Testing: Coronary artery calcium to risk stratify in primary prevention

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What the test entails

  • Single Computer tomography (CT) scan of the chest using either electron beam CT (EBCT) or multidetector CT (MDCT)
  • A radiologist or cardiologist evaluates the CT images and quantifies calcification of the coronary arteries (a marker of atherosclerotic plaque buildup) using the Agatston score

Evidence

A 2004 meta-analysis identified the coronary artery calcium (CAC) score as an independent risk factor for coronary artery disease events (coronary death, non-fatal MI or revascularization)

  • CAC score: odds ratio (OR) for coronary heart disease event
    • No calcification (0): OR 1 (reference)
    • Low (1-100): OR 2.1
    • Medium (101-400): OR 5.4
    • High (>400): OR 10

The Multi-Ethnic Study of Atherosclerosis (MESA) population-based cohort provides the best evidence for use of the coronary artery calcium (CAC) score in risk stratification.

  • In a primary prevention cohort that included patients with a low (<5%), intermediate (5-20%) and high (>20%) 10-year risk of CVD based on the Framingham risk score, the CAC score was a statistically significant predictor of coronary or total CV events, but added little extra accuracy to the Framingham risk score used alone.
    • Indescriminate testing is the main limitation of these results. There is little value in obtaining a CAC score in a patient who is at low risk of a CV event based on their risk factors. Similarly, a CAC score is unlikely to reclassify a patient with a high Framingham score down into a low-risk category that doesn't warrant treatment.
  • To account with the limitations of the above study, the MESA investigators evaluated the performance of the CAC score (& other novel risk markers) in a sub-cohort of 1330 patients without diabetes with an "intermediate" Framingham score (10-year risk of coronary artery disease of 5-20%) over a median follow-up period of 7.6 years.
    • Addition of CAC score to the Framingham risk score correctly reclassified
      • ~25% of patients from an intermediate- to high-risk group (i.e. changed their estimated 10-year risk of a coronary event from 5-20% to >20%)
      • ~40% of patients from the intermediate- to low-risk group

Bottom line

  • Patients who should NOT get CAC scoring (low likelihood of altering management)
    • Low Framingham score
    • High Framingham score
    • Patients already receiving primary prevention therapies
    • Patients who have already made a decision for/against medical therapy for primary prevention
  • Patients for whom CAC scoring could be useful
    • Intermediate Framingham score + patient undecided about initiating therapy, or wishing for further stratification
    • High Framingham score + undecided about therapy
  • Clinicians can integrate the CAC score with traditional clinical risk factors to estimate a patient's 10-year CV risk using this calculator.

 

Prepared by: Ricky Turgeon BSc(Pharm), ACPR, PharmD

Last updated: 9 Sept 2016

Calcified LAD

NORSTENT - Drug-eluting versus bare-metal stent for CAD (short)

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Bonaa KH, et al. Drug-eluting or bare-metal stents for coronary artery disease. N Engl J Med 2016 [online]

Bottom-line: In patients with CAD who received PCI with coronary stent placement and received DAPT with ASA + clopidogrel x9 months, there were no difference in death or MI whether patients received 2nd-gen drug-eluting stents or bare-metal stents. 

Drug-eluting stents reduced the need for further revascularization by 3.3% (absolute) at 6 years.

Also worth mentioning: Regardless of stent type implanted, patients received 9 months of dual-antiplatelet therapy (DAPT; with clopidogrel). Despite this, patients with drug-eluting stents had lower risk of stent thrombosis than those with bare-metal stents. Combined with the evidence showing no statistically-significant difference in stent thrombosis risk between 3 vs 12 months of DAPT in patients with 2nd-generation drug-eluting stents, this provides evidence against using bare-metal stents in patients with increased risk of bleeding to permit shorter DAPT duration.

 

Context:

Patients (n=9013)

  • Multicenter (all 8 Norwegian PCI cneters); every person who got PCI in Norway Sept 2008-Feb 2014 potentially eligible for this trial
  • Inclusion:
    • Adults presenting with stable angina or ACS with lesion in native coronary arteries or coronary-artery grafts amenable to stent implantation
  • Exclusion:
    • Previous coronary stent
    • Bifurcation lesion requiring 2+ stent technique
    • On warfarin
    • Life expectancy <5 y due to condition other than CAD
  • 12,425 eligible -> 9013 randomized
  • Average patient
    • 63 y/o
    • Male 75%
    • Smoker ~35%
    • Diabetes ~13%
    • PCI indication: stable angina 30%, UA 12%, NSTEMI 31%, STEMI 27%
    • Multivessel disease 40%
    • Procedure characteristics: 1-2 stents implanted, total length ~27 mm

Interventions

  • I: Drug-eluting stent (DES)
    • ost common: Everolimus-eluting (Promus 67%, Xience 15%), zotarolimus-eluting (Endeavor Resolute 11%)
  • C: Bare-metal stent (BMS)
    • Most common: Driver 43%, Integrity 22%, Liberte 18%)
  • Co-interventions common to both groups:
    • ASA 75 mg/d indefinitely
    • Clopidogrel 75 mg/d x9 months
    • Other secondary prevention therapy per current guidelines

Results @ ~6 years

  • No significant difference in primary outcome (death, non-fatal spontaneous MI)
    • DES 16.6% vs BMS 17.1% (p=0.66)
  • Other non-significant secondary outcomes:
    • Death: 8.5% vs 8.4%
    • Spontaneous MI: 11.4% vs 12.5%
    • Stroke: 3.4% vs 3.0%
  • Statistically-significantly different secondary outcomes:
    • Any revascularization (CABG or PCI): 16.5% vs 19.8% (p<0.001, number needed to treat 31 at 6 years)
    • Definite stent thrombosis: 0.8% vs 1.2% (p=0.05)

Issue with internal validity?

  • No: Allocation-concealed, open-label RCT analyzing intention-to-treat population, 0% lost-to-follow-up
    • Low risk of allocation, performance, detection or attrition bias

HPS2-THRIVE - Niacin for CV prevention

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HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.

Clinical Question

In patients with cardiovascular disease receiving moderate-intensity statin +/- ezetimibe, does niacin (+ laropiprant) safely reduce cardiovascular events?

Bottom Line

  • In patients with cardiovascular disease already receiving moderate-intensity statin therapy (& half taking ezetimibe) who tolerated niacin for a month, niacin does not reduce cardiovascular events, definitely increases serious adverse events due to numerous causes (NNH 35), and may increase the risk of death (NNH 200) over 4 years.

  • Niacin has no clear role in prevention of cardiovascular disease.

Design

Allocation-concealed "superiority" RCT with all (patients, clinicians, investigators) blinded, low loss-to-follow-up (<1%), analyzed using the intention-to-treat population.

Note 1: All patients subjected to pre-randomization run-in phase where they discontinued previous statin therapy & switched to simvastatin 40 mg/day

  • If total cholesterol >3.50 mmol/L or increased from previous therapy after 4 weeks, added ezetimibe 10 mg/d
  • Once stable on LDL-lowering therapy, all patients given a single daily tablet of niacin extended-release 1 g + laropiprant 20 mg, if tolerated this was doubled x3-6 weeks
  • Patients who tolerated the regimen without clinically-significant adverse effects were randomized to niacin/laropiprant or placebo

Note 2: Randomization performed using minimization algorithm.

Patients and Setting

  • China, Scandinavia, UK, 245 centers
  • April 2007 - July 2010
  • Inclusion criteria:
    1. Men or women 50-80 y/o
    2. History of
      • Cerebrovascular atherosclerotic disease (previous ischemic stroke/TIA, carotid revascularization)
      • MI
      • PAD (intermittent claudication or previous revascularization)
      • Diabetes with above or symptomatic CAD
  • Key exclusion criteria:
    • Receiving LDL-lowering therapy "more intensive" than simvastatin 40 mg + ezetimibe 10 mg
    • <3 months since ACS/MI or stroke
    • Planned revascularization procedure <3 months after randomization
    • SOB at rest for any reason
    • Contraindications to niacin/statin
      • Chronic liver disease, or current ALT >1.5x upper normal limit
      • Serum creatinine >200 mcmol/L
      • Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or CK >3x upper normal limit
    • Concurrent treatment with ezetimibe, fibrate, or potent CYP3A4 inhibitor
  • 51,698 screened -> 42,424 entered run-in phase -> 25,673 randomized (~50% screened)
  • Average patient:
    • 64.9 y/o
    • 17% female
    • Region: Europe 57%, China 43%
    • PMHx
      • Cerebrovascular disease 32%
      • MI 68%
      • PAD 12%
      • Diabetes 32%
    • Lipids (after run-in phase on simvastatin 40 mg +/- ezetimibe 10 mg)
      • Total cholesterol 3.31 mmol/L 
      • HDL 1.14 mmol/L
      • LDL 1.64 mmol/L

Intervention and Control

  • Intervention: Niacin extended-release 2 g + laropiprant 40 mg once daily
    • Average adherence during study: 78%
  • Control: Placeb
    • Average adherence during study: 86%
  • Co-interventions common to both groups: Simvastatin 40 mg +/- ezetimibe 10 mg to achieve total cholesterol <3.50 mmol/L
    • Simvastatin 40 mg: 100%
    • Ezetimibe 10 mg: 47%

Outcomes

  • @ median 3.9 years
  • Niacin improved lipids versus placebo
    • HDL +0.16 mmol/L
    • LDL -0.25 mmol/L
    • Triglycerides -0.37 mmol/L
  • Efficacy: No benefit whatsoever of niacin.
  • Safety: 
    • Significant INCREASE in serious adverse events with niacin (NNH 35), both due to predicted adverse effects of niacin (gastrointestinal issues, new/worsening diabetes), but also adverse effects not yet appreciated to be caused by niacin (serious bleeds & infections)
    • More patients in the niacin group discontinued study due to intolerable side-effects (1/4 patients in the group; NNH 12 versus placebo), despite every patient taking niacin x3-6 weeks in the run-in phase
  • No benefit in any of the 30+ subgroup analyses conducted.

HPS2-THRIVE outcomes

Key Considerations

Generalizability: 

  • This was a secondary prevention trial of patients with existing atherosclerotic cardiovascular disease (cerebrovascular, coronary or peripheral) also taking simvastatin 40 mg/d (all patients) +/- ezetimibe (~1/2 of patients)
  • Although there were no specific lipid criteria for enrollment, there was also lack of efficacy in the half of patients who had "low HDL [<1.0 mmol/L])
  • Laropiprant is an antagonist of prostaglandin D2 (receptor responsible for niacin flush), designed to improve tolerability of niacin. Despite combining this drug with niacin, tolerability of niacin was abysmal.

Internal validity:

  • This study was "enriched" to demonstrate a benefit with a rigorous run-in phase designed to enroll patients unlikely to discontinue niacin.
    • Despite this, more patients in the niacin group experience serious adverse events & discontinued drug therapy due to intolerability.

Context

  • AIM-HIGH trial (2011) in patients with low HDL also taking moderate-intensity statin: Niacin provided no cardiovascular benefit.

  • In a 2014 meta-analysis, fibrates, niacin & CETP inhibitors (drugs that lower HDL) did not reduce cardiovascular outcomes when added to statins.

  • The Coronary Drug Project trial (1975), which enrolled its first patient in 1966, is the only trial that has demonstrated the cardiovascular benefit of niacin. In a population of men aged 30-64 years with prior MI, niacin reduced the risk of non-fatal MI over ~6 years (NNT 28), with no effect on mortality.

    • This trial is not generalizable to today's practice, being conducted >40 years ago in men with prior MI in an era where aspirin, ACE inhibitors, beta-blockers, statins, and PCI were not yet available/in use.

British aneurysm nimodipine trial: Nimodipine in subarachnoid hemorrhage

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Pickard JD, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. Br med J 1989;298:636-42.

 

Clinical Question

In patients with subarachnoid hemorrhage (SAH) +/- confirmed ruptured aneurysm as the cause, does nimodipine reduce the risk of delayed cerebral infarct and improve long-term functional outcome?

 

Bottom Line

In patients with SAH (of whom only 2/3 had confirmed aneurysmal SAH), nimodipine reduced the risk of poor functional outcome (NNT 8) at 3 months without causing significant adverse events.

The benefits of nimodipine may be even larger in the current era of rapidly identifying aneurysm rupture as the cause for SAH via CTA.

 

Design

Allocation-concealed "superiority" RCT with all (patients, clinicians, investigators) blinded, no loss-to-follow-up, analyzed using the intention-to-treat population.

 

Patients and Setting

  • 4 centres in the UK
  • June 1985 - September 1987
  • Inclusion criteria:
    1. SAH confirmed by LP or CT
    2. Within 96h of onset of symptoms of SAH
    3. NOTE: No angiography (CTA or digital subtraction angiography [DSA]) confirming ruptured aneurysm required prior to enrollment into trial
  • Key exclusion criteria:
    • Pre-existing "cardiac decompensation" or myocardial infarction <6 months or major dysfunction of another organ
    • Within 1 week of another SAH that led to coma
  • 1115 screened -> 554 enrolled & randomized
    • Most common reason for exlusion was >96h since symptom onset (317 patients)
  • Average patient at baseline:
    • 47 y/o
    • 60% female
    • Previous SAH 15%
    • Clinical grade on admission (using World Federation of Neurosurgical Societies [WFNS] classification)
      • I (Glasgow Coma Scale [GCS] 15, no focal neuro deficits): 4%
      • II (GCS 15, cranial nerve palsy): 59%
      • III (GCS 13-14): 27%
      • IV (GCS 8-12): 8%
      • V (GCS 3-7): 3%
    • Time from symptom onset to CT: 1.5 days
      • Fisher grade IV (i.e. presence of intraventricular hemorrhage [IVH]): 30%
      • Hydrocephalus: 13%
    • Confirmed aneurysmal SAH (by DSA): 66%
      • Spasm present: 18%
    • Time from symptom onset to OR: 11 days
      • OR prior to enrollment: 42%

 

Intervention and Control

  • Intervention: Nimodipine 60 mg PO q4h x21 days
    • 25% stopped before 21 days, mainly due to negative DSA (i.e. no ruptured aneurysm)
    • Protocol allowed for dose reduction if hypotension occurred, though this was not required in any patient
  • Control: Matching placebo
  • Co-interventions common to both groups:
    • CT head, non-contrast at 24h after admission
    • Further imaging, surgery, other management per attending MD

 

Outcomes

  • @ 3 months
  • Efficacy: Clinically & statistically significant reduction in poor outcome (NNT 8), mainly driven by a reduction in cerebral infarct (NNT 12).
  • Safety:
    • No statistically significance increase in adverse events
    • No dosage reduction required for hypotension in either group
      • From baseline to day 21, nimodipine reduced blood pressure by ~7/4 mm Hg

Key Considerations

Generalizability: Despite major changes in various aspects of diagnosis and management of SAH, the results of this trial likely still apply to today's patients.

  •  Current management emphasizes identifying a ruptured aneurysm (CT angiography) and securing it early (<24 hours) to prevent re-rupture and re-bleed, the risk of which is 4% in the first 24h and 1.5%/day in the subsequent 2 weeks.
    • In this trial, aneurysms were identified with DSA, often longer than 4 days after symptom onset. More concerning, patients waited an average of 11 days prior to surgical clipping of their aneurysm.
      • Nimodipine was reported as equally beneficial in patients regardless of whether they underwent surgical clipping (versus no intervention).
    • Notably, endovascular coiling is another modality now available to secure aneurysms, particularly for those with narrow necks found in the posterior cerebral circulation. This procedure was not available in the era when this trial was conducted.
      • Endovascular coiling doesn't reduce delayed cerebral ischemia versus surgical clipping, & produces similar long-term functional outcomes; therefore, shouldn't impact effects of nimodipine.
  • A sizable portion of patients enrolled in this trial (44%) did not have proven aneurysmal SAH at enrollment, & up to a quarter of all patients had non-aneurysmal SAH later diagnosed by angiography.
    • The patients with non-aneurysmal SAH could not benefit from nimodipine, which likely led to the dilution of nimodipine's efficacy.
    • This means that the true absolute reduction in poor outcomes with nimodipine is likely larger than reported, & the NNT is likely smaller than 8 (which is already impressive).

Additional logistic considerations for nimodipine:

  • Nimodipine does not reduce cerebral vasospasm; this is not its underlying mechanism (which remains unknown)
    • Because of this, nimodipine should ideally be continued in patients being treated for "clinical vasospasm," unless it is impairing the ability to achieve the blood pressure goals of hypertensive therapy ("triple-H therapy")
  • Cost of a 21-day course: ~$3,100 (~$150/day)
    • Many patients recover & are well enough to go home prior to the completion of the 21-day course of nimodipine. In these patients, risk of delayed cerebral ischemia is very low, particularly beyond 10 days of symptom onset, so nimodipine should be discontinued on discharge to avoid unnecessary cost (& difficulty in adhering to q4h dosing) to the patient.

 

Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD
Summary date: Updated 14 July 2016

ATACH-2 - Intensive BP lowering in ICH

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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