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Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease
Yusuf S, Phil D., Lonn Eva, Pais Prem, et al. Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. N Engl J Med
2016; 374:2032-2043.
Background
Most cardiovascular events occur in patient populations that are at average risk w ith no previous cardiovascular disease.
Systolic blood pressure and LDL cholesterol have associations w ith CV disease and in combination account for a majority of
patients’ risk to CV disease.
Previous Literature
The Polypill concept hypothesized that a combination of 4 drugs (aspirin, a β-blocker, a statin, and an angiotensin-converting
enzyme [ACE] inhibitor) could reduce CVD events by 75% in those w ith vascular disease, and Wald and Law proposed a polypill
containing 3 blood pressure (BP) low ering drugs from different classes each at half doses, aspirin, a statin, and folic acid for all
individuals w ith established CVD and all those older than 55 years w ithout CVD and estimated that this approach w ould safely
reduce ischemic heart disease (IHD) events by 88% and strokes by 80%.
INTERHEART Study: Identified population attributable risk for myocardial infarction associated w ith 7 major modifiable risk factors
overall and by region.
SPRINT targeted a high-risk population. In SPRINT, most patients w ere already receiving antihypertensive therapy. SPRINT and
ACCORD suggest that high-risk patients can derive modest additional benefit from more aggressive treatment as opposed to less
aggressive treatment.
Study support
o Funded by the Canadian Institutes of Health Research and AstraZeneca. AstraZeneca provided the trialdrug, and served as a single
voting member on the 24-member steering committee. Severalkey contributors to the study report receiving grant support from
AstraZeneca as wellas travelsupport; no other conflicts of interest wererelevant to the study.
Study objective
o To evaluate the efficacy and safetyof the combination of LDL cholesterollow ering and blood pressure lowering versusplacebo.
Methods
Study Design
o Multicenter, long-term, international, double-blind, randomized placebo controlled trial (RCT)
o Conducted at 228 centers in 21 countries over 7 year span
Eligibility Criteria
o Inclusion Criteria
Men > 55 of Age
Women > 65 of Age or Women > 60 years of age w ith at least 2 additional risk factors besides age
No cardiovasculardisease +at least 1 additional risk factor besides age
o Exclusion Criteria
Patients w ith CV disease
Patients w ith an indication for statins, ARBs, ACE-I, or thiazide diuretic
Patients w ith a contraindication to for statins, ARBs, ACE-I, or thiazide diuretic
Population Enrollment
o 12,705 participants who adhered to the regimen and completed the run-in phase underwent randomization
o Run-in phase consisted of a 4-weekperiod where patient received both active treatments
o 3,180 w ere assigned to candesartan-hydrochlorothiazide +rosuvastatin (combined therapy)
o 3,181 w ere assigned to rosuvastatin +placebo
o 3,176 w ere assigned to candesartan-hydrochlorothiazide +placebo
o 3,168 w ere assigned to placebo +placebo
o 74.6% of combined group w as adherent at end of trial; 71.8% of dualplacebo group w asadherent at end of trial
TreatmentRegimens
o Patients given candesartan-hydrochlorothiazide were given 16-12.5 mg per day or placebo
o Patients given rosuvastatin were given 10 mg per day or placebo
o Open-label statins could be prescribed at the physician’s discretion, in w hich case trialrosuvastatin or placebo w asdiscontinued
Information Sources, SearchStrategy, Study Selection
o Trial w as designed by the steering committee w ho, along w ith staff at the Population Health Research Institute, oversaw the conduct
of the trial, the collection and analysis of the data, and the interpretation of the results.
o The first author drafted the manuscript, and all the authors made the decision to submit the manuscript for publication
Quality assessment
o The first author along w ith three other authors fromthe Population Health Research Institute had full access to the data and vouch for
the accuracy and completeness of the data and analysis and for the fidelity of the report to the protocol.
Outcome Measures
Primary Outcomes Secondary Outcomes Other Significant Outcomes
Composite of death fromCV causes,
nonfatalmyocardial infarction, or
nonfatalstroke
Composite of these events plus
resuscitated cardiac arrest, heart
failure, or revascularization
Composite of events comprising the
secondary coprimary outcome plus
angina w ith evidence of ischemia
Death from any cause
Components of the coprimary
outcomes
New -onset diabetes
Cognitive Function (>70 y/o)
Erectile Dysfunction (Men)
Data Handling, Statistical Analysis, and StatisticalConsiderations
o Intention-to-treat principle, using P value of less than 0.05 to test primary outcomes comparing combined group to dual placebo group
o Survivalcurves werecomputed w ith the use of Kaplan-Meier procedure
o 80% pow er wasused to detect a risk of the coprimary outcomes w ith combination therapy that w as at least 35% low er than the risk
w ith dualplacebo
Cox proportional-hazards modelw as used to estimate treatment effects and to evaluate effectsin subgroups.](https://image.slidesharecdn.com/433839e5-514c-42a3-ac5d-716b8e5a6084-161116154909/85/CV-journal-Club-1-320.jpg)
CV journal Club
- 1. 1 Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease Yusuf S, Phil D., Lonn Eva, Pais Prem, et al. Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. N Engl J Med 2016; 374:2032-2043. Background Most cardiovascular events occur in patient populations that are at average risk w ith no previous cardiovascular disease. Systolic blood pressure and LDL cholesterol have associations w ith CV disease and in combination account for a majority of patients’ risk to CV disease. Previous Literature The Polypill concept hypothesized that a combination of 4 drugs (aspirin, a β-blocker, a statin, and an angiotensin-converting enzyme [ACE] inhibitor) could reduce CVD events by 75% in those w ith vascular disease, and Wald and Law proposed a polypill containing 3 blood pressure (BP) low ering drugs from different classes each at half doses, aspirin, a statin, and folic acid for all individuals w ith established CVD and all those older than 55 years w ithout CVD and estimated that this approach w ould safely reduce ischemic heart disease (IHD) events by 88% and strokes by 80%. INTERHEART Study: Identified population attributable risk for myocardial infarction associated w ith 7 major modifiable risk factors overall and by region. SPRINT targeted a high-risk population. In SPRINT, most patients w ere already receiving antihypertensive therapy. SPRINT and ACCORD suggest that high-risk patients can derive modest additional benefit from more aggressive treatment as opposed to less aggressive treatment. Study support o Funded by the Canadian Institutes of Health Research and AstraZeneca. AstraZeneca provided the trialdrug, and served as a single voting member on the 24-member steering committee. Severalkey contributors to the study report receiving grant support from AstraZeneca as wellas travelsupport; no other conflicts of interest wererelevant to the study. Study objective o To evaluate the efficacy and safetyof the combination of LDL cholesterollow ering and blood pressure lowering versusplacebo. Methods Study Design o Multicenter, long-term, international, double-blind, randomized placebo controlled trial (RCT) o Conducted at 228 centers in 21 countries over 7 year span Eligibility Criteria o Inclusion Criteria Men > 55 of Age Women > 65 of Age or Women > 60 years of age w ith at least 2 additional risk factors besides age No cardiovasculardisease +at least 1 additional risk factor besides age o Exclusion Criteria Patients w ith CV disease Patients w ith an indication for statins, ARBs, ACE-I, or thiazide diuretic Patients w ith a contraindication to for statins, ARBs, ACE-I, or thiazide diuretic Population Enrollment o 12,705 participants who adhered to the regimen and completed the run-in phase underwent randomization o Run-in phase consisted of a 4-weekperiod where patient received both active treatments o 3,180 w ere assigned to candesartan-hydrochlorothiazide +rosuvastatin (combined therapy) o 3,181 w ere assigned to rosuvastatin +placebo o 3,176 w ere assigned to candesartan-hydrochlorothiazide +placebo o 3,168 w ere assigned to placebo +placebo o 74.6% of combined group w as adherent at end of trial; 71.8% of dualplacebo group w asadherent at end of trial TreatmentRegimens o Patients given candesartan-hydrochlorothiazide were given 16-12.5 mg per day or placebo o Patients given rosuvastatin were given 10 mg per day or placebo o Open-label statins could be prescribed at the physician’s discretion, in w hich case trialrosuvastatin or placebo w asdiscontinued Information Sources, SearchStrategy, Study Selection o Trial w as designed by the steering committee w ho, along w ith staff at the Population Health Research Institute, oversaw the conduct of the trial, the collection and analysis of the data, and the interpretation of the results. o The first author drafted the manuscript, and all the authors made the decision to submit the manuscript for publication Quality assessment o The first author along w ith three other authors fromthe Population Health Research Institute had full access to the data and vouch for the accuracy and completeness of the data and analysis and for the fidelity of the report to the protocol. Outcome Measures Primary Outcomes Secondary Outcomes Other Significant Outcomes Composite of death fromCV causes, nonfatalmyocardial infarction, or nonfatalstroke Composite of these events plus resuscitated cardiac arrest, heart failure, or revascularization Composite of events comprising the secondary coprimary outcome plus angina w ith evidence of ischemia Death from any cause Components of the coprimary outcomes New -onset diabetes Cognitive Function (>70 y/o) Erectile Dysfunction (Men) Data Handling, Statistical Analysis, and StatisticalConsiderations o Intention-to-treat principle, using P value of less than 0.05 to test primary outcomes comparing combined group to dual placebo group o Survivalcurves werecomputed w ith the use of Kaplan-Meier procedure o 80% pow er wasused to detect a risk of the coprimary outcomes w ith combination therapy that w as at least 35% low er than the risk w ith dualplacebo Cox proportional-hazards modelw as used to estimate treatment effects and to evaluate effectsin subgroups.
- 2. 2 Results Baseline Characteristics o Mean Age: 65.7 years, 46.2% Women, Mean Systolic BP: 138.1, Mean LDL: 127.8 mg, Mean Follow -up: 5.6 years Primary Endpoint o First primary outcome occurred in 113 (3.6%) in the combined therapy group and in 157 participants (5%) in the dual placebo group (hazard ratio, 0.71; 95% CI 0.56 to 0.90; P = 0.005, relative difference 29%, absolute difference 1.4%) o Second primary outcome occurred in 136 (4.3%) of combined therapy group and in 187 (5.9%) in the dual placebo group (hazard ratio, 0.72; 95% CI 0.57 to 0.89; P=0.003; relative difference 28%, absolute difference 1.6%) o In post hoc analysis, there w ere fewerfirst and recurrent eventsof the first coprimary therapythan w ith dualplacebo therapy (hazard ratio 0.68; 95% CI, 0.53 to 0.87; P = 0.002) and few er first and recurrent eventsof the second coprimary outcome (hazard ratio, 0.66; 95% CI, 0.52 to 0.84; P = 0.001) Other Relevant Outcomes o On average the mean systolic BPw as lower by 6.2 mmHg in combined group than in dualplacebo group; mean diastolic BP w as low er by 3.2 mmHg, and mean LDL w as low er by 33.7 mg/dL (P<0.001) o Secondary outcome occurred in 147 (4.6%) in combined therapy group and in 205 (6.5%) in the dual placebo group (hazard ratio 0.71; 95% CI, 0.57 to 0.87; P = 0.001) o There w ere no significant treatment-by-subgroup interactions with respect to first and second primary outcomes according to stroke risk, LDL level, and systolic BP at baseline. o There w as no significant heterogeneity in the effectsof combined therapy in the subgroups according to age, sex, or ethnic group/race. o There w as a nonsignificant trend toward a lowerriskof the first coprimary outcome w ith rosuvastatin plus placebo thanwith candesartan- HCTZ plus placebo (122 (3.8%) participants vs. 147 (4.6%), respectively; hazard ratio, 0.82; 95% CI, 0.65 to 1.05; P = 0.11) o There w as a significant difference in the risk of the second coprimary outcome (141 participants (4.4%) w ith rosuvastatin plus placebo vs. 176 (5.5%) w ith candesartan-HCTZ plus placebo; hazard ratio, 0.79; 95% CI, 0.64 to 0.99; P = 0.04) o Trial patients w ith the highest third of blood pressure at baseline (above 143 mm Hg) derived benefit fromantihypertensive therapy. For patients in the middle third antihypertensive therapy had a neutraleffect. For patients in the low est third antihypertensive therapy had a harmful effect. Among participants in the upper third, the risk of the tw o coprimary outcomes w as approximately 40% low er with combined therapy than w ith dual placebo, whereas the relative risk was only about 20% lower among participants with lower systolic blood pressure. o There w as no significant differencesbetween combined therapy group and dual placebo group in the rate of new -onset diabetes, renal dysfunction, syncope, liver function abnormalities, eye problems, or cancers. o There w ere 163 deaths in combined therapy group and 178 deaths in dual placebo group; few erCV deaths in combined therapy group Follow Up o Follow -up visits occurred at 6 w eeks and 6 months after randomization and every 6 months thereafter; BPw as recorded at each visti in the first year and then annually; lipid levels w ere measured at baseline in all participants and at 1 year, at 3 years, and at the end of the trial in 10-20% of participants. Safety/Adverse Events o Muscle w eaknessand dizziness were more common in combined therapy group than in dual placebo group; incidence of muscle w eaknesswassimilar to rosuvastatin-plus-placebo group and incidence of dizzinessand hypotension was similar to the candesartan- HCTZ-plus-placebo group. o Rates of permanent discontinuation for any reason did not differ significantly between the combined therapy group and the dual placebo group (26.3% vs 28.8%, respectively), nor did the rates of serious adverse events o There w as only one case of rhabdomyolysis (in rosuvastatin-plus-placebo group) indicating little need for routine blood testing w ith combined therapy. Discussion and Conclusions Author Conclusions o Combined therapy w asassociated with a significantly lower risk of CV events than dualplacebo in patients w ith intermediate-risk w ithout previous CV disease. o The NNT for 5.6 years to prevent one event of the first coprimary outcome w as 72, and the NNT to prevent one event of the sec ond coprimary outcome w as 63. o LDL reduction w assimilar to w hat wasexpected; systolic BPreduction w as less than expected. o Effects of rosuvastatin in trialw ere independent of BP or lipid levels suggesting that combined therapy w ould performbest in persons w ith elevated BP, w hereas statinsalone w ould performbetter in those w ithout elevated BP. Strengths o Rates of adherence w ere high so results w ere more representative than in low er adherence trials o Large sample size enhances generalizability of study o Novel research perspective in that it focused on preventative use of antihypertensives and statins as opposed to treatment. o Longer duration of study show slong-termtrends w ith outcomes Limitations o Only one of each class of drug w as chosen, and there w as no rationale for w hy those specific drugs were selected. o Many of the referenced trials and articles w ere written by the same authors of this trial. o It is unknow n w hat effect on efficacyand safety there w ould be if increased doses of each drug w ere used, or if a three drug BP regimen w ould increase the results on BP. o Results are only applicable to older patients. o Generalizability in US populations is somew hat decreased because the study only included 2% AA population, and the AA population in the US accounts for closer to 14%. o While results w ere statistically significant, there overall gain for the patient seemed marginal based on the NNT and rate of outcomes in combined therapy group vs. dual placebo group in regards to BP, thus not clinically significant. LDL w as considerably more affected and thus should be considered in treatment and prevention of CV disease. Clinical Application Statins may significantly reduce adverse cardiovascular events in people w ith average cholesteroland blood pressure (BP) levels w ho are considered to be at intermediate risk for cardiovascular disease, w hile the use of BP-low ering medications may be beneficial only in hypertensive patient. Thus it follow s that clinicians may not need to give dyslipidemic people an antihypertensive; how ever, it may be appropriate to give antihypertensive therapy and statins to those w ho are hypertensive." Ultimately, the trial supports a broader -- but by no means universal -- approach to primary prevention.