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American College of Cardiology 2016
This year’s annual meeting was host to more than 18,000 cardiology specialists from April 2 to 5 in Chicago. The review below focuses on the large-scale (more than 12,000 patients) HOPE-3 trial, assessing a “polypill” concept for primary prevention, and on a Canadian provincewide program of community pharmacists prescribing to reduce cardiovascular risk.
The Heart Outcomes Prevention Evaluation (HOPE)-3 Trial
HOPE-3 evaluated blood pressure (BP) lowering with candesartan 16 mg daily added to hydrochlorothiazide (HCTZ) 12.5 mg daily combined with cholesterol lowering with rosuvastatin 10 mg daily in an intermediate-risk population (N = 12,705). The trial assessed the effects of this regimen and of the BP-lowering and cholesterol-lowering components separately on cardiovascular events in patients without cardiovascular disease.
Dr. Lonn said that the lack of strict BP or hypertension history or low-density lipoprotein-cholesterol (LDL-C) criteria for trial entry along with the ethnically diverse population made this global trial unique. Mean age was 66 years (46% female), with mean BP of 138/82 mm Hg and mean LDL-C of 128 mg/dL. Waist-to-hip ratio was elevated in 87% of subjects.
Blood Pressure–Lowering Component
After a median follow-up (99.1%) of 5.6 years, the mean change in systolic blood pressure was –6.0 mm Hg (–3.0 mm Hg for placebo). The composite primary outcomes (first, cardiovascular death, myocardial infarction [MI], or stroke; and second, the same plus resuscitated cardiac arrest, heart failure, or revascularizations) were reported at similar rates between the candesartan plus HCTZ and placebo arms (coprimary 1: 4.1% candasartan plus HCTZ versus 4.4% placebo, P = 0.40; coprimary 2: 4.9% candasartan plus HCTZ versus 5.2% placebo, P = 0.51). Rates for individual components were all similar.
A prespecified analysis of the coprimary outcomes with stratification according to thirds of BP found a significant benefit for candesartan plus HCTZ versus placebo among subjects with BP above 143.5 mm Hg (mean, 154 mm Hg) for both the first coprimary outcome (95% confidence interval [CI], 0.56–0.94; hazard ratio [HR] = 0.73) and the second coprimary outcome (95% CI, 0.60–0.96; HR = 0.76,). For patients in the middle third, results were neutral. There was a suggestion of possible harm with the candesartan plus HCTZ combination in patients without very high BP at baseline (131.5 mm Hg or lower systolic blood pressure; CI, 0.92–1.70; HR = 1.25), Dr. Lonn said.
Although treatment discontinuation rates were similar between the treatment arms, lightheadedness was significantly more common in the combination group (3.4% versus 2.0% placebo; P < 0.001).
“The overall main message is treat blood pressure when it’s elevated; don’t treat when there’s no increase,” Dr. Lonn said. She noted that the Eighth Joint National Committee Guidelines for the Management of Hypertension in Adults and the European guidelines still debate the precise entry level for uncomplicated mild hypertension. “Our trial helps define the thresholds at which patients should be treated.”
American College of Cardiology (ACC) discussant Valentin Fuster, MD, Director of Mount Sinai Heart in New York, pointed out that the patients in SPRINT, a trial with results seeming to indicate “treat blood pressure to the lowest level you can,” included patients at significantly higher risk. “You have to individualize,” he said.
Cholesterol-Lowering Arm Results
HOPE-3 studied moderate-risk primary prevention in diverse ethnic groups, Dr. Bosch said. There were no lipid-level entry criteria and no routine monitoring. While the fixed dose of 10 mg daily is low, she commented, rosuvastatin is a potent statin. The mean reduction in LDL-C from baseline was 34.5 mg/dL as compared with placebo at the study end (P < 0.001). Reductions in apolipoprotein B100 (mean ∆ 0.23 g/L) and C-reactive protein (CRP) (log mean ∆ 0.19 mg/L) compared with placebo were also observed.
Outcomes analysis revealed significant reductions with rosuvastatin for the two coprimary endpoints (24% and 25%; P = 0.002 and P = 0.0004) and for myocardial infarction (35%; P = 0.02), stroke (30%; P = 0.02), and cardiovascular hospitalizations (25%; P = 0.0003). The 11% reduction in cardiovascular death, however, was not statistically significant (P = 0.31).
Regarding the reduction in the second coprimary outcome (cardiovascular death, MI, stroke, cardiac arrest, revascularization, heart failure), Dr. Bosch noted that the rosuvastatin and placebo curves start to diverge at about one year and continue separating out to 5.6 years and beyond. A pattern of somewhat later but consistently diverging curves in favor of rosuvastatin over placebo was apparent for coronary heart disease and stroke.
While trends favoring better outcomes with rosuvastatin in subjects with LDL-C 112 mg/dL or lower, INTERHEART Risk Score tertile 1 less than or equal to 12, systolic BP 131.5 mm Hg or lower, and European descent were noted, interactions between events and subgroup categories overall were nonsignificant.
Permanent discontinuations were more common in the placebo group (23.7% rosuvastatin versus 26.2% placebo; P = 0.001), but muscle pain/weakness (5.8% rosuvastatin versus 4.7% placebo; P = 0.005) and the need for cataract surgery (3.3% rosuvastatin versus 2.6% placebo; P = 0.02) were higher for rosuvastatin. Dr. Bosch emphasized that muscle pain/weakness was generally reversible with temporary discontinuations. “There were no increases in serious adverse events such as rhabdomyolysis or new diabetes,” she said.
Dr. Bosch concluded that rosuvastatin 10 mg/day reduced cardiovascular disease by 25% and that benefits were consistent regardless of LDL-C levels, systolic BP, overall risk, CRP, or ethnicity.
Combined Blood-Pressure and Cholesterol Lowering Versus Double Placebo
Dr. Yusuf, at an ACC press briefing, pointed out that HOPE-3 was the first formal testing of clinical events with the “polypill” concept. While patients in HOPE-3 did not actually receive a polypill, the combined regimen did test the concept.
Among the 6,356 patients receiving the candasartan 16 mg plus HCTZ 12.5 mg regimen versus double placebo (n = 6,349), the mean reductions in systolic BP were ∆ 6.2 mm Hg and those in LDL-C were 33.7 mg/dL.
The coprimary endpoint rate for the double-active-agent arm was 3.6%, a significant reduction (95% CI 0.56–0.90; HR = 0.71; P = 0.0054) from the 5.0% rate in the double-placebo arm. For the second coprimary endpoint, the finding was similar at 4.3% for candasartan plus HCTZ and 5.9% for double placebo (95% CI 0.57–0.89; HR = 0.72; P = 00030). Rates for MI, stroke, and cardiovascular hospitalization also favored the double-active group (P = 0.026/0.009/0.0046, respectively) compared with double placebo. The reduction in cardiovascular death (2.4% candasartan plus HCTZ versus 2.9% double placebo) did not reach statistical significance (P = 0.19).
The prespecified evaluation of the combination versus double placebo relative risk reduction (RRR) by systolic BP tertiles showed no benefit in the lower two tertiles of systolic BP patients for the triple combination of rosuvastatin plus HCTZ and candesartan (20%) versus rosuvastatin alone (31%) or candesartan plus HCTZ (–7%). In the highest systolic BP tertile, however, the RRR for the combination was 39%, compared with 18% for rosuvastatin alone and 21% for the dual antihypertensive arm.
Dr. Yusuf also noted, “These trials of five or six years tend to underestimate the benefit.” He pointed out that in the curves for stroke and coronary heart disease (fatal/nonfatal MI, coronary revascularization) benefit, the second three years showed greater statin/antihypertensive benefit than the first three years, with the curve separation widening over time.
Dr. Fuster reiterated that over time, the benefits of combination therapy in primary prevention will accumulate.
Safety was nearly identical between the combination and double-placebo arms, with increase in lightheadedness (with antihypertensives only) and more muscle pain/weakness for the combination (6.2% versus 4.1%). Permanent discontinuations were similar (21.9% combination versus 23.9% double placebo).
Dr. Yusuf concluded, “Overall, it seems that most of the benefits from the combination come through statins—but that hides the fact that in those with elevated blood pressure about half of the 40% reduction in major vascular events comes from blood pressure lowering.”
“An important implication,” Dr. Yusuf said, “is that you don’t need to measure lipids or certainly not frequently. Also, you don’t need to bring people back for intensive monitoring to titrate drugs. When you reduce visits like this, you save money both at the health care level and for individuals … you can avoid many indirect costs.”
Dr. Fuster commented, “The future of prevention, no question, is simplicity.” He also cautioned that emphasizing a relative risk reduction of 30%, when the absolute reduction is 1.5% to 2%, is misleading to many. Still, he added, over time that absolute reduction “means a lot.”
The Effect of Community Pharmacist Prescribing And Care on Cardiovascular Risk Reduction: The RxEACH Multicenter Randomized Controlled Trial
Dr. Tsuyuki said that while cardiovascular diseases are among the leading causes of death, most cardiovascular deaths are caused by modifiable risk factors. “Yet their identification and control are still suboptimal. Pharmacists, though, are accessible, front-line primary health care providers who frequently see patients with or at risk for cardiovascular events,” he said.
Dr. Tsuyuki’s trial assessed a province-wide program in Alberta, Canada, where pharmacists presently can independently prescribe and order laboratory tests. The primary objective was to evaluate the effects of community pharmacy-based case finding and intervention in patients at high risk for cardiovascular events. Researchers looked specifically at reductions in estimated major cardiovascular event risk among patients using 56 community pharmacies across Alberta.
Adults at high risk for cardiovascular events because of diabetes, chronic kidney disease (CKD), established atherosclerotic vascular disease, or multiple risk factors and Framingham risk scores above 20% were eligible, as well as those with at least one uncontrolled risk factor (blood pressure [BP], low-density lipoprotein-cholesterol [LDL-C], elevated hemoglobin A1c [HbA1c], current smoking). All had a standard medication therapy management consultation including the following: 1) patient assessment (BP, waist circumference, weight, and height); 2) lab assessment of HbA1c, lipids, and kidney function; 3) individualized cardiovascular disease risk calculation and education about this risk; 4) treatment recommendations, prescription adaptation, and prescribing as appropriate to meet treatment targets as per the latest Canadian practice guidelines; 5) follow-up every three to four weeks for three months.
Patients were randomized to RxEACH advanced care or to usual pharmacy/physician care with no specific interventions or follow-up. After three months, patients in the usual care group crossed over to the RxEACH intervention.
The primary outcome was the difference from baseline in estimated risk for future cardiovascular events based on validated risk engines (United Kingdom Prospective Diabetes Study, International, Framingham).
Dr. Tsuyuki noted that 79% of subjects at baseline had uncontrolled HbA1c, 72% had uncontrolled BP, 58% had uncontrolled LDL-C, and 27% were current smokers. Mean age was 62 years (58% male). Of 720 enrolled patients, 41% had CKD, 81% had diabetes, 85% had hypertension (uncontrolled in 72%), and 32% had atherosclerotic vascular disease. At baseline in the initial intervention group, mean HbA1c was 8.6% (uncontrolled in 79%); mean glucose was 9.2 mmol/L, and mean estimated glomerular filtration rate was 78.7 mL/min/1.73m2. Mean BP was 137/81 mm Hg. Twenty-six percent were current smokers. At baseline, the most common medications were metformin (57.0%), insulin (28.9%), diuretics (34.6%), angiotensin-converting enzyme inhibitors (39.5%), angiotensin II receptor blockers (28.7%), calcium-channel blockers (29.2%), beta blockers (25.4%), and statins (60.5%).
As a result of assessment in the intervention group, medication changes (dosage change, cessation, or new drug started) were ordered for hypoglycemics in 39.1%, for antihypertensives in 28.7%, and for antidyslipidemics in 18.6%.
Dr. Tsuyuki reported that guideline targets were achieved more commonly in the intervention group. LDL-C targets were met in 55.5% and 45.6% in the intervention and usual care groups, respectively. BP targets were met in 50.9% and 27.8%, and HbA1c in 42.2% and 24.6% respectively. Current smoking was lower, as well (19.7% versus 26.6%, a 20.2% drop; P < 0.001). The relative reduction for estimated cardiovascular risk (RRR) from baseline in the intervention group was 21% (absolute RR, –5.37; 95% CI –6.56 to –4.17; P < 0.001). Risk remained constant in the usual care group. BP changes in the intervention group were –9.37 mm Hg/–2.92 mm Hg (P < 0.001); LDL-C was lowered by 0.2 mmol/L (P = 0.001) and HbA1c was reduced by 0.92% (P < 0.001).
Dr. Tsuyuki concluded, “A community pharmacist case-finding and intervention program reduced the estimated risk for cardiovascular events by 21% in only three months through improvements in all major risk factors. This provides a new paradigm for community-based cardiovascular risk reduction that is complementary to and in collaboration with physician care.”
Dr. Tsuyuki cited a few comments from pharmacists on their reactions to participating in the study. One wrote: “It was very interesting and exciting to be part of a study where you can feel like you’re making a difference for your patients.”