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

 

A-HeFT, V-HeFT, V-HeFT - Hydralazine+nitrate in HFrEF

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Interventions

Results in context

  • V-HeFT was the first trial demonstrating a mortality benefit with any drug for heart failure. It was published prior to studies showing benefits of ACEI/ARB, beta-blocker, and mineralocorticoid receptor antagonists
    • V-HeFT demonstrated that hydralazine/ISDN improved outcomes in HF, & that this was not due to a generic "vasodilator" effect, as demonstrated by an INCREASE in mortality with prazosin
  • V-HeFT II came hot off the heels of CONSENSUS (published in 1987), which demonstrated a great benefit to ACEI in NYHA class IV HF
    • Although the results of the comparison of enalapril to hydralazine/ISDN in V-HeFT II were not "statistically" significant, with a p=0.08 for mortality, it provided convincing evidence of the superiority of RAAS inhibition with an ACEI over hydralazine/ISDN
    • After V-HeFT II, hydralazine/ISDN was put on the sideline & no further outcome RCTs were conducted until A-HeFT
  • In 1999, subgroup analyses of the two V-HeFT trials demonstrated borderline race-based differences in response to hydralazine/ISDN (p=0.09-0.11 for interaction by race) & formed the basis to conduct A-HeFT
    • Mortality in V-HeFT according to race
      • Black: Hydralazine/ISDN 9.7%, placebo 17.3% (NNT 14)
      • White: Hydralazine/ISDN 16.9%, placebo 18.8%
    • Mortality in V-HeFT II according to race
      • Black: Enalapril 12.8%, hydralazine/ISDN 12.9%
      • White: Enalapril 11.0%, hydralazine/ISDN 14.9% (NNT 26)
    • Of note, these analyses were underpowered to rule out a benefit of hydralazine/ISDN in whites
  • A-HeFT demonstrated a large reduction in mortality with hydralazine/ISDN in black HFrEF patients with mostly NYHA functional class III
    • Hydralazine/ISDN therefore has a role as add-on therapy to ACEI/ARB in symptomatic black HFrEF patients who can tolerate additional vasodilator therapy
    •  It's unclear based on the available evidence if the results of A-HeFT can translate to non-black HFrEF patients. Given the borderline subgroup analyses noted above, hydralazine/ISDN likely still has a role for non-black patients as a 3rd line agent in those who cannot tolerated an ACEI or ARB due to hyperkalemia or renal dysfunction.

 

PROSPER - Statins in the elderly

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Shepherd J, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet 2002;360:1623-30.

Bottom-line: In elderly patients with at least 1 additional CV risk factor or existing CVD, statin therapy reduces the risk of CV death, MI or stroke (NNT 48) over 3.2 years. 

As in other scenarios, the absolute benefit of statins depends on the underlying risk for CVD events, as well as competing causes of morbidity & mortality.

 

Patients (n=5804)

  • Included
    • Age 70-82 y
    • Total cholesterol 4.0-9.0 mmol/L
    • Plus either:
      • Existing vascular disease (cerebrovascular disease, CAD, PAD)
      • 1+ other risk factor: smoking, HTN, diabetes
  • Excluded
    • Poor cognitive function (MMSE <24)
      • Triglycerides >6.0 mmol/L
  • 23,770 screened -> 7056 entered run-in -> 5804 randomized
  • "Typical" study patient
    • Age 75 y
    • Female 52%
    • PMHx
      • Any vascular disease 43%: MI (14%), angina (26%) stroke/TIA (11%)
      • Smoker 27%
      • HTN 62%
      • Diabetes 11%
    • SBP 154/84 mm Hg
    • Lipids: Total cholesterol 5.7 mmol/L, LDL 3.8 mmol/L

Interventions

  • I: Pravastatin 40 mg PO once daily
  • C: Matching placebo

Results @ mean 3.2 years

  • LDL
    • @ baseline: 3.8 mmol/L
    • @ 3 months: Pravastatin 2.5 mmol/L (34% lower than placebo)
  • Death: Pravastatin 10.3%, placebo 10.5% (hazard ratio 0.97, 0.83-1.14)
  • Primary outcome (coronary death, non-fatal MI, fatal or non-fatal stroke): 14.1% vs 16.2% (HR 0.85, 0.74-0.97), NNT 48
    • MI: 10.1% vs 12.2%
    • Stroke: 4.7% vs 4.5%
  • Adverse events
    • New cancer: HR 1.25, 1.04-1.51
      • Note: Analyses considering all statin studies show that this likely represents a chance finding
    • Myalgia: 1.2% vs 1.1%
    • Rhabdomyolysis: 0% in both groups
  • Subgroup analyses did not demonstrate significant test for interaction for relative reduction of primary outcome comparing secondary or primary prevention (p=0.19), despite numerical differences in hazard ratios

Generalizability

  • Represents a mix of elderly/very elderly with a primary or secondary prevention indication for statin therapy
  • Run-in phase: 4-week single-blind placebo to ensure adherence to at least 75% of doses

Internal validity

  • Low risk of allocation, performance, detection and attrition bias
    • Central allocation
    • All personnel & adjudicators unaware of allocation
    • <1% withdrew consent or lost-to-follow-up
    • Intention-to-treat analysis

 

HPS - Statins in secondary prevention & patients with diabetes

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Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: A randomised placebo controlled trial. Lancet 2002;360:7-22.

Bottom-line: In patients with existing CVD or diabetes, statin therapy reduced the risk of death (NNT 56) & all major vascular events (NNT 19) over 5 years.

In this population that initially tolerated simvastatin during a 4-6 week run-in phase & was not taking other lipid-lowering therapy, moderate-dose simvastatin did not increase the risk of cancer, cognitive impairment, liver enzyme abnormalities, myalgias or myopathy. 

 

Patients (n=20,536)

  • Included
    • Age 40-80 y
    • Total cholesterol (non-fasting) 3.5+ mmol/L
    • High risk for coronary death based on a past medical history of any of:
      • CAD (past ACS, stable angina, CABG or PCI)
      • Cerebrovascular disease (non-disabling non-hemorrhagic stroke, TIA, carotid endarterectomy)
      • PAD (intermittent claudication)
      • Other arterial surgery or angioplasty
      • Diabetes (type 1 or 2)
      • None of the above, but >65 y/o male with treated HTN
  • Excluded
    • Statin "clearly indicated"
    • Severe HF
    • Chronic liver disease (cirrhosis, hepatitis or ALT >1.5x ULN)
    • Creatinine >200 umol/L
    • Muscle disease (inflammatory muscle disease or CK >3x ULN)
    • Concurrent treatment with cyclosporine, fibrates or high-dose niacin
  • 63,603 screened -> 32,145 entered run-in -> 20,536 randomized -> 20,469 analyzed
  • "Typical" study patient
    • Age >64 y 46%
    • Female 25%
    • PMHx
      • MI 41%
      • Other CAD 24%
      • No coronary hx 35%
        • Cerebrovascular disease 9%
        • PAD 13%
        • Diabetes 19%
        • HTN as only inclusion criterion 1%
    • Lipids: Total cholesterol 5.9 mmol/L, LDL 3.4 mmol/L, apoB 1.14 g/L
    • Meds (CAD subgroup)
      • ASA 63% (77%)
      • ACEI 20% (10%)
      • Beta-blocker 26% (23%)

Interventions

  • I: Simvastatin 40 mg PO once daily
    • Adherence to >80% of doses: 89% @ 1 y, 82% @ 5 y
  • C: Matching placebo
    • Open-label statin use: 4% @ 1 y, 32% @ 5 y

Results @ mean 5 years

  • LDL
    • @ baseline: 3.4 mmol/L
    • Difference: -1.3 mmol/L @ 1 y, -0.7 mmol/L @ 5 y
  • Death: Simvastatin 12.9%, placebo 14.7% (hazard ratio 0.87, 0.81-0.94), NNT 56
  • Major vascular event (components below): 19.8% vs 25.2% (HR 0.76, 0.72-0.81), NNT 19
    • Non-fatal MI or coronary death: 8.7% vs 11.8%
    • Stroke: 4.3% vs 5.7%
    • Coronary revascularization: 5.0% vs 7.1%
    • Non-coronary revascularization: 4.4% vs 5.2%
  • Adverse effects
    • Cancer: 7.9% vs 7.8%
    • Cognitive impairment: 23.7% vs 24.2%
    • ALT >4x ULN: 0.4% vs 0.3%
    • Unexplained muscle pain/weakness reported at least once: 32.9% vs 33.2%
    • CK
      • 4-10x ULN: 0.2% vs 0.1%
      • >10x ULN: 0.11% vs 0.06%
    • Subgroup analyses demonstrated consistent relative risk reduction in major vascular event across different high-risk inclusion criteria, so absolute benefit dependent on baseline risk. 5-year risk in placebo group (NNT with statin) in relevant subgroups:
      • CAD only: 22.5% (NNT 16)
      • No CAD
        • Cerebrovascular disease: 23.6% (NNT 18)
        • PAD: 30.5% (NNT 14)
        • Diabetes: 18.6 (NNT 23)

Generalizability

  • Represents a wide spectrum of patients with existing vascular disease or diabetes with poor use of other secondary CV prevention interventions, particularly in the CAD subgroup
  • Run-in phase: Placebo x4 weeks, then simvastatin 40 mg/d x4-6 weeks
    • To ensure long-term adherence + "responsiveness" to LDL lowering
    • 36% who entered run-in did not undergo randomization, mostly due to unwillingness or inability to adhere for a planned 5 years
    • Therefore, represents a population that did not have intolerable adverse events after a month of statin therapy

Internal validity

  • Low risk of allocation, performance, detection & attrition bias

    • Central telephone randomization

    • Patients, clinicians, adjudicators unaware of treatment allocation

    • Loss-to-follow-up <0.5%

    • Intention-to-treat analysis

  • High risk of contamination bias

    • By year 5, 32% of patients in placebo group were receiving an open-label statin

    • This acts as a conservative bias, as it attenuates the apparent benefit of statin therapy