ALLHAT-LLT Elderly

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Han BH, et al. "Effect of Statin Treatment vs Usual Care on Primary Cardiovascular Prevention Among Older Adults: The ALLHAT-LLT Randomized Clinical Trial". JAMA Intern Med. 2017. 177(7):955-965.
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Clinical Question

In patients aged 65 and older with moderate hyperlipidemia and hypertension without atherosclerotic cardiovascular disease (ASCVD), does the addition of statin therapy for primary prevention reduce all-cause mortality when compared to usual care alone?

Bottom Line

Statin therapy for primary prevention has no impact on all-cause or cardiovascular mortality when given for primary prevention of an ASCVD in the elderly with moderate hyperlipidemia/hypertension. Rather, individualizing treatment based on patient risk factors may be more effective.

Major Points

Previous studies have quantified that 28% of patients 75-79 and 22% of patients 80 and older take statins for primary prevention[1], and statin use for primary prevention in patients older than 79 has increased from 8.8% in 1999-2000 to 34.1% in 2011-2012[2]. A 2015 Markov model[3] reported that while statins may be cost effective for primary prevention in patients 75 years and older, any benefit could be easily offset by an increase in adverse events.

The original ALLHAT trial[4] was published in 2002, and included patients over the age of 55, with or without a history of heart disease with a total population of 10 335. Because statin use for primary ASCVD prevention in the elderly has been an area of limited data, this study focuses on the population 65 and older taking pravastatin for primary prevention. This analysis included 2867 patients randomized in a 1:1 fashion for pravastatin therapy plus one of four antihypertensives (Chlorthalidone, Amlodipine, Lisinopril, or Doxazosin). The primary outcome of all-cause mortality found no statistically significance difference with the addition of pravastatin (1.3% vs. 1.2%, P = 0.9). When then looking specifically at deaths associated with cardiovascular disease, no difference again was seen. (0.9% vs. 0.9%, P = 0.36) and when comparing patients above and below 75 years of age, no difference was seen.

Guidelines

2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult,[5] adapted:

  • Consider pharmacotherapy with statin if:
    • High FRS[6] (≥ 20%) [Strong Recommendation; High-Quality Evidence], or
    • Intermediate FRS (10%-19%), and
      • LDL-C ≥ 3.5 mmol/L, OR non-HDL-C ≥ 4.3 mmol/L, OR ApoB ≥ 1.2 g/L, OR men ≥ 50 and women ≥ 60 years and 1 additional CVD risk factor [Strong Recommendation; High-Quality Evidence]
  • Target for these patients:
    • LDL-C < 2.0 mmol/L or > 50%↓, ApoB < 0.8 g/L, or non-HDL-C < 2.6 mmol/L

Design

  • Post hoc analyses of a randomized, open-label, controlled trial
  • N=10,335 (2,867 in this analysis)
    • Pravastatin (n=5170, 1467 in this analysis)
    • Usual Care (n=5185, 1400 in this analysis)
  • Setting: 513 clinical sites primarily across the United States
  • Enrollment: February 1994 to March 2002
  • Mean follow-up: 4.77 years
  • Analysis: Intent-to-treat
  • Primary outcome: All-cause mortality at 6 years

Population

Inclusion Criteria

  • Ambulatory
  • ≥ 55 years old
    • ≥ 65 years old included in analysis
  • Stage 1 or 2 hypertension plus ≥ 1 Chronic Heart Disease risk factors:
    • Current cigarette smoking
    • Type 2 diabetes
    • Left Ventricular Hypertrophy in past 2 yrs
    • HDL cholesterol under 35 mg/dL [0.9 mmol/L] twice in past 5 yrs
    • 2 fasting LDL-C readings of 120-189 mg/dL [3-5 mmol/L]
    • Fasting triglycerides < 350 mg/dL [< 9 mmol/L]

Exclusion Criteria

  • Currently lipid-lowering therapy
  • Statin intolerance
  • Manifested significant liver/kidney disease
  • Known secondary cause of hyperlipidemia
  • Evidence of ASCVD (previous stroke/MI, CHD, PVD, CVD, history of angina pectoris, any arterial stenosis)

Baseline Characteristics

Pravastatin group displayed

  • Demographics: mean age 71.3, 48% female, White non-hispanic 39%, Black non-hispanic 35%, White hispanic 16.7%, Black hispanic 4%, Other 5%, mean years of education 10
  • Co-morbidities: Current smokers 23.2%, Type 2 Diabetes 51%
  • Physiologic parameters: mean Blood Pressure 147 / 83 mm Hg, mean fasting glucose 130.9 mg/dL [7.3 mol/L], mean serum cholesterol 225 mg/dL [5.8 mmol/L], mean LDL-C 147.7 mg/dL [3.8 mmol/L], mean HDL-C 47.2 mg/dL [1.2 mmol/L], mean fasting triglycerides 150.3 mg/dL [3.9 mmol/L]
  • Anthropomorphics: mean BMI 29.5, BMI >30 40.8%
  • Medication use: Female taking estrogens 11%, ASA 26%, Antihypertensives 90%
    • Antihypertensive Randomization, no. (%):
      • Chlorthalidone: 35.9% vs. 36.2%
      • Amlodipine: 22.6% vs. 22.9%
      • Lisinopril: 20.9% vs. 20.2%
      • Doxazosin: 20.7% vs. 20.6%

Interventions

  • Pravastatin Group:
    • Randomized in 1:1 ratio to receive Pravastatin 40 mg daily with or without 1 of 4 antihypertensives:
      • Chlorthalidone
      • Amlodipine
      • Lisinopril
      • Doxazosin
    • Initially patients were started on Pravastatin 20 mg and titrated upward to a 25% decrease in baseline LDL-C
      • After the first 1000 patients this was changed to a starting dose of 40 mg
  • Usual Care: group was treated for LDL-C based on discretion of primary care physician.

Outcomes

Comparisons are Pravastatin group vs. Usual care.

Primary Outcomes

All-Cause Mortality
1.3% vs. 1.2% (ARI = 0.1%, 95% CI 1.18 (0.97-1.42), P = 0.9)

Secondary Outcomes

Cardiovascular Disease (CVD) deaths
0.9% vs. 0.9% (ARR = 0%, HR = 1.14 (0.86-1.52), P = 0.36)
Coronary Heart Disease (CHD) deaths
0.6% vs. 0.7% (ARR = 0.1%, HR = 0.97 (0.65-1.44), P = 0.87)
Stroke deaths
0.3% vs. 0.4% (ARR = 0.1%, HR = 1.36 (0.67-2.78), P = 0.40)
Non-CVD deaths
1.1% vs. 1.0% (ARI = 0.1%, HR = 1.21 (0.93-1.59), P = 0.16)
Unknown cause of death
0.5% vs. 0.3% (ARI = 0.2%, HR = 1.14 (0.54-2.39), P = 0.57)
Fatal CHD and nonfatal MI
0.9% vs. 1.0% (ARR = 0.1%, HR = 0.81 (0.63-1.05), P = 0.12)
Stroke, fatal and nonfatal
0.9% vs. 0.8% (ARI = 0.1%, HR = 1.06 (0.76-1.49), P = 0.72)
Heart failure, hospitalized or fatal
1.0% vs. 1.1% (ARR = 0.1%, HR = 1.00 (0.73-1.36), P = 0.98)
Cancer, fatal and nonfatal
1.1% vs. 1.0% (ARI = 0.1%, HR = 1.14 (0.88-1.46), P = 0.32)

Subgroup Analysis

Sub-group comparing participants 65-74 years vs. ≥ 75 years showed no significant difference.

Adverse Events

About half of patients discontinuing pravastatin cited a reason relating to adverse reactions, however the specific data of adverse reactions was not recorded.

Criticisms

  • Post-hoc secondary analysis of a sub-group of the ALLHAT-LLC trial
  • Excluded patients receiving lipid lowering agents at baseline
  • Lack of specific adverse event data
  • Due to sub-group analysis, may have been underpowered
  • Open label design
  • ALLHAT-LLT did not account for non-pharmacologic means of lowering cholesterol, lifestyle/diet/exercise
  • Patients were initially started on pravastatin 20 mg and titrated upward. After about 1000 patients this was changed to 40 mg as initial therapy, which had the potential to confound results.
  • Some of the data may be confounded from patients in the usual care group starting on lipid lowering therapy after the beginning of the trial, and a decrease in adherence from the pravastatin group.
  • This study uses ALLHAT-LLT data from 2002. Criteria for diagnosing ASCVD and standards of treatment for comorbidities have since changed. Although treatments groups were represented similarly at baseline, this 15 year time gap could affect the applicability of this data to modern statin protocols and use.

Funding

  • Funded by the National Heart, Lung, and Blood Institute
  • Medications provided by pharmaceutical companies:
    • Pfizer (amlodipine besylate and doxazosin mesylate)
    • Astrazeneca (atenolol and lisinopril)
    • Bristol-Myers Squibb (pravastatin)

Further Reading

  1. Chokshi NP et al. Appropriateness of statins in patients aged ≥80 years and comparison to other age groups. Am. J. Cardiol. 2012. 110:1477-81.
  2. Johansen ME & Green LA Statin Use in Very Elderly Individuals, 1999-2012. JAMA Intern Med 2015. 175:1715-6.
  3. Odden MC et al. Cost-effectiveness and population impact of statins for primary prevention in adults aged 75 years or older in the United States. Ann. Intern. Med. 2015. 162:533-41.
  4. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002. 288:2998-3007.
  5. Anderson TJ et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol 2016. 32:1263-1282.
  6. Pencina MJ et al. Application of new cholesterol guidelines to a population-based sample. N. Engl. J. Med. 2014. 370:1422-31.