Beta-blocker side-effects

in ,

Ko DT, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288:351-7.

Bottom line: In patients with HF, MI or HTN, beta-blockers increased the risk of fatigue (NNH 34) & sexual dysfunction (NNH 24), particularly erectile dysfunction in men.

 

Design

  • Systematic review and meta-analysis of 15 trials (n= ~35,000) published up to 2001
  • Included RCTs HF, MI or HTN with >100 patients & >6 months of follow-up

Results @ 0.5-6 years

  • Fatigue: Beta-blockers 33.4% vs placebo 30.4% (NNH 34), relative risk (RR) 1.15 (1.05-1.26)
    • Absolute risk increase 1.8%/year
    • Risk greater for older beta-blockers (e.g. propranolol; RR 1.78) than new beta-blockers (e.g. atenolol, metoprolol; RR 1.06)
  • Sexual dysfunction: Beta-blockers 21.6% vs placebo 17.4%, RR 1.10 (0.96-1.25)
    • Impotence in men: RR 1.22 (1.05-1.41)
  • Depression: Beta-blockers 20.1% vs placebo 20.5%, relative risk RR 1.12 (0.89-1.41)
  • None of the risks differed based on lipid solubility

ARBs vs ACEIs patients post-MI or at high risk of CVD

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Dickstein K, et al. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:752-60.

The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.

VALIANT: Pfeffer MA, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.

Bottom line:

  • In patients post-MI or at high risk of CVD, telmisartan & valsartan generally prevent CV events as well as ACE inhibitors with similar safety;

  • The combination of ACEI+ARB is no better than monotherapy & increases the risk of adverse events (e.g. hypotension, hyperkalemia & renal impairment);

  • Losartan is inferior to captopril for prevention of CV events.

 

Patients

Interventions

  • OPTIMAAL: ARB vs ACEI
    • ARB: Losartan started at 12.5 mg PO daily; increased to target 50 mg PO daily
      • 83% achieved target dose
    • ACEI: Captopril started at 12.5 mg PO TID; increased to target 50 mg PO TID
      • 81% achieved target dose
  • ONTARGET: ARB, ACEI or combination of both
    • ARB: Telmisartan started at 20 mg PO daily; increased to target 80 mg PO daily
      • 87% achieved target dose
    • ACEI: Ramipril started at 2.5 mg PO daily; increased to target 10 mg PO daily (HOPE dose)
      • 82% achieved target dose
  • VALIANT: ARB, ACEI or combination of both
    • ARB: Valsartan started at 20 mg PO BID; increased to target 160 mg PO BID
    • ACEI: Captopril started at 6.25 mg PO TID; increased to target 50 mg PO TID
    • 56% in each monotherapy group achieved target dose, 47% in combination group achieved target doses

Results @ 2-4.7 years

Generalizability & internal validity

  • Design of these trials essentially identical to the original 'ACEI vs placebo' trials that they mimic
    • I.e. high-quality allocation-concealed double-blind RCTs
  • All 3 trials are non-inferiority trials with fair non-inferiority margins and analyses
    • Note: OPTIMAAL is the only of the 3 that does not demonstrate of the ARB (losartan) & in fact points towards significant inferiority to an ACEI
  • As with the 'ACEI vs placebo' RCTs, results of these trials apply to patients that are post-MI, especially those with clinical HF & LV dysfunction, and those at high risk of CVD

CAPRICORN - Carvedilol in LV dysfunction post-MI

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The CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001;357:1385-90.

Bottom-line: In patients with LV dysfunction post-MI, carvedilol reduces the risk of death, MI & ventricular arrhythmias (NNT 34 for each) at ~1 year.

Patients (n=1959)

  • Included
    • Age 18+ y
    • 3-21 days post-MI
    • LVEF 40% or less
    • Receiving ACEI >48h with stable dose >24h (or intolerance to ACEI)
  • Excluded
    • Uncontrolled HF or HF requiring IV diuretics or inotropes
    • Unstable angina
    • SBP <90 mm Hg or uncontrolled HTN
    • HR <60 bpm
  • Typical study patient
    • Age 63 y
    • Female 27%
    • Site: Anterior (57%), inferior (21%)
    • PMHx
      • Prior MI 31%, angina 57%
      • Smoker 33%
      • HTN 55%
      • Diabetes 21%
    • BP 121/74 mm Hg
    • HR 77 bpm
    • LVEF 33%
    • Meds
      • ASA 86%
      • ACEI 98%

Interventions

  • I: Carvedilol
    • Initial dose of 6.25 mg PO BID, doubled or halved to max target dose of 25 mg PO BID
    • Conditions for uptitration, done q3-10 days:
      • Absence of clinical HF or adverse events
      • SBP >80 mm Hg & HR >50 bpm
    • 74% achieved target dose
  • C: Matching placebo

Results @ mean 1.3 years

  • Death: Carvedilol 12%, placebo 15% (hazard ratio 0.77, 0.60-0.98), NNT 34
  • Death or CV hospitalization: 35% vs 37% (HR 0.92, 0.80-1.07)
    • HF hospitalization: 12% vs 14% (HT 0.86, 0.67-1.09)
  • Non-fatal MI: 3% vs 6% (HR 0.59, 0.39-0.90), NNT 34%
  • Ventricular arrhythmia (tach/flutter/fib): 0.9% vs 3.9% (HR 0.24, 0.11-0.49), NNT 34

 

Statin dose & CV events

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Bottom-line:

  • In patients with CAD, high-dose statin therapy vs low/moderate statin doses further reduces the risk of CV events by an ~15% (relative risk reduction).

  • In Japanese patients with CAD, moderate-dose statin reduces the risk of CV events and death versus a very low dose by ~19% (relative risk reduction).

 

    Summary of 6 largest trials (n=52,666) 

    statin dose.png

    Latest trial: REAL-CAD summarized below:

    • Design: RCT with open-label, blinded-outcome-adjudication design
    • 13,054 randomized -> 12,413 analyzed in ITT population
    • Included: 
      • Age 20-80 y/o +
      • CAD (history of ACS, prior PCI/CABG, or angiographic coronary artery stenosis >75%) +
      • LDL-C >2.6 mmol/L (excluded if LDL-C >3.0 mmol/L on pitavastatin 1 mg/d during run-in phase)
    • Excluded: Known FH, contraindication to statin, HF NYHA 3-4 or LVEF <30%
    • Baseline characteristics:
      • Age 68 y, male 83%
      • Prior MI 52% (mean 5 years ago), HF 5%, ischemic stroke 7%
      • Statin before run-in: 91%, ASA 92%, ACEI/ARB 67%, beta-blocker 42%
      • LDL-C: before run-in 2.4 mmol/L, after run-in on pitavastatin 1 mg/d: 2.2 mmol/L
    • Interventions: Pitavastatin 4 mg/d (equivalent to ~atorvastatin 20-40 mg/d)
      • Reduced LDL-C by an additional 0.4 mmol/L (18%) vs lower dose
    • Control: Pitavastatin 1 mg/d (equivalent to ~atorvastatin 5 mg/d)
    • Follow-up: 3.9 years (median)

    Results from 5 largest RCTs

    statin dose outcomes.png

    Results from REAL-CAD

    • Primary outcome (CV death, MI, ischemic stroke or unstable angina requiring hospitalization):
      • Higher dose 4.3%, lower dose 5.4% - 1.1% absolute risk reduction (ARR)
      • HR 0.81, 95% CI 0.69-0.95
    • Death: 3.3% vs 4.2% - 0.9% ARR; HR 0.81, 0.69-0.98
    • MI: 0.6% vs 1.2% - 0.6% ARR; HR 0.57, 0.38-0.83
    • Any muscle complaints: 1.9% vs 0.7% - 1.2% absolute risk increase
    • No difference in rhabdo (<0.1%), CK increase >5xULN (0.7% vs 0.6%) or liver enzyme elevations (2.9% vs 2.7%, p=0.46)

    Meta analysis comparing high- to moderate-dose statins @ mean 2.5 years

    • Systematic review of 10 databases (including MEDLINE, Embase, CENTRAL) to Dec 2010
    • Included 10 RCTs enrolling 41,778 patients
    • Results
      • Statistically significant reduction with higher dose in
        • Coronary death or MI: Relative risk 0.90 (0.84-0.96), low heterogeneity (I^2=0%) in 9 trials
        • Stroke (excluding TIA): RR 0.86 (0.77-0.96), I^2=0% in 10 trials
          • Non-fatal MI: RR 0.82 (0.76-0.90), I^2=0% in 5 trials
      • No statistically significant difference in
        • Death: RR 0.92 (0.83-1.03), I^2=38% in 10 trials
      • Lab abnormalities, elevated
        • Liver enzymes, for ALT: RR 1.57 (1.29-1.91)
        • CK: RR 2.86 (2.02-4.04)
      • Subgroup analysis limited to 3 trials of patients with recent ACS (A-Z, PROVE-IT, Colivicchi et al) found possible reduction in death with higher dose (RR 0.75, p=0.005)

    Article links

    de Lemos JA, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z Trial. JAMA 2004;292:1307-16.

    Cannon CP, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.

    Pedersen TR, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: The IDEAL study: A randomized controlled trial. JAMA 2005;294:2437-45.

    LaRosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.

    SEARCH Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin dialy in 12 064 survivors of myocardial infarction: A double-blind randomised trial. Lancet 2010;376:1658-69.

    Taguchi I, et al. High-dose versus low-dose pitavastatin in Japanese patients with stable coronary artery disease (REAL-CAD): a randomized superiority trial. Circulation 2018;137:1997-2009.

    MIRACL - High-dose statin early post-ACS

    in ,

    Schwartz GG, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: A randomized controlled trial. JAMA 2001;285:1711-8.

    Bottom line: In patients with ACS (without Q wave formation & not treated with PCI), high-dose atorvastatin reduced the short-term risk of symptomatic ischemia (NNT 46) or stroke (NNT 125).

    Reporting of safety events was limited, but high-dose atorvastatin increased the likelihood of liver enzyme elevation >3x ULN, which has unknown clinical significance.

     

    Patients (n=3086)

    • Included
      • Age 18+ y
      • Within 24-96h after hospital admission for ACS (unstable angina or non-Q-wave MI)
    • Excluded
      • Total cholesterol >7 mmol/L
      • Coronary revascularization planned or anticipated
      • Hx of Q-wave MI within 4 weeks, CABG within 3 months, PCI within 6 months
      • LBBB or paced ventricular rhythm
      • HF with NYHA functional class IIIb-IV
      • Treatment with other lipid-lowering agents or vitamin E
      • Severe anemia, renal failure requiring dialysis, ALT >2x ULN, insulin-dependent diabetes
    • ? screened -> 3086 randomized & analyzed
    • Typical patient in study
      • Age 65 y
      • Female 35%
      • ACS: UA 46%, non-Q-wave MI 54%
      • PMHx
        • Prior MI 25%, CABG 7%, PCI 3%
        • HF 8%
        • CVA 9%
        • Peripheral vascular disease 9%
        • Smoker 28%
        • HTN 55%
        • Diabetes 23%
      • Meds
        • ASA ~90%, OAC 8%
        • ACEI or ARB ~50%
        • Beta-blocker 77%
        • Used in hospital: Heparin 75%, fibrinolytic 8%

    Intervention

    • I: Atorvastatin 80 mg PO once daily
      • Patients on average took 86% of all doses
      • 11.2% discontinued prematurely
    • C: Matching placebo
      • 10.3% discontinued prematurely

    Results @ 4 months

    • LDL
      • @ baseline: 3.2 mmol/L
      • @ 4 months: Atorvastatin 1.9 mmol/L, placebo 3.5 mmol/L (46% reduction vs placebo)
    • Statistically significant reduction in
      • Primary outcome (death, non-fatal MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization): 14.8% vs 17.4% (hazard ratio 0.84, 0.70-1.00), NNT 39
      • Symptomatic ischemia with objective evidence: 6.2% vs 8.4% (HR 0.74, 0.57-0.95), NNT 46
      • Stroke (fatal or non-fatal): 0.8% vs 1.6% (HR 0.50, 0.26-0.99), NNT 125
    • No statistically significant difference in
      • Coronary revascularization: 16.5% vs 16.1%
      • Non-fatal MI: 6.6% vs 7.3%
      • Worsening angina without new objective evidence of ischemia: 5.9% vs 6.8%
      • Death: 4.2% vs 4.4%
      • New/worsening HF requiring hospitalization: 2.6% vs 2.8%
      • Resuscitated cardiac arrest: 0.5% vs 0.6%
    • Safety
      • Liver enzymes >3x ULN at any time: 2.5% vs 0.6% (NNH 53)
      • Myalgias, muscle weakness, CK changes or rhabdo: Not reported

    Generalizability

    • Representative ~intermediate-risk ACS population
      • Despite exclusion of patients Q-wave MI, likely included some STEMI patients, particularly since ~8% received lytic therapy
      • Likely included an ACS population at low-intermediate risk by excluding Q-wave MI, patients planned for revascularization, recent CV event, or any significant non-CV comorbidity
    • Short-term follow-up intended only to evaluate acute effects of high-dose statin therapy; 4-month follow-up precludes meaningful evaluation of long-term benefit, particularly for "secondary prevention"

    Internal validity

    • Allocation & performance bias
      • Insufficient description of random-sequence generation, allocation concealment - likely low risk
    • Low risk of detection bias
      • Assuming proper allocation concealment & blinding, though not sufficiently described
      • Endpoints adjudicated by committee of cardiologists unaware of treatment allocation
    • Low risk of attrition bias
      • Intention-to-treat analysis including all randomized patients
      • <1% lost to follow-up

    Corroborating evidence from other studies

    • A secondary analysis of the PROVE IT trial evaluating the early and late benefit of high-intensity statin (atorvastatin 80 mg/d) versus low-intensity statin (pravastatin 40 mg/d) found a statistically significant improvement in the first 30 days:
      • 30-day risk of composite CV outcome (death, MI or ACS hospitalization): High-intensity 3.0% vs low-intensity 4.2%, HR 0.72 (0.52-0.99)