PROSPER - Statins in the elderly

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

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

Statin dose & CV events

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) 

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

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

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)

Reducing LDL & improving CV outcomes - systematic review

Silverman MG, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA 2016;316:1289-97.

Clinical question: Does reduction of CV outcomes with lipid-lowering therapy correlate with degree of LDL-lowering?

Bottom line:

• The value of this study is mechanistic; it does not provide clinical guidance. 

• The analysis demonstrates that CV outcome reduction of proven lipid-lowering drugs is closely associated with degree of LDL-lowering. This supports the lipid hypothesis, i.e. that lipid-lowering drugs which lower CV risk outcomes (statins, bile acid sequestrants, & ezetimibe) do so primarily by lowering LDL.

• This study does not validate a particular lipid target, nor does it support using interventions with neutral, harmful or conflicting evidence (fibrates, niacin, or CETP inhibitors) to achieve a lipid target.

Search

• Databases: MEDLINE, Embase
• Timeframe: 1966 to July 2016
• Inclusion criteria:
  • Randomized controlled trials (RCTs)
  • Compared (1) LDL-lowering intervention to control/placebo or (2) more vs less intensive statin therapy
  • Reported cardiovascular outcomes including MI
  • Duration of at least 6 months
  • At least 50 events
• Exclusion criteria: Trial with populations with "significant competing risks", including heart failure & chronic kidney disease
• Additional measures for comprehensiveness:
  • References lists of identified studies, review and meta-analyses
  • Reviewed abstracts of major cardiovascular meetings held in past 2 years (no mention of which)
  • Contacted content experts

Results of systematic review

• Included 49 RCTs (n=312,175)
  • Statin (25 trials)
  • Fibrate (9 trials)
  • Diet (4 trials)
  • CETP inhibitor (3 trials)
  • Niacin (3 trials)
  • Bile acid sequestrants (2 trials)
  • PCSK9 inhibitor (2 trials)
  • Ezetimibe (1 trial)
  • Ileal bypass surgery (1 trial)

Results of the meta-analysis

• Mean follow-up 4.3 years
• Mean ~absolute reduction in LDL vs placebo in trials
  • PCSK9 inhibitor -1.85 mmol/L
  • Ileal bypass -1.6 mmol/L
  • Bile acid sequestrant -0.90 mmol/L
  • Statin -0.85 mmol/L (all drugs & doses pooled)
  • Diet -0.75 mmol/L
  • Niacin -0.35 mmol/L
  • Ezetimibe -0.3 mmol/L
  • Fibrate -0.25 mmol/L
• ~23% relative risk reduction (RRR) in major vascular events per 1 mmol/L reduction in LDL with any interventions except CETP inhibitors

Considerations & limitations

• Generalizability & internal validity
  • Investigators excluded studies that included patients with "significant competing risk", which includes some of the landmark "negative" statin trials (CORONA, GISSI-HF, 4D, etc)
    • Results of this analysis don't apply to the subpopulations of these studies (primarily heart failure & chronic kidney disease)
    • The analysis may overestimate the true relative risk reduction since this exclusion criterion primarily excluded "negative" studies.
  • Numerous differences in populations between trials, including
    • Era (e.g. 1st fibrate/niacin trial conducted in 60s, most statin trials conducted in 1990s-2000s)
    • Primary vs secondary prevention
    • LDL before initiation of study treatment & background CV therapies
• Results
  • Although interventions produced comparable RRRs in CV outcomes per 1-mmol/L reduction in LDL, actual achievable LDL reduction & therefore realistic CV reductions with each agent are quite different
  • This study evaluated a composite CV outcome, which bundles together outcomes of different severity & importance to patients. Different interventions may have the same effect on a composite CV outcome, but not specific components. For example, statins reduce every type of CV event (death, MI, stroke, revascularization), whereas fibrates only reduce non-fatal MI, but not death or stroke.