Blood-pressure and cholesterol lowering in persons without cardiovascular disease

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Yusuf S, et al. "Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease". New England Journal of Medicine. 2016. 374(21):2032-2043.
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Clinical Question

In adults without cardiovascular (CV) disease, but at an intermediate risk, does taking a combination of lipid lowering and anti-hypertensive medications significantly reduce the risk of cardiovascular-related morbidity and mortality?

Bottom Line

The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day) and hydrochlorothiazide (12.5 mg per day) decreased the rate of CV events as compared to a dual placebo among persons at intermediate risk for CV disease but had not been diagnosed with having the disease. The intervention did not affect cardiovascular-related death or death from any cause.

Major Points

Elevation in blood pressure and LDL cholesterol is associated with an increased risk of cardiovascular events. Two-thirds of the population with cardiovascular diseases have high blood pressure and high LDL levels. Lowering both of these levels has a greater effect on decreasing the risk of cardiovascular events than only lowering one of levels1.

Population Health Research Institute conducted a trial with a 2-by-2 factorial design, which randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to rosuvastatin (10 mg per day) or placebo and to candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) or placebo. The trial compared the 3180 participants assigned to combined therapy (with rosuvastatin and the two antihypertensive agents) with the 3168 participants assigned to dual placebo1.

The mean systolic blood pressure was lower by 6.2 mm Hg in the combined- therapy group than in the dual-placebo group. The mean diastolic blood pressure was lower by 3.2 mm Hg, and the mean LDL cholesterol level was lower by 33.7 mg per deciliter (0.87 mmol per liter). With this data, it was concluded the combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) was linked with a significantly lower rate of cardiovascular events than dual placebo among persons who did not have cardiovascular disease. The relative risk reduction of myocardial infarction was 45% lower in the combined-therapy group than in the placebo group and 44% lower for the risk of a stroke over the 5.6 years of the trial1.

The results of the combination regimen rosuvastatin, candesartan, and hydrochlorothiazide compared to the placebo were shown to be statistically significant in lowering fatal or non-fatal myocardial infarctions, fatal or non-fatal strokes,and hospitalizations due to cardiovascular events1.

Guidelines

The article does not specify when to start or stop therapy. Therefore, this decision should be made at the discretion of the patient’s PCP or medical specialist. When making the decision, please incorporate relevant recommendations from the ACC/AHA lipid guidelines (http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a) These guidelines suggest starting statin based on baseline CV risk as opposed to specific lipid value – much like the study design. However, the “cut points” for starting lipid therapy are different between the guideline and the study.

The ACA/AHA 2013 guidelines for statin use made recommendations based on ASCVD risk. It is recommended to adhere to a heart healthy diet, exercise regularly, avoid tobacco products, and maintain a healthy weight to reduce ASCVD risk, both prior to and in concert with the use of cholesterol- lowering drug therapies.

Their algorithm was first broken down into adults >21 years old who were statin candidates and whether they had history of clinical ASCVD. The American college of Cardiology states clinical ASCVD includes acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin. Those included were then separated into moderate vs high level statins based on their age. The other related recommendation was the 10 year ASCVD risk. For those whose risk was >7.5% using the Pooled Cohort Equations, a moderate to high level statin is recommended.

Design

Multi-center, long-term, international, double-blinded, randomized, placebo-control trial by 2-by-2 factorial design N=12,705

  • Combined therapy (rosuvastatin 10 mg and candesartan-hydrochlorothiazide 16mg/12.5mg), n=3180
  • Rosuvastatin plus placebo, n=3181
  • Candesartan-hydrochlorothiazide plus placebo, n=3176
  • Dual placebo, n=3168

Setting: 228 centers in 21 countries

Enrollment: median observation of 5.6 years

Follow-up: 6 weeks and 6 months after randomization and every 6 months, thereafter

Analysis: Intention-to-treat

Primary outcome: The composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (first coprimary outcome) and the composite of these events plus resuscitated cardiac arrest, heart failure or revascularization (second coprimary outcome).

Population

Inclusion Criteria

Men 55 years of age or older or Women 65 years of age or older without cardiovascular disease and with at least one of the following risk factor:

  • Waist/hip ratio greater than or equal to 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 diabetes only)
  • Early renal dysfunction
  • Family history of premature coronary heart disease in first degree relatives (men <55 years or women <65 years of age)

Provision of informed consent

We also included women 60 years of age or older who had at least two such risk factors.


Exclusion Criteria

  • Documented clinically manifest atherothrombotic CVD
  • Indication to statins and/or ARB, ACE inhibitors, or thiazide diuretics
  • Contraindication to statins and/or ARB or thiazide diuretics
  • Symptomatic hypotension
  • Chronic liver disease (cirrhosis or persistent hepatitis) or abnormal liver function (ALT or AST >3 x ULN)
  • Inflammatory muscle disease (such as dermatomyositis or polymyositis) or creatine kinase (CK > 3 x ULN)
  • Moderate renal dysfunction defined as serum creatinine > 2.0mg/dL or GFR < 45mL/min/1.73m^2
  • Treatment with cyclosporine or fibrates
  • Other serious condition(s) likely to interfere with study participation or with the ability to complete the trial
  • Concurrent use of any experimental pharmacologic agent
  • Also those with clear indications for or contraindications to trial drugs, according to the judgment of the local physician and taking into account local guidelines and standards of practice were excluded from participation.

Baseline Characteristics

  • Age: 65.7 YOA
  • Female sex: 45.5
  • CV risk:
    • Elevated waist to hip ratio: 87%
    • Recent or current smoking: 28%
    • Low Concentration of HDL cholesterol: 35.5%
    • Impaired fasting glucose or impaired glucose tolerance: 12.5%
    • Early diabetes mellitus: 6%
    • Family History of premature coronary heart disease: 26.2%
    • Early renal dysfunction: 2.7%
    • Hypertension: 37.8%
    • 2 Risk Factors: 46.7%
    • Greater than 3 Risk Factors: 24.%
  • Demographics:
    • Representation in the Trial
    • Chinese (29%),
    • Hispanic (27%),
    • White (20%),
    • South Asian (14.5%),
    • Other Asian (5.3%),
    • Black (1.7%)
    • Other (1.5%)
  • Any Central LDL-Cholesterol Measurement at baseline:
    • European Descent 21%
    • Latin American 29%
    • Asian 47%
    • Black African 1.9%
    • Other 1.3%
  • Any Central hs-CRP Measurement:
    • European Descent 21%
    • Latin American 29%
    • Asian 46%
    • Black African 1.9%
    • Other 1.3%
  • All Serial Central Lipid or hs-CRP Measurement at All 4 Time Points (baseline, 1 year 1, 3 year1 and study end):
  • Lipid N
    • European Descent 31%
    • Latin American 29%
    • Asian 46%
    • Black African 6.5%
    • Other 2.3%
  • CRP N
    • European Descent 31%
    • Latin American 20%
    • Asian 40%
    • Black African 6.5%
    • Other 2.2%

Interventions

A total of 12,705 participants who adhered to the regimen and did not have an unacceptable level of adverse events during the run-in period underwent randomization.

Combination therapy:

  • Rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day)
  • Rosuvastatin (10 mg per day) plus placebo
  • Candesartan-hydrochlorothiazide (16 mg per day, 12.5 mg per day) plus placebo
  • Dual placebo

Outcomes

Rosuvastatin and hydrochlorothiazide plus candesartan vs dual placebo

Primary Outcomes

Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
3.6% vs 5.0% (HR 0.71; CI 0.56-0.90 P=0.005, NNT 72)
Death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest, heart failure, or revascularization
4.3% vs 5.9% (HR 0.72; CI 0.57-0.89 P=0.003, NNT 63)

Secondary Outcomes

Composite of events comprising the second coprimary outcome plus angina with evidence of ischemia
4.6% vs 6.5% (HR 0.71; CI 0.57-0.87 P=0.001)
Death from cardiovascular causes
2.4% vs 2.9% (HR 0.82; CI 0.60-1.11)
Death from any causes
5.1% vs 5.6% (HR 0.91; CI 0.73-1.12)
Fatal or Nonfatal myocardial infarction
0.7% vs 1.2% (HR 0.55; CI 0.32-0.93)

Subgroup Analysis

No significant treatment-by-subgroup interactions with respect to the first and second coprimary outcomes in the in the prespecified subgroups defined as stroke risk, LDL cholesterol level, and systolic blood pressure at baseline. There was also no significant heterogeneity in the effects of combination therapy in subgroups defined according to age,sex, or race or ethnic group.

Adverse Events

The main adverse effects of muscle weakness and dizziness were associated with the combined therapy groups compared to the dual placebo group. Permanent discontinuation, for any reason, did not differ significantly between combined therapy group vs dual placebo group (26.3% vs 28.8%) nor did the rate of serious adverse effects. Reported serious unexpected suspected adverse reactions in the Candesartan/HCTZ and Placebo Groups was 1.5% and 1.4% respectively.

Criticisms

The trial was funded by a major pharmaceutical firm, AstraZeneca, and although it had a minor role in the trial, simply their presence may have swayed the steering committee. Some of the references used by the Trial were also funded by AstraZeneca or were conducted by the physicians who worked on this trial

Funding

Funding was provided by the Canadian Institutes of Health Research and AstraZeneca. AstraZeneca provided the trial drug, served as a single voting member on the 24-member steering committee, and had no other role in the trial.

Further Reading