MRFIT

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MRFIT Writers. "Multiple risk factor intervention trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group". JAMA. 1982. 248(12):1465-1477.
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Clinical Question

In high-risk male patients, does a multi-factor intervention program decrease mortality from coronary heart disease (CHD) as compared to usual medical care?

Bottom Line

In high-risk male patients, the MRFIT trial did not show any benefit of a multi-factor intervention program on mortality from CHD as compared to usual medical care. It is important to note that the trial was not blinded and also under-powered due to lower than anticipated mortality rates.

Major Points

In the 1970s, as it still is today,[1] CVD (including CHD) was a leading cause of death among US adults. The seminal Framingham Heart Study identified the "conventional" risk factors for CHD, including smoking, elevated cholesterol, and elevated BP.[2] Whether modifying these risk factors reduced CHD deaths was unknown. The Multiple Risk Factor Intervention Trial (MRFIT) was a seminal clinical trial in CHD risk prevention that randomized 12,866 men between 35 to 57 years old with high risk of death from CHD to receive a multi-factor "special intervention" (SI) program or usual medical care. Participants received 1. Smoking cessation counseling, 2. BP lowering with antihypertensives, and 3. Cholesterol lowering through dietary counseling. The 7-year results did not show any benefit of the multi-factor intervention program on mortality from CHD as compared to usual medical care, possibly because of lower-than-expected CHD events. Further analyses later found a reduction in a combined fatal and non-fatal CHD events.

MRFIT is historically relevant for several reasons. First, the study screened an enormous number of participants for inclusion -- 356,222 -- and performed baseline assessment of risk factors on each. This screening population was followed as a cohort. This cohort showed a continuous, graded association between known CHD risk factors (e.g., smoking, cholesterol, BP) and subsequent CHD events.[3][4][5] Second, it highlights important advancements in biostatistics since the 1980s. For example, the statistical analysis in this primary publication did not incorporate Cox proportional hazards modeling, which is now the standard for clinical trials with time-to-event data. Later analyses identified a higher risk of lung cancer death at 16 years in the group that received the special intervention, which included smoking cessation. In a time before widespread adoption of competing risk methodologies, the authors of this analysis thought that this observation was due to random chance.[6] Third, it included only men, compounding the dearth of evidence for CHD/CVD risk prevention in women. (NIH policies now require representation of women and minorities in clinical research.)[7] Finally, in a time before statins and PCSK9 inhibitors, MRFIT highlighted the limited options for cholesterol modification for CHD prevention.

Guidelines

ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults (2010, adapted)[8]

  • An exercise ECG may be considered for cardiovascular risk assessment in intermediate-risk asymptomatic adults (including sedentary adults considering starting a vigorous exercise program), particularly when attention is paid to non-ECG markers such as exercise capacity. (Class IIb; Level of Evidence: B)

Design

  • Randomized trial
  • N=12,866
    • Special intervention (SI) (n=6,428)
    • Usual care (UC) (n=6,438)
  • Setting: 22 centers in US
  • Enrolment: December 1973 to February 1976
  • Mean follow-up: 7 years
  • Analysis: intention-to-threat
  • Primary outcome: Mortality from coronary heart disease (CHD)

Population

Inclusion Criteria

  • Male patients
  • Aged 35-57 years old
  • Increased risk of death from CHD as determined by 3 risk factors: cholesterol level, cigarette smoking, and blood pressure
    • Patients are included if the 3 risk factors place them in the upper 15% of a risk score distribution based on the Framingham Heart Study
    • The cut-off was revised to 10% at the second screening phase of the study

Exclusion Criteria

  • History or ECG evidence of myocardial infarction (MI)
  • Diabetes mellitus (DM) requiring medication (revised to untreated symptomatic DM in second screening phase)
  • Serum cholesterol ≥350 mg/dL
  • diastolic BP ≥115 mmHg (cut-off revised to ≥120 mmHg in second screening phase)
  • body weight >150% of ideal weight
  • angina as determined by the Rose questionnaire
  • diets not compatible with the MRFIT food pattern
  • treatment with guanethidine, hydralazine, insulin, oral hypoglycemic agents or lipid-lowering agents
  • illnesses or disabilities which prevent full participation in the trial
  • geographic limitations

Baseline Characteristics

From the SI group.

  • Age (years): 46.2
  • Mean weight (pound): 189.3
  • Ethnic origin (black): 7.2%
  • Mean systolic BP (mmHg): 135.7
  • Mean diastolic BP (mmHg): 91.0
  • Hypertension (diastolic BP ≥90 mmHg or on anti-hypertensive): 62.5%
  • Smokers (%): 63.8
  • Plasma cholesterol (mg/dL): 240.3
  • LDL cholesterol (mg/dL): 159.8
  • HDL cholesterol (mg/dL): 42.0
  • Triglyceride (mg/dL): 194.7
  • Framingham 6-year risk of CHD death (%): 3.12

Interventions

Presented elsewhere.[9]
Special intervention (SI) group:

  • Intervention targeting the 3 major risk factors (BP, cholesterol, smoking):
    • Smoking:[10] Initial intervention in group or individual format, followed by an extended intervention or maintenance program
    • BP:[11] stepped care starting with chlorthalidone or hydrochlorothiazide, followed by the addition of reserpine, hydralazine then guanethidine with target BP of diastolic BP of 89 mmHg, or 10 mmHg less than the average diastolic BP at that visit.
    • Cholesterol:[12] dietary plan to limit cholesterol intake <300 mg/day, with <10% of calories as saturated fat and <10% as polyunsaturated fat.
    • The initial intervention program consisted of an average of 10 group sessions involving patients and their spouses or friends to discuss about addressing the 3 major risk factors weekly.
    • After the initial phase, Individual counselling was delivered by a multidisciplinary team.

Usual care (UC) group:

  • Invited for a yearly check-up consisting of medical history, physical examination and laboratory studies

Outcomes

Comparisons are special intervention vs. usual care

Primary Outcome

7-year cumulative mortality from CHD
17.9 vs. 19.3 deaths/1000 people

In the SI group, mortality from CHD was 7.1% (90% CI -15% to 25%; P=NS) less than the UC group.

Secondary Outcomes

7-year cumulative mortality from cardiovascular disease (CVD)
21.5 vs. 22.5 deaths/1000 people (P=NS)

In the SI group, mortality from CVD was 4.7% (P=NS) less than the UC group.

7-year all-cause mortality
41.2 vs. 40.4 deaths/1000 people (P=NS)
7-year CHD death or non-fatal MI[13]
6.14% vs. 6.69% (risk reduction 8%; 95% CI -5% to 20%; P=NS)

Additional Analyses

Published elsewhere.[14]

7-year composite CHD outcome (CHD death, all cases of MI, CHF and coronary artery surgery)
8.1% vs. 9.4% (HR 0.86; 95% CI 0.76-0.97; P=0.01)
7-year composite CVD outcome (CHD endpoints, all cases of CVD deaths, stroke and renal impairment)
9.0% vs. 10.1% (HR 0.89; 95% CI 0.79-0.99; P=0.04)

Subgroup Analysis

No significant differences when results were analysed according to the subgroups: hypertensive vs. non-hypertensive, smoker vs. non-smoker and hypercholesterolemia vs. no hypercholesterolemia.

Criticisms

  • The trial was under-powered due to fewer deaths in the trial than anticipated.[15]
  • The study was not blinded to researchers, patients nor clinicians. Therefore there is no way to ensure that the UC group did not receive or make any changes to modify their cardiovascular risk factors.[16]
  • By comparison with serum thiocyanate levels, patient-reported reduction in smoking rate may be inaccurate and may have caused overestimation.[17]
  • Exclusion criteria may have differentiated the study population from that of the Framingham Heart Study so the sample-size calculations may be imprecise.[18]

Funding

  • National Heart, Lung, and Blood Institute (NHLBI)
  • Drugs used in the study were supplied by different companies- Ciba-Geigy Corporation, USV Pharmaceutical and Ayerst Laboratories.

Further Reading

  1. Virani SS et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation 2021. 143:e254-e743.
  2. Wilson PW & Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 1994. 7:7S-12S.
  3. Neaton JD et al. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med 1992. 152:1490-500.
  4. Stamler J & Neaton JD The Multiple Risk Factor Intervention Trial (MRFIT)--importance then and now. JAMA 2008. 300:1343-5.
  5. Berry JD et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012. 366:321-9.
  6. Shaten BJ et al. Lung cancer mortality after 16 years in MRFIT participants in intervention and usual-care groups. Multiple Risk Factor Intervention Trial. Ann Epidemiol 1997. 7:125-36.
  7. NIH Policy on the inclusion of women and minorities in clinical research.
  8. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol. 2010;56(25):e50-e103. doi:10.1016/j.jacc.2010.09.001.
  9. Benfari RC: The Multiple Risk Factor Intervention Trial (MRFIT): III. The model for intervention . Prev Med 1981;10:426-442.
  10. Hughes GH, Hymowitz N, Ockene JK, et al:  The Multiple Risk Factor Intervention Trial (MRFIT): V. Intervention on smoking . Prev Med 1981;10:476-500.
  11. Cohen JD, Grimm RH Jr, Smith WM:  The Multiple Risk Factor Intervention Trial (MRFIT): VI. Intervention on blood pressure . Prev Med 1981;10:501-518.
  12. Caggiula AW, Christakis G, Farrand M, et al:  The Multiple Risk Factor Intervention Trial (MRFIT): IV. Intervention on blood lipids . Prev Med 1981;10:443-475.
  13. Coronary heart disease death, nonfatal acute myocardial infarction and other clinical outcomes in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group. Am J Cardiol 1986. 58:1-13.
  14. Stamler J, Neaton JD, Cohen JD, Cutler J, Eberly L, Grandits G, Kuller LH, Ockene J, Prineas R; MRFIT Research Group. Multiple risk factor intervention trial revisited: a new perspective based on nonfatal and fatal composite endpoints, coronary and cardiovascular, during the trial. J Am Heart Assoc. 2012 Oct;1(5):e003640. doi: 10.1161/JAHA.112.003640. Epub 2012 Oct 25. PMID: 23316301; PMCID: PMC3541632.
  15. The multiple risk factor intervention trial (mrfit): A national study of primary prevention of coronary heart disease. JAMA. 1976 Feb 23;235(8):825–7.
  16. Lundberg GD & MRFIT and the goals of The Journal. JAMA 1982. 248:1501.
  17. Ebrahim S et al. Multiple risk factor interventions for primary prevention of coronary heart disease. Cochrane Database Syst Rev 2011. :CD001561.
  18. Gotto AM & The Multiple Risk Factor Intervention Trial (MRFIT). A return to a landmark trial. JAMA 1997. 277:595-7.