Critically Appraised Topic on the HOPE 3 trial: statins beneficial for primary prevention on intermediate to high risk individuals

I. THE CLINICAL SCENARIO

Fifty-eight year old male who works as a vendor asks if he should start taking medications for his cholesterol. Total cholesterol was 219 mg/dL, LDL 166mg/dL  and HDL was 29 mg/dL. Blood pressure measured at home ranges from 110/80. He is non-diabetic, non-asthmatic. He denies anginal nor failure symptoms. Has good baseline functional capacity claiming that he is able to climb 2 flights of stairs (stairs in their house). No family history of hypertension and diabetes. He is an occasional alcoholic beverage drinker and a non smoker.

On physical examination, he was noted to be awake, conscious, coherent, not in distress. Blood Pressure that time was 120/90 HR was 72 RR was 16. Rest of the physical examination was unremarkable. You are contemplating whether statin therapy be started on this patient.

II. THE CLINICAL QUESTION

Among males more than 55 years with at least one risk factor without cardiovascular disease, would cholesterol lowering provide significant benefit in lowering mortality and adverse cardiac events?

III. ARTICLE TITLE AND CITATION

Yusuf et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease (HOPE 3 Trial). N Engl J Med 2016;374:2021-31. DOI: 10.1056/NEJMoa1600176

APPRAISAL OF THE ARTICLE

  1. DIRECTNESS

 SCENARIOARTICLE
PopulationPatients with at least one risk factors without cardiovascular diseaseMen 55 years of age or older and women 65 years of age or older without cardiovascular disease and with at least one additional risk factor besides age
• Waist/hip ratio ≥ 0.85 in women and ≥ 0.90 in men
• History of current or recent smoking (regular tobacco use within 5 years)
• Low HDL-C ( HDL-C < 1.0 mmol/L in men and <1.3 mmol/L in women)
• Dysglycemia (impaired fasting glucose, impaired glucose tolerance or uncomplicated diabetes treated with diet only)†
• Early renal dysfunction‡
• Family history of premature coronary heart disease in first degree relatives (men < 55 years or women <65 years)
ExposureCholesterol loweringCholesterol lowering
ComparisonNot applicablePlacebo
OutcomePrevention of mortality and adverse cardiac eventsComposite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second co-primary outcome additionally included heart failure, cardiac arrest, or revascularization
MethodsRecent RCTs, MetaRCT, Meta

II. VALIDITY

CRITERIAREMARKS
RandomizationYes.
It was stated that the study is a randomized controlled trial.
“We conducted this pragmatic, multicenter, longterm,
international, double-blind, randomized,
placebo-controlled trial…”
Page 2022 Column 1 Paragraph 1
AllocationNot mentioned.
There was no mention of allocation method.
Baseline CharacteristicsYes.
Baseline characteristics were similar as shown in Table 1.
Table 1 Page 2024-2025
Blinding of PatientsYes.
Trial subjects were blinded of the treatment groups. As mentioned in a double-blinded study design
“We conducted this pragmatic, multicenter, longterm,
international, double-blind, randomized,
placebo-controlled trial…”
Page 2022 Column 1 Paragraph 1
Blinding of CaregiversYes.
Caregivers were blinded of the treatment groups.
As mentioned in a double-blinded study design
“We conducted this pragmatic, multicenter, longterm,
international, double-blind, randomized,
placebo-controlled trial…”
Page 2022 Column 1 Paragraph 1
Blinding of Outcome AssessorsNot clearly stated.
Page 2023 column 1 paragraph 4
Intention to TreatYes.
It was mentioned that data was analysed based on intention to treat principle.
“The main analyses were performed according to the intention-to-treat principle”
Page 2023 column 2 paragraph 3
Follow Up RateYes.
Follow up was adequate.

III. RESULTS

  • 12,705 patients, 5.6 years follow up

OutcomeRosuvastatin GroupPlacebo GroupHR(95% CI)RRRARRRRNNT
First Coprimary (death from cardiovascular diseases, fatal or nonfatal MI and fatal or nonfatal CVD)3.7%4.8%0.76(0.64–0.91)23%1.10.7790
Death from Cardiovascular causes2.4%2.7%0.89(0.72–1.11)----
Myocardial infarction0.7%1.1%0.65(0.44–0.94)36%0.40.63250
Stroke1.1%1.6%0.70(0.52–0.95)31%0.50.69200

IV. APPLICABILITY ISSUES

  • Scrap

SEXNone.
Both genders are well represented in the study
CO-MORBIDSNone.
Presence of co-morbidities were excluded in the study and our patient has no other co-morbids.
RACENone.
Asians are well represented in the study and Philippines is actually a part of this study.
AGENone. The patient’s age has been well represented
PATHOLOGYNone.
SOCIOECONOMICNone.
There are affordable anti-hypertensive medications and statins across classes

V. INDIVIDUALIZING THE RESULTS

  • Estimate of Risk for patient using Framingham Criteria Risk Score: 7% (Rc)
  • To estimate post-treatment risk we use RR and Rc.
    • RT/7 = 0.77
    • RT = 0.77(7)
    • RT = 5.39
  • Absolute Risk Reduction
    • = Rc-Rt
    • = 11.2-8.6
    • = 1.61%
  • Number Needed to Treat = 100/ARR
    • NNT = 100/2.6
    • NNT = 62

 

Benefit
*For every 62 patients treated with a combination, you reducue 1 co-primary outcome – cardiovascular death, MI and stroke.

INNOVATOR DRUG

 Amount
Average Cost of Statin Therapy per dayPhp 58.00
Total expenses per dayPhp 58.00/day
Total expenses per monthPhp 1,740.00/month
Total expenses per yearPhp 20,88.00/year
Total to cost to prevent 1 event in 62 people in 6 yearsPhp 7,767,360.00
Estimated Cost of Care for Non-fatal MI not needing revascularization (regular room, medical therapy, labs, 5 hospital days)Php 30,000-40,000
Estimated Cost of Care for MI with CA + PTCAPhp 150,000-300,000

BIOEQUIVALENT

 Amount
Average Cost of Statin Therapy per dayPhp 26.00
Total expenses per dayPhp 26.00/day
Total expenses per monthPhp 780.00/month
Total expenses per yearPhp 9,360.00/year
Total to cost to prevent 1 event in 62 people in 6 yearsPhp 3,481,920.00
Estimated Cost of Care for Non-fatal MI not needing revascularization (regular room, medical therapy, labs, 5 hospital days)Php 30,000-40,000
Estimated Cost of Care for MI with CA + PTCAPhp 150,000-300,000

V. AUTHOR’S CONCLUSION
Treatment with low doses of rosuvastatin was associated with a significantly lower risk of cardiovascular events than the risk with placebo among intermediate-risk persons without previous cardiovascular disease.

VI. REVIEWER’S CONCLUSION
Based on our clinical scenario, the article is direct and relevant in answering our clinical dilemma. In the article’s appraisal, the article has satisfied the validity criteria. However, there are some points which are not clearly stated and explained in the article such as allocation concealment and blinding of outcome assessors. Risk and benefit (NNT/NNH) Cholesterol lowering in patients with intermediate risk may have some benefit in reducing death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

VII. CLINICAL BOTTOM-LINE
Initiation of statin therapy are guided by the recommendations in Philippine Dyslipidemia guidelines. In the initiation of  statin therapy, the Philippine Guidelines recommend to initiate statin therapy in patients with at least 2 risk factors and those with LDL of at least 130. However, based on the results of the HOPE-3 trial, initiation of statin therapy can be recommended to reduce adverse cardiovascular outcomes. It is important to note that the recommendation of HOPE 3 trial parallels the Philippine Dyslipidemia guidelines in initiating statin therapy.

 

Prepared by:
 

Arnolfo B. Tomas Jr., MD
1st Year Cardiology Fellow-in-Training
UP-Philippine General Hospital

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