HR 0.84, 0.68-1.04) or serious adverse events (HR 1.53, 0.80-2.93)
  • Bottom line of SPS3: Does not rule out clinically important benefit of lower SBP target
• Conflicting results between low vs standard BP target in other studies of overall HTN population
  • HOT (low target diastolic BP in overall HTN population):
    • Open-label RCT of 18,790 patients with baseline diastolic BP 100-115 mm Hg (baseline BP 170/105 mm Hg) randomized to target DBP <80, <85, or <90
    • Mean achieved SBP 140 vs 141 vs 144 mm Hg (mean SBP difference 4 mm Hg between DBP <80 and <90 groups)
      • Standard BP med step-wise process: Step 1 (felodipine), step 2 (ACEI or beta-blocker), step 3 (increase felodipine), step 4 (increase ACEI/BB), step 5 (add diuretic)
    • At mean 3.8 years, no difference between groups in primary outcome or individual CV outcomes in overall population
    • Investigators performed subgroup analysis in patients with diabetes (without appropriately performing a test for interaction to assess for a subgroup effect of diabetes vs no diabetes)
      • Identified a lower risk of the primary outcome & CV mortality, but not MI or stroke, with a target DBP <80 vs <90 in diabetes
    • Bottom line of HOT: No reduction in CV events with a lower target DBP using the aforementioned 5-step regimen; HOT diabetic subgroup effect is questionable at best
  • Cardio-Sis (target SBP <130 in HTN with 1 other CV risk factor)
    • Open-label RCT of 1111 patients with baseline SBP >150 randomized to target SBP <130 vs 140 mm Hg 
    • Mean achieved SBP 132 vs 136 mm Hg (mean SBP difference 4 mm Hg)
    • At 2 years, reduction in patients with new-onset LVH (primary outcome), as well as a broad CV composite outcome (death, MI, angina, coronary revascularization, stroke/TIA, AF, HF admission; NNT 22, RRR 50%)

INVEST - Verapamil- vs atenolol-based HTN treatment in CAD

Pepine CJ, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 2003;290:2805-16.

Bottom line:

• Although INVEST technically demonstrated "equivalence" of a HTN regimen based primarily on verapamil SR + trandolapril versus atenolol + hydrochlorothiazide in patients with CAD & HTN, this does not generalize to patients with (1) HF or LV dysfunction or (2) recent MI without contraindication for a beta-blocker.

• Additionally, this likely does not generalize to patients on better evidence-based thiazides (chlorthalidone or indapamide), & possibly not to other beta-blockers.

• Overall, there was no clinically relevant benefit of the verapamil-based regimen in CAD that would justify using this agent over a beta-blocker in this population.

 

Patients (n=22,576)

• Included
  • Age 50+ y
  • CAD, clinically stable, defined as any of:
    • Remote MI >3 months ago;
    • Stenosis of >50% of at least 1 coronary artery on angiography;
    • "Classic" angina
    • Ischemia on 2+ non-invasive investigations (EKG, echo, and/or nuclear imaging)
  • Hypertension (HTN)
• Exclusion
  • HF NYHA functional class IV (I-III could be enrolled)
  • Taking beta-blockers for an MI that occurred <1 year
• Typical study patient
  • Age 66 y (~33% >70 y)
  • Female 52%
  • Inclusion criteria
    • Angina 67%
    • Coronary stenosis on angiogram 39%
    • MI 32%
    • Abnormal stress test 21%
  • PMHx
    • CABG or PCI 27%
    • Stroke 5%
    • HF (NYHA I-III) 5-6%
    • Current smoker 12%
    • Dyslipidemia 56%
    • Diabetes 28%
  • BP 150/86 mm Hg
  • HR 76 bpm
  • Meds
    • Antiplatelet 57%
    • Lipid-lowering 37%
    • Hormone replacement therapy 18% of women

Interventions

• Both groups received treatment for HTN to target office-based BP <140/90 mm Hg (<130/85 mm Hg for patients with diabetes or renal dysfunction)
• I: Verapamil SR-based HTN regimen
  • Step 1: Verapamil SR 240 mg PO once daily (if HF, diabetes, or renal impairment: also add trandolapril 2 mg/d)
  • Step 2: Add trandolapril 2 mg PO daily
  • Step 3: Increase verapamil to 180 mg PO BID & trandolapril to 2 mg PO BID
  • Step 4: Add hydrochlorothiazide 25 mg PO daily
  • Steps 5+: Max doses of verapamil 480 mg/d, trandolapril 8 mg/d, hydrochlorothiazide 100 mg/d, non-beta-blocker non-study antihypertensive
  • At 2 y, 82% on verapamil SR
• C: Atenolol-based HTN regimen
  • tep 1: Atenolol 50 mg PO once daily (if HF, diabetes, or renal impairment: also add trandolapril 2 mg/d)
  • Step 2: Add hydrochlorothiazide 25 mg PO daily
  • Step 3: Increase both atenolol & hydrochlorothiazide to BID
  • Step 4: Add trandolapril 2 mg/d
  • Steps 5+: Max doses of atenolol 200 mg/d, hydrochlorothiazide 100 mg/d, trandolapril 8 mg/d, non-CCB non-study antihypertensive
  • At 2 y, 77% taking atenolol

Results @ mean 2.7 years

• Vitals @ year 2
  • BP reduction of ~19/10 mm Hg in both groups
  • Achieved BP <140/90 mm Hg: 71.7% vs 70.7%
  • Mean resting HR 73 bpm vs 69 bpm
• Primary outcome (death, non-fatal MI, non-fatal stroke): 9.9% vs 10.2%, relative risk (RR) 0.98 (0.90-1.06)
  • Death: 7.75% vs 7.9%
  • Non-fatal MI: 1.3% in both groups
  • Non-fatal stroke: 1.2% vs 1.3%
• Angina:
  • Baseline: 1.5 episodes/week in both groups
  • At 2 years: 1.3 vs 1.6 episodes/week (p=0.02)
• Adverse events:
  • Lightheadedness: 0.4% vs 0.6%
  • Symptomatic bradycardia: 0.7% vs 1.3%
  • Dyspnea: 1% vs 0.7%
  • Wheezing: 0.2% vs 0.4%
• Subgroup analyses:
  • Different effect based on whether patients had HF (possibly ~5% absolute risk reduction with beta-blockers in primary outcome) versus those who did not (no difference)
  • Otherwise, no other baseline characteristics had a significant subgroup effect

Generalizability

• Population widely representative CAD population, with key caveats:
  • First, those with an MI in the last year who were already on a beta-blocker were excluded. Thus, this trial likely selected out patients who may benefit most from beta-blockers.
  • Second, this trial included patients with clinical HF. Notably, although only 5-6% of the population, there appeared to be much worse outcomes in those receiving verapamil subgroup, which is consistent with previous concerns of HF-related mortality due to the negative inotropic effect of non-dihydropyridine CCBs like verapamil. It should therefore be avoided in this population.
  • Third, there was generally poor use of CAD secondary prevention therapies such as ASA & lipid-lowering, & uncharacteristically high use of hormone replacement therapy (55% of enrolled patients were female & 18% of them were receiving HRT despite a confirmed CAD history). This would be expected to increase the underlying risk of primary outcome events in both treatment groups.
• Multiple considerations regarding the intervention arms are required to interpret the results:
  • First, the interventions represent BP-lowering "regimens" focused on using verapamil or atenolol, rather than a true head-to-head comparison of these agents;
  • Second, although it lowers BP, atenolol seems to reduce the risk of CV events less than antihypertensive agents from other classes in patients with HTN. Similarly, hydrochlorothiazide is a weaker antihypertensive agent & generally has less evidence supporting its use than other thiazides, which have a clearer signal for benefit. This combination may have therefore been disadvantaged versus using a beta-blocker + thiazide combination with more robust supporting evidence (e.g. bisoprolol plus chlorthalidone).
  • Third, adherence to the primary drug of the regimen (verapamil & atenolol) as well as to BP goals was fairly poor, with only 75-80% in each group still taking this drug & only ~70% with BP <140/90 mm Hg at year 2.

Internal validity

• Low risk of allocation bias due to appropriate sequence generation & allocation concealment (centralized, automated Internet-based randomization with permuted blocks).
• As this trial was a "prospective, randomized, open-label, blinded-endpoint" (PROBE) trial, it is by default at high risk of performance & detection bias due to knowledge of clinicians & patients of the allocated treatment
  • The risk of performance bias was minimized with a standardized treatment algorithm for HTN & a similarly low proportion of patients (~70%) achieved their BP target. Additionally, few patients had revascularization procedures & there were similar rates of crossover between groups
  • Investigators attempted to minimize the risk of detection bias by adjudication of events by a committee unaware of treatment allocation, however, they could not eliminate this bias as well as if they would have blinded patients and clinicians to allocation to verapamil or atenolol. Given that this was a feasible option with a few minor changes to the study HTN treatment algorithm, it is not possible to give the investigators "a pass" for this.
• Low risk of attrition bias as analyses followed intention-to-treat principles, & loss-to-follow-up was low at ~2-3% in both groups
• This trial was technically designed as an equivalence trial, with an equivalence boundary for the relative risk of 0.83-1.20.

BP lowering: High-dose monotherapy or low-dose combo?

Law MR, et al. Value of low dose combination treatment with blood pressure lowering drugs: Analysis of 354 randomised trials. BMJ 2003;326:1427.

Bottom-line: In patients with hypertension, addition of an extra BP-lowering agent at a low dose provides greater BP-lowering with fewer side effects than increasing the dose of a single agent.

Each additional low-dose BP-lowering drug reduces BP by an extra ~6/3 mm Hg & cause side effects in an extra 1 out of every ~50 people. Conversely, doubling the dose of a BP-lowering agent will further reduce BP by ~2/1 mm Hg & cause side effects in an extra 1 out of every 12-30 people.

 

Design summary

• Systematic review with meta-analysis of 354 randomized controlled trials (RCTs) including 39,879 patients receiving active treatment & 15,817 receiving placebo
  • Databases searched: MEDLINE, Cochrane Library, Web of Science
  • Search date: Unclear (before June 2003)
  • Study eligibility criteria: Double-blind RCTs of at least 2-weeks duration evaluating dose response + effect of combination of antihypertensives

Patients & interventions

• Key baseline characteristics
  • Age, mean: 53 y
  • BP, median: 154/97 mm Hg
• Drug classes included: ACE inhibitors, ARBs, beta-blockers, calcium-channel blockers, thiazide diuretics

Outcomes at 2-12 weeks

• BP lowering (similar across all 5 drug classes at comparable doses)
  • By dose
    • 1/2 standard dose: ~7/4 mm Hg
    • Standard dose (defined as typical maintenance dose based on British National Formulary, e.g. amlodipine or ramipril 2.5 mg/d): ~9/6 mm Hg
    • Double standard dose: ~11/7 mm Hg
    • In other words, doubling the dose of BP-lowering therapy further lowered BP by ~2/1 mm Hg
  • By # of drugs from different classes at 1/2 standard dose
    • 1 drug: ~7/4 mm Hg
    • 2 drugs: 13/7 mm Hg
    • 3 drugs: 20/11 mm Hg
    • In other words, BP-lowering drugs have additive efficacy
• % with adverse effects
  • By class based on dose
    • ACE inhibitor: ~4% at all doses
    • ARB: ~0-2% at all doses
    • Beta-blocker
      • 1/2 standard dose: ~5-6%
      • Standard dose: ~7-8%
      • Double standard dose: ~9-10%
    • Calcium-channel blocker
      • 1/2 standard dose: 2%
      • Standard dose: 8%
      • Double standard dose: 15%
    • Thiazide diuretic
      • 1/2 standard dose: 2%
      • Standard dose: 10%
      • Double standard dose: 18%
  • By # of drugs
    • 1 drug: ~5%
    • 2 drugs: 7-8%
    • 3 drugs: Not studied