ACTION - Nifedipine for stable CAD

in ,

Poole-Wilson PA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): Randomized controlled trial. Lancet 2004;364:849-57.

Bottom line: In patients with stable angina already treated with at least 1 maintenance anti-anginal drug, nifedipine for 4.5-6 years did not reduce major CV events.

    Patients

    • Inclusion:
      • Age 35+ y
      • Angina stable for at least 1 month
      • Needing treatment of angina (note: not necessarily uncontrolled or symptomatic at baseline)
      • Plus one of the following
        1. Hx of MI
        2. No hx of MI, but angiographically-confirmed CAD
        3. No hx of MI or angiography, but CAD by positive exercise test or perfusion defect
    • Exclusion
      • Overt HF
      • LVEF <40%
      • Any majr CV event or intervention in the past 3 months
      • Planned coronary angiography or intervention
      • Clinically significant valvular or pulmonary disease
      • Unstable insulin-dependent diabetes
      • Any GI disorder that could impair absorption of long-acting nifedipine formulation
      • Any other condition other than CAD that could limit life expectancy
      • Symptomatic orthostatic hypotension, or supine SBP <90 mm Hg
      • SBP 200+ mm Hg, DBP 105+ mm Hg
      • Renal dysfunction (SCr >2x ULN)
      • Liver dysfunction (ALT/AST >3x ULN)
    • From 1996-1998, ? screened -> 7797 randomized -> 7665 analyzed
    • "Average" patient
      • Age 63.5 y
      • Male 80%
      • Enrollment criterion met
        • Hx of MI ~50%
        • No MI, angiographically-confirmed CAD 33%
        • No MI or angiography, but positive exercise or perfusion defect 17%
      • Current NYHA class II-III symptoms 46%
      • Hx of angina attacks 93%
      • Baseline vitals
        • BP 137/80
        • HR 64
      • Mean LVEF 48%
      • Concomitant meds
        • Any anti-anginal drug 99%
          • Beta-blocker 79%
          • Nitrate (daily maintenance) 38%
          • Nitrate PRN use 56%
        • ASA 86%
        • Statin 63%
        • Any BP lowering 30% - ACEI 20%

    Generalizability: Who do these results apply to?

    • Normotensive individuals with CAD without LV dysfunction, most of whom with a previous MI (of unreported age, but at least 3 months ago), already taking at least 1 daily anti-anginal drug.
    • Does not apply to patients with:
      • Recent MI
      • Angina at rest or with minimal activity
      • Optimized secondary prevention therapy
      • Overt HF or reduced LVEF
      • Patients with uncontrolled HTN

    Interventions

    • I: Nifedipine
      • Initial dose: 30 mg PO once daily
      • If initial dose tolerated, increased to 60 mg PO once daily within 6 weeks
      • Dose could be reduced or interrupted
    • C: Matching placebo
    • The following drugs couldn't be used during the study:
      • Non-study calcium-channel blocker (if on prior to study, 2-week washout before study enrollment)
      • Digoxin (unless used for supraventricular arrhythmias such as afib) or other positive inotropes
      • Antiarrhythmics, class I or III (exceptions: amiodarone or sotalol)
      • Cimetidine
      • Anticonvulsants
      • Antipsychotics
      • Rifampicin

    Results @ planned follow-up of 4.5-6 y (97% of patients met minimal planned follow-up)

    • Effect on vitals
      • BP reduced by ~5/3 mm Hg (not reported; estimated from Figure 2)
        • Patients with BP <140/90: 65% vs 53%
      • HR increased by 1 bpm
    • No statistically significant difference in primary composite outcome and multiple components of this outcome
      • Primary outcome (time to first occurrence of either all-cause death, MI, refractory angina, new over HF, debilitating stroke, or peripheral revascularization): ~22% in both groups (hazard ratio 0.97, 95% confidence interval 0.88-1.07, p=0.54)
      • Death: 8% vs 7.6% (HR 1.07, 95% CI 0.91-1.25)
      • Debilitating stroke: 2% vs 2.6% (HR 0.78, 0.58-1.05)
      • MI: 7.0% vs 6.7% (HR 1.04, 0.88-1.24)
      • Refractory angina (defined as angina at rest, prolonged administration of IV nitrates or equivalent plus a coronary angiogram <1 week after onset of symptoms): 3.9% vs 4.5% (HR 0.86, 0.69-1.07)
      • PCI: 10.1% vs 10.9% (HR 0.92, 0.80-1.06)
    • Certain components of the primary composite outcome were statistically reduced with nifedipine
      • New overt HF: 2.2% vs 3.2% (HR 0.71, 0.54-0.94)
      • Coronary angiography: 23.4% vs 27.8% (HR 0.82, 0.75-0.90)
      • CABG: 7.7% 9.7% (HR 0.79, 0.68-0.92)
    • Subgroups: Of 11 subgroup analyses, only separation of patients based on BP 140/90 or greater vs <140/90 had a significant test for interaction (p=0.015), suggesting benefit of nifedipine in patients with CAD + HTN

    Issues with internal validity?

    • No: Randomized, allocation-concealed, blinded (patients, clinicians, investigators) trial with unclear loss-to-follow-up (~5% terminated study earlier than intended) analyzed using a modified intention-to-treat population (all patients who took at least 1 dose of study drug)
    • Note: No run-in phase

    Additional considerations

    • A deeper look at secondary outcomes and subgroup analyses does not clearly support either the role of nifedipine as a antihypertensive drug in patients with CAD, or as an effective anti-anginal.

      • Antihypertensive: Subgroup analysis demonstrated potential benefit in patients with BP 140/90 mm Hg or greater, but there was no statistically significant reduction in debilitating stroke in the overall study population (the outcome most closely associated with HTN in observational studies).

      • Anti-anginal: Though a reduction in the need for coronary angiography and CABG both suggest a reduction in myocardial ischemia, there was no reduction in the proportion of patients with MI, refractory angina, or PCI.

    • The results of this study conflict with those of the previously-covered CAMELOT trial of amlodipine, which argues against a class effect of dihydropyridine calcium-channel blockers in CAD.

    ATACH-2 - Intensive BP lowering in ICH

    in

    Qureshi AI, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. NEJM 2016;online

     

    Clinical Question

    In patients with intracerebral hemorrhage (ICH), does an SBP goal 110-140 mmHg improve functional outcomes compared to an SBP goal of 140-179 mmHg?

     

    Bottom Line

    In patients with ICH, more intensive BP control did not improve functional outcomes. Based on the results of this study, SBP should be maintained ~140-180 mmHg.

     

    Design

    Allocation-concealed, open-label RCT, 4% loss-to-follow-up, analyzed using the intention-to-treat population.

    Notes:

    • The trial was truncated (stopped early) after the 2nd pre-specified interim analysis for futility.
    • A central radiologist blind to treatment allocation read the baseline & 24h head CT to determine hematoma expansion.
    • The 3-month outcome assessor was not involved in the randomization or inpatient management of participants, but was not specifically blinded to treatment allocation.

     

    Patients and Setting

    • 6 countries (China, Germany, Japan, South Korea, Taiwan, USA), 110 centers
    • May 2011 - September 2015
    • Inclusion criteria:
      1. Men or women 18+ y
      2. Intracerebral hemorrhage, as defined by
        • Clinical signs consistent with dx of stroke
        • Head CT demonstrates intraparenchymal hematoma, volume <60 mL
      3. Initial NIHSS score 4+ (/42)
      4. GCS 5+ (/15)
      5. Onset of new neuro deficits within 2.5 h
      6. Admission SBP 180-240 mmHg on 2 repeat measurements >5 min apart, but <10 min apart
      7. IV nicardipine could be started within 4.5 h of symptom onset
    • Key exclusion criteria:
      • Considered a candidate for immediate neurosurgical intervention (e.g. ventriculostomy insertion, evacuation)
      • Secondary causes of ICH
        • Previously known neoplasms, AVM, aneurysms
        • traumatic ICH
      • Infratentorial ICH (e.g. pons, cerebellum)
      • Presence of intraventricular hemorrhage (IVH) that completely fills 1 lateral ventricule or >1/2 of both ventricles
      • Pre-morbid modified Rankin Scale (mRS) score 4+ (/6)
      • Increased risk of bleeding
        • Hx of bleeding diathesis or coagulopathy
        • Warfarin use in last 5 days
        • Platelets <50
    • 8,532 screened -> 1,000 randomized -> 961 analyzed @ 3 months
    • Average patient:
      • 62 y
      • 38% female
      • Race: 56% Asian, 28% White, 12% Black
      • PMHx
        • Prior stroke/TIA 16%
        • HTN 80%, previous use of BP meds 50%)
      • GCS: 15 (55%), 12-14 (30%), 3-11 (15%)
      • Mean SBP at presentation 200 mmHg
      • Median NIHSS score 11
      • ICH volume
        • >30 cm^3 (10%)
        • Median 10 cm^3
      • IVH 25%
      • Hemorrhage location: Basal ganglia (51%), thalamus (37%), lobar (10%)

     

    Intervention and Control

    • Intervention: Target SBP 110-139 mmHg x24h 
      • 71% started <3h of symptom onset, 29% started 3-4.5h after symptom onset
      • Mean minimum SBP during initial 2h of starting tx: 129 mmHg
      • Reached target SBP within 2h of starting tx: 88%
    • Control: Target SBP 140-179 mmHg x24h
      • 64% started <3h of symptom onset, 36% started 3-4.5h after symptom onset
      • Mean minimum SBP during initial 2h of starting tx: 141 mmHg
      • Reached target SBP within 2h of starting tx: 99.2%
    • Co-interventions common to both groups:
      • Adjunctive care according to the American Stroke Association guidelines
      • Mean time between symptom onset & randomization: ~3 hours in both groups
      • 1st-line antihypertensive: Nicardipine IV
        • Initial dose of 5 mg/h
        • Titrated q15min by 2.5 mg/h
        • Max rate 15 mg/h
      • 2nd-line: Labetalol IV (used if SBP higher than target despite max nicardipine rate x30 min)
        • Diltiazem or urapidil IV used in countries where labetalol was not available
      • CT head, non-contrast @ 24h after start of treatment

     

    Outcomes

    ATACH-2 Outcomes

    ATACH-2 organ-specific SAEs

    • Long-term outcomes (@ 3 months):
      • No statistically significant difference in death or disability (modified Rankin Scale [mRS] 4-6), or in any mRS score.
      • No statistically significant difference in median quality of life scores, with wide variation from terrible to favorable health state in each group.
      • Possible 5.6% absolute risk increase in serious adverse events (SAEs) in the intensive BP control group (NNH 18). This increased risk in overall SAEs isn't explained by increase in any organ-specific SAE, and is therefore difficult to accept as a real effect.
    • Short-term outcomes
      • Neurological deterioration within 24h of treatment onset (reminder: the randomized treatment target was maintained for 24h) was not statistically significant between groups
      • The proportion of patients with hematoma expansion >33% was not statistically significantly different between groups, though the confidence interval could not rule out a difference of up to 10% in favor of the intensive treatment group. Still, this is only a surrogate for long-term functional outcome, which was not improved in this trial.
      • Hypotension during the treatment phase was rare and similar between groups (~1%).
    • Subgroup analyses: Intensive BP control was not statistically significantly better (or worse) in any of the subgroup analyses performed (sex, race, geography, T2DM, GCS, hematoma volume or location, IVH, meeting/not meeting SBP target at 2h).

    Key Considerations

    Generalizability:

    • P: ATACH-2 participants appear to be representative of patients with ICH seen in real-world practice. Notably, however, only 1/8 of patients considered for enrollment were randomized, with no further definition of reason for exclusion.
    • I/C: Notably, the BP-lowering intervention was delivered quickly & effectively, with 88% of patients in the intervention group achieving target SBP, & near all in the control group achieving target SBP. There was also an early, large separation in SBP between groups. The lack of benefit from intensive BP control cannot therefore be explained by inability to achieve this BP goal.
    • O: The long-term outcomes of this trial, including mRS, quality of life measures and serious adverse events, are patient-centered and highly important.

    Internal validity:

    • The open-label nature of the study was unavoidable. This "opens" the study up to performance and detection bias, though the risk for these is likely low in this context.
      • Performance bias is unlikely given the otherwise standardized care processes in ICH management.
      • Detection bias could be problematic, especially given that the outcome assessor was unlikely to be blinded. None of the objective outcomes (death) or "relatively" objective outcomes (moderate-severe, severe disability on the mRS; overall serious adverse events) favored intensive BP control.

     

    How To Reconcile the Results of ATACH-2 and INTERACT2

    Summary of INTERACT2:

    • P: Enrolled 2,839 patients with spontaneous ICH within 6h of symptom onset with GCS 6-15 & baseline SBP 150-220 mmHg in whom neurosurgical intervention was not planned
      • Average patient: 63.5 y, 2/3 male, median GCS 14, median NIHSS score 10-11, use of antiplatelet/oral anticoagulant ~10%, median baseline ICH volume 11 mL, ~84% located in basal ganglia or thalamus, 28% with IVH
    • I/C: Assigned to target SBP <140 mmHg or <180 mmHg to be achieved within 1h and maintained x7 days, starting with locally-available IV antihypertensives
      • IV antihypertensive used in 90% of target SBP <140 mmHg group vs 43% of SBP <180 mm Hg group
      • Wide variety of agent used, including alpha1-antagonists (32% vs 13%), CCB such as nicardipine or nimodipine (16% vs 8%), labetalol (14% vs 6%), or others
      • Mean SBP achieved at 1h were 150 mmHg in the intensive group (33% achieved target) & 164 mmHg in the control group.
    • O:
      • Non-significant reduction in primary outcome of mRS 3-6 with intensive BP lowering (52.0% vs 55.6%, p=0.06) that was statistically-significant using a secondary analysis method (ordinal analysis p=0.04)
      • Statistically significant reduction in EQ-5D utility index (0.60 vs 0.55, p=0.002) and certain individual quality of life measures
      • No statistically significant difference in any other outcome, including any specific mRS category, serious adverse events, duration of hospital stay, neuro deterioration <24h, hematoma growth, and hypotension.

    Key similarities & differences between ATACH-2 and INTERACT2:

    • P
      • Enrolled patients with similar severity of illness, hematoma size & location
      • Baseline SBP higher in ATACH-2 vs INTERACT2 (~200 vs 180 mmHg) due to higher requirement for inclusion (180-240 mmHg vs 150-220 mmHg)
    • I
      • ATACH-2 participants achieved target SBP more quickly & more frequently than in INTERACT2
        • In fact, achieved BP in INTERACT2 intervention arm closer to ATACH-2 control arm (mean SBP @ 1h 150 mm Hg & minimum SBP <1h 141 mm Hg, respectively)
      • ATACH-2 used nicardipine IV infusion as 1st line in all patients, whereas used infrequently in INTERACT2, with more frequent use of intermittent boluses of alpha1-antagonists and other agents
      • The intervention duration in ATACH-2 was limited to the first 24h, whereas INTERACT2 targeted both acute (first 24h) and subacute (post-admission day 1-7) BP control.
    • O
      • Similar outcome measures in both trials with slightly different definitions of "bad" functional outcome (mRS 4-6 in ATACH-2 versus 3-6 in INTERACT2)
      • Both trials showed no statistically significant difference in functional outcome in the primary analysis, & no clinically significant difference in any single mRS category
      • INTERACT2 showed statistically significant improvement in long-term quality of life with intensive BP control, whereas ATACH-2 did not.

     

    Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD
    Summary date: 23 June 2016

    HOPE-3 (BP lowering)

    in

    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.

    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)

    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