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.

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.

ACTION - Nifedipine for stable CAD

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.

CAMELOT - Amlodipine, enalapril or placebo in CAD

Nissen SE, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217-25.

Bottom line: In patients with symptomatic, angiographically-confirmed CAD without heart failure symptoms or LV dysfunction, amlodipine, but not enalapril, reduced the risk of ischemia-driven outcomes, including coronary revascularization (NNT 26) and hospitalization for angina (NNT 20), consistent with its anti-anginal mechanism.

Notably, neither amlodipine or enalapril reduced "hard" clinical outcomes, including death, MI or stroke, compared to placebo over the duration of this trial. This likely reflects a low/intermediate-risk population (e.g. risk of MI ~1.5%/year in placebo group) due to high use of other interventions that reduce CV risk, and short study duration.

Patients

• Inclusion:
  • Adults aged 30-79 requiring coronary angiography for evaluation for chest pain or PCI
  • 1 or more lesions in native coronary artery with >20% stenosis
  • Diastolic BP <100 mm Hg by manual BP measurement (could be taking antihypertensives at time of measurement)
• Exclusion:
  • Moderate-severe HF
  • LVEF <40%
  • Left main coronary artery stenosis >50%
• 2865 screened -> 1997 randomized -> 1991 analyzed
• "Average" patient:
  • 58 y
  • Male 75%
  • White 89%
  • Number of coronary arteries with stenosis >20% - 1 (~30%), 2 (~33%), 3 (~35%)
  • BP 129/77
  • PMHx
    • MI 37-40%
    • PCI 26-30%
    • Angina CCS class 4 - 8-9%
    • HTN 60%
    • Diabetes 17-19%
  • Concomitant meds
    • ASA 95%
    • Statin 83%
    • Beta-blocker ~75%
    • Diuretic 26-33%

Generalizability: Who do these results apply to?

• These results apply to patients with angina and angiographically-confirmed CAD without hypertension, most of whom did not have a previous MI, with no/minimal HF symptoms & normal LVEF
• These results do not apply to patients who:
  • Qualify for the HOPE or EUROPA trials
  • Have HFrEF, or who are post-MI with LV dysfunction

Interventions

• Intervention 1: Amlodipine
  • Initial dose: 5 mg PO daily
  • If initial dose tolerated, doubled to 10 mg PO daily at end of week 2
  • If intolerable adverse effect, dose halved & uptitration tried at a later point
  • Titrated to full target dose: 86.7%
  • BP reduced by ~5/2 mm Hg
• Intervention 2: Enalapril
  • Initial dose: 10 mg PO daily
  • If initial dose tolerated, doubled to 20 mg PO daily at end of week 2
  • If intolerable adverse effect, dose halved & uptitration tried at a later point
  • Titrated to full target dose: 84.3%
  • BP reduced by ~5/2 mm Hg
• Control: Placebo
• Co-interventions:
  • Diuretics, alpha-1 blockers, & beta-blockers were permitted
  • Non-study ACEI, ARB & CCBs were not permitted (discontinued over 2-6-week period before study initiation)

Results @ 2 years

• Statistically significant reduction in the primary outcome with amlodipine, but not enalapril, versus placebo
  • Amlodipine vs placebo: Hazard ratio 0.69 (0.54-0.88)
  • Enalapril vs placebo: HR 0.85 (0.67-1.07)
  • Amlodipine 16.6%, enalapril 20.2%, placebo 23.1%
• Beneficial effects of amlodipine versus placebo on primary outcome driven by softer, "ischemic" outcomes
  • Coronary revascularization: 11.8% vs 15.7% (NNT 26, p=0.03)
  • Hospitalization for angina: 7.7% vs 12.8% (NNT 20, p=0.002)
• No statistically significant difference between groups in "hard" clinical outcomes (listed as amlodipine, enalapril, placebo):
  • All-cause mortality, MI or stroke: 3.3%, 3.4%, 4.7%
    • All-cause mortality: 1.1%, 1.2%, 0.9%
    • Non-fatal MI: 2.1%, 1.6%, 2.9%
    • Stroke or TIA: 0.9%, 1.2%, 1.8%
  • Hospitalization for HF: 0.5%, 0.6%, 0.8%
• Safety:
  • Discontinued study medication: 29.3%, 35.1%, 31.1% (differences between groups not statistically significant, p=0.07)
  • Hypotension: 3.3%, 9.5%, 3.2% (NNH 16 for enalapril vs placebo)
  • Cough: 5.1%, 12.5%, 5.8% (NNH 15 for enalapril vs placebo)
  • Peripheral edema: 32.4%, 9.5%, 9.6% (NNH 5 for amlodipine vs placebo)

Issues with internal validity?

• No: Randomized, allocation-concealed, blinded (patients, clinicians & outcome adjudicators) trial with low loss-to-follow-up (<0.5%) analyzed using the intent-to-treat population.
• Notes:
  • Minor baseline imbalances in baseline characteristics, e.g. age (amlodipine 57.3 y vs enalapril 58.5 y) & history of MI (amlodipine 37.4% versus enalapril 40.3%) do not suggest compromised allocation concealment or impact results
  • 2-week placebo run-in period to exclude non-adherent patients (took <80% of doses).

British aneurysm nimodipine trial: Nimodipine in subarachnoid hemorrhage

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

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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

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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