1. Navigating Conflicting Recommendations: Hypertension and Dyslipidemia
Liza Wilson, PharmD, BCACP
Assistant Professor
University of Colorado Anschutz Medical Campus

2. Objectives
Compare and contrast evidence-based guidelines with other expert recommendations for hypertension and dyslipidemia management.
Review evidence that is not included in evidence-based guidelines with other expert recommendations for hypertension and dyslipidemia management.
Devise treatment plans for patients presenting with hypertension and/or dyslipidemia.

4. Hypertension

5. Patient Case
65‐year‐old African American man with obesity, hypertension and dyslipidemia. Drinks 2‐3 beers/day, follows no particular diet, 1 ppd smoker (x 40 years), limited exercise. Current medications are: atorvastatin 20 mg daily, hydrochlorothiazide 25 mg daily. BP is 146/82 mm Hg, HR 80 bpm.

7. Goal BP Recommendations
JNC 8 Report
Age < 60 years:
<140/90 mmHg
Age ≥ 60 years:
< 150/90 mmHg
< 140/90 mmHg if diabetes or CKD
ASH/ISH Guidelines
Age < 60 years:
<140/90 mmHg
Age ≥ 80 years:
< 150/90 mmHg
< 140/90 mmHg if diabetes or CKD
Weber MA et al. J Hypertens. 2014;32(1):14‐26. 
James PA et al. JAMA. 2014; 311(5):507‐20

8. Additional BP Goals
American Diabetes Association (ADA) 2017 Standards of Care:
< 140/90 mmHg
< 130/80 mmHg in some patients
Kidney Disease: Improving Global Outcomes (KDIGO) 2012:
≤ 130/80 mmHg in patients with CKD and persistent albuminuria
American Diabetes Association. Diabetes Care 2017;40 (suppl 1):s75‐s87.
KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.

9. Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.
SPRINT Trial
Systolic Blood Pressure Intervention Trial (SPRINT)
Multicenter, randomized, controlled trial including 9,361 patients
Assigned to systolic blood pressure target of < 120 mm Hg (intensive) or < 140 mm Hg (standard)
Primary composite outcomes:
Myocardial infarction
Other acute coronary syndromes
Stroke
Heart failure
Death from CV causes
Subgroups: CKD, CVD, elderly (≥ 75 years)
Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.

10. SPRINT Inclusion Criteria
Age > 50 years
Systolic blood pressure of 130 – 180 mm Hg
Increased risk of CV disease
Clinical or subclinical cardiovascular disease (other than stroke)
Chronic kidney disease with eGFR of 20 to < 60 ml/min/1.73 m2
Framingham risk score of >15%
Age > 75 years
Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.

11. SPRINT Exclusion Criteria
Secondary hypertension
Diabetes mellitus
Previous stroke
CV event within 3 months
Symptomatic heart failure within 6 mo or EF < 35%
Proteinuria (> 1g/day), polycystic kidney disease, glomerulonephritis, eGFR < 20 ml/min/1.73 m2, or end stage renal disease
Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.

12. Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.
SPRINT Protocol
Medications
First line: ACEi/ARB, CCB, thiazide diuretic; beta-blocker in CHD
Chlorthalidone encouraged as thiazide diuretic
Amlodipine preferred CCB
Medication titration
Average of 3 office BP measurements (at 1 minute intervals) in the seated position using an automated device after a 5 minute rest period alone
BP measured 1 minute after standing at screening, baseline, 1 mo., 6 mo., 12 mo., and annually thereafter
Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.

13. SPRINT Patient Characteristics
Intensive
Standard
Baseline Characteristics
Mean SBP (mm Hg)
Women (%)
Mean age (yr)
Age ≥ 75 (%)
CKD (%)
Black
Hispanic
139.7
36.0
67.9
28.2
28.5
29.5
10.8
35.2
28.1
30.4
10.3
Results:
Mean SBP at 1 year (mm Hg)
Mean no. BP medications
121.4
2.8
136.2
1.8
Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.

14. Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.
SPRINT Results
Cumulative Hazard
Years
319 Events
243 Events
Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.

15. Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.
SPRINT Results
Outcome
Intensive
N = 4678; no.(%)
Standard
N = 4683; no.(%)
Hazard Ration
(p value)
NNT
Primary Outcome
243 (5.2)
319 (6.8)
0.75 (<0.001) 61
Secondary Outcomes
Myocardial infarction
97 (2.1)
116 (2.5)
0.83 (0.19) -
ACS
40 (0.9)
1.00 (0.99)
Stroke
62 (1.3)
70 (1.5)
0.89 (0.50)
Heart Failure
63 (1.3)
100 (2.1)
0.62 (0.002)
123
Death from CV causes
37 (0.8)
65 (1.4)
0.57 (0.005)
172
Death from any cause
155 (3.3)
210 (4.5)
0.73 (0.003) 90
Primary outcome or death
332 (7.1)
423 (9.0)
0.78 (<0.001) 52
Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.

16. SPRINT Safety Outcomes
Intensive
N = 4678; no.(%)
Standard
N = 4683; no.(%)
Hazard Ration
(p value)
NNH
Serious Adverse Event (SAE)
1793 (38.3)
1736 (37.1)
1.04 (0.25) -
Individual SAEs
Hypotension
110 (2.4)
66 (1.4)
1.67 (0.001)
100
Syncope
107 (2.3)
80 (1.7)
1.33 (0.05)
Bradycardia
87 (1.9)
73 (1.6)
1.19 (0.28)
Electrolyte abnormality
144 (3.1)
1.35 (0.02)
125
Injurious fall
105 (2.2)
110 (2.3)
0.95 (0.71)
AKI or acute renal failure
191 (4.3)
117 (2.5)
1.66 (<0.001) 56
Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.

17. Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.
Author Conclusions
Among patients at high risk for cardiovascular events but without diabetes, a systolic blood pressure of < 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause
There are significantly higher rates of some adverse in the intensive-treatment group
– SPRINT provides robust evidence that treating to lower BP goals (SBP < 120 mm Hg) is better than standard BP goals (SBP < 120) is better than standard BP goals (SBP
Sprint Research Group. N Engl J Med. 2015;373(22):2103‐2106.

18. What About Older Patients?
SPRINT-Senior
Subgroup analysis
2,636 patients ≥ 75 years
Included measures of functional status and frailty
Additional exclusion criteria:
Dementia
Expected survival < 3 years
Unintentional weight loss
SBP <110 mmHg after 1 minute of standing
Nursing home residents
Objective: Evaluate effects of intensive compared with standard SBP in persons ≥75 yr with HTN • Setting: Pre‐planned subgroup analysis of SPRINT participants • Patients: – Intensive group: N=1317 – Standard group: N=1319 • Outcomes: – Primary: composite of MI, ACS not resulting in MI, nonfatal stroke, nonfatal acute decompensated HF, death from CV causes – Secondary: All‐cause mortality
Williamson JD, et al. JAMA. 2016;315(24):2673‐82. doi: /jama

19. SPRINT-Senior Results
Significant reductions in:
CVD (↓ 33%; NNT = 27)
Heart failure (↓ 37%; NNT = 67)
All cause mortality (↓ 32%; NNT = 41)
Primary outcome or death (↓ 31%; NNT = 22)
Exploratory analysis showed consistent benefits in frail and reduced gait speed
Serious adverse events comparable, including by frailty level
Greater benefit estimates in seniors due to greater risk and higher event rates
Williamson JD, et al. JAMA. 2016;315(24):2673‐82. doi: /jama

20. SPRINT Criticism
Many exclustions
*diabetes
Method of BP measurement

21. What does this mean?
Serious concerns about higher BP goals for elderly advocated in current guidelines
Lower goals may be appropriate in patients at increased risk of CVD
ACC/AHA set to release Hypertension guidelines in 2017
Revised (lower) blood pressure goals likely

22. Patient Case
65‐year‐old African American man with obesity, hypertension and dyslipidemia. Drinks 2‐3 beers/day, follows no particular diet, 1 ppd smoker (x 40 years), limited exercise. Current medications are: atorvastatin 20 mg daily, hydrochlorothiazide 25 mg daily. BP is 146/82 mm Hg, HR 80 bpm.

24. Dyslipidemia

25. Patient Case
54-year-old man with a past medical history of dyslipidemia and hypertension. Six weeks ago, presented to the emergency room with a chief complaint of chest pain that radiated to the jaw, and he was diagnosed with chronic stable angina. He was also started on atorvastatin 80 mg daily at that time.
Meds:
metoprolol succinate 100 mg po daily
nitroglycerin 0.4 mg SL prn
aspirin 81 mg po daily
atorvastatin 80 mg po daily
Vital Signs: BP = 136/86; HR = 82 beats/min; Wt = 230 lbs; ht = 75
Lipid Panel (mg/dL): TC = 175; HDL-C = 35; TG = 150; LDL-C = 110
Diet:  cholesterol/fat diet
Exercise: Very little
SHx: non-smoker; social ethanol use infrequently

27. ACC/AHA Cholesterol Guidelines
≥7.5% estimated
10-y ASCVD risk Age yr
Clinical ASCVD
LDL-C
≥190 mg/dL
Diabetes
Type 1 or 2
Age yr
Moderate-to-High Intensity Statin
High-intensity statin
Moderate-intensity statin
High-intensity statin if 10-y ASCVD risk ≥7.5%
High-intensity statin if age ≤75 yr
Moderate-intensity statin if age >75 yr or not candidate for high-intensity
Stone NJ et al. Circulation. 2014; 129(25 suppl 2):S1-45.

28. Statin Intensities High Intensity Moderate Intensity Low Intensity
Daily dose lowers LDL–C on average, by ~ ≥ 50%
Daily dose lowers LDL–C on average, by ~ 30 to < 50%
Daily dose lowers LDL–C on average, by < 30%
Atorvastatin 40–80 mg Rosuvastatin mg
Atorvastatin mg Rosuvastatin 5-10 mg Simvastatin 20–40 mg Pravastatin mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2–4 mg
Simvastatin 10 mg Pravastatin 10–20 mg Lovastatin 20 mg Fluvastatin 20–40 mg Pitavastatin 1 mg

29. 2016 ACC Expert Consensus Decision Pathway (EDCP): Role of Non-statin Therapies
Statin therapy as the initial approach
For patients in one of the four 2013 ACC/AHA statin benefit groups
Maximize statin therapy if needed
Evaluate LDL‐C to determine need for non‐statin therapy
Absolute LDL‐C value on therapy or % LDL‐C reduction from baseline as the “threshold” to considering addition of a non‐statin
Non‐HDL‐C may be a consideration for patients with diabetes mellitus
Lloyd-Jones DM, et al. J Am Coll Cardiol doi: /j.jack

30. 2016 ACC ECDP: Stable Clinical ASCVD with Comorbidities
Optional non-statin
medications to consider
≥ 50% LDL-C reduction (may consider LDL-C <70 mg/dL) on maximally tolerated statin
CLINICAN-PATIENT DISCUSSION REGARDING TREATMENT FACTORS
Consider ezetimibe first
(consider bile acid sequestrant if ezetimibe intolerant and triglycerides <300 mg/dL)
Consider adding or replacing with PCSK9 inhibitor second
≥ 50% LDL-C reduction (may consider LDL-C <70 mg/dL or
non-HDL-C <100 mg/dL in diabetes) on maximally tolerated statin
Continue to monitor adherence, treatment, LDL-C response
Yes No
Decision for no additional medication 1 2
Comorbidities are defined as diabetes, recent (< 3mo) ASCVD event, ASCVD event while already taking a statin, baseline LDL-C >190 mg/dL not due to secondary causes, poorly controlled other major ASCVD risk factors, elevated lipoprotein (a) or CKD
Lloyd-Jones DM, et al. J Am Coll Cardiol doi: /j.jack

31. 2016 ACC ECDP: Stable Clinical ASCVD without Comorbidities
Optional non-statin
medications to consider
≥ 50% LDL-C reduction (may consider LDL-C <100 mg/dL) on maximally tolerated statin
CLINICAN-PATIENT DISCUSSION REGARDING TREATMENT FACTORS
Consider ezetimibe first
(consider bile acid sequestrant if ezetimibe intolerant and triglycerides <300 mg/dL)
Consider adding or replacing with PCSK9 inhibitor second
≥ 50% LDL-C reduction (may consider LDL-C <100 mg/dL or
non-HDL-C <100 mg/dL in diabetes) on maximally tolerated statin
Continue to monitor adherence, treatment, LDL-C response
Yes No
Decision for no additional medication 1 2
Comorbidities are defined as diabetes, recent (< 3mo) ASCVD event, ASCVD event while already taking a statin, baseline LDL-C >190 mg/dL not due to secondary causes, poorly controlled other major ASCVD risk factors, elevated lipoprotein (a) or CKD
Lloyd-Jones DM, et al. J Am Coll Cardiol doi: /j.jack

32. IMPROVE-IT Trial: Ezetimibe
~18,000 patients stabilized post ACS
Randomized to ezetimibe + simvastatin or simvastatin alone over 7 years
LDL range from 50 – 125 mg/dL (mean 95 mg/dL)
Primary composite endpoint: CV death, MI, hospital admission for unstable angina, revascularization or stroke
32.7% event rate in ezetimibe + simva vs. 34.7% in placebo + simva
Lowered LDL by additional 16.7 mg/dL compared to placebo
Canon CP et al. N Engl J Med 2015; 372:

33. LDL degradation and LDL-R recycling PCSK9 mediated LDL-R degradation
PCSK9 inhibitors
Hepatocyte
LDL Receptor (LDL-R)
LDL Particle
Recycling of LDL-R
Endosome
Clarthrin-coated vesicle
LDL degradation and LDL-R recycling
Lysosome
PCSK9 mediated LDL-R degradation
Endocytosis
PCSK9
Lambert G, et al. J Lipid Research 2012; 53:

34. PCSK9 inhibitors Aliroculmab and Evolocumab FDA approval: Dosing
Adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (FH) or clinical ASCVD, who require additional lowering of LDL-C
Evolocumab also approved for homozygous FH
Dosing
Alirocumab (Praluent)
75 – 150 mg sq every 2 weeks
Evolocumab (Repatha)
140 sq every 2 weeks or
420 mg once monthly in homozygous FH patients

35. FOURIER Trial: PCSK9 inhibitors
Multicenter, randomized controlled trial including ~27,500 patients
Assigned to evolocumab or placebo
Primary composite outcomes
Cardiovascular death
Myocardial infarction
Hospitalization for unstable angina, stroke, or coronary revascularization
Key secondary composite outcomes
Stroke
Sabatine MS et al. N Engl J Med May 4;376(18):

36. FOURIER Trial: Inclusion
Age years
History of ASCVD
LDL ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL
Fasting triglycerides ≤ 400 mg/dL
Sabatine MS et al. N Engl J Med May 4;376(18):

37. FOURIER Trial: Exclusion
Heart failure class III or IV, or last known left ventricular ejection fraction < 30%
Uncontrolled hypertension
Uncontrolled or recurrent ventricular tachycardia
Untreated hyperthyroidism or hypothyroidism
Homozygous familial hypercholesterolemia
LDL or plasma apheresis
Sabatine MS et al. N Engl J Med May 4;376(18):

38. FOURIER Trial: Protocol
Optimize statin therapy
Atorvastatin ≥ 20 mg or equivalent
± ezetimibe
Intervention
Evolocumab
140 sq every 2 weeks or
420 mg once monthly
Placebo
Every 2 weeks or
Monthly
Intended follow-up 4-5 years (median = 2.2 years)
Sabatine MS et al. N Engl J Med May 4;376(18):

39. FOURIER Trial: Patient Characteristics
Evolocumab
Placebo
Baseline Characteristics
LDL (mg/dL)
HDL (mg/dL)
Mean Age
Statin Use - no. (%)
High intensity
Moderate intensity
Ezetimibe Use – no. (%) 92 44
62.5
9,585 (69.5)
4,161 (30.2)
726 (5.3)
9,518 (69.1)
4,231 (30.7)
714 (5.2)
Lipid Results:
Achieved LDL (% of patients)
≤ 70 mg/dL
≤ 40 mg/dL
≤ 25% 87 67 42 18
0.5
<0.1
Sabatine MS et al. N Engl J Med May 4;376(18):

40. FOURIER Trial: Results
2 year results
Significant reduction in primary (15%) and key secondary (20%) endpoints
NNT at 2 years = 76
Primary Endpoint
Key Secondary Endpoints
Cumulative Incidence (%)
Cumulative Incidence (%)
if follow-up is extended to 36 months, the NNT to prevent one cardiovascular death, MI, or stroke is closer to 50. Extrapolated to 5 years, which is the duration of the major clinical trials testing statins, the NNT to prevent one event is approximately 30. Cost-effectiveness analyses are underway, he added.
Months
Months
Sabatine MS et al. N Engl J Med May 4;376(18):

41. FOURIER: Safety Outcomes
No significant between-group differences:
Overall rates of adverse events
Serious adverse events
Adverse events thought to be related to the study agent and leading to discontinuation of the study regimen
Muscle related events, neurocognitive effects, cataracts
Aminotransferase/CK
Significant difference in injection site reactions
evolocumab (2.1%) compared to placebo (1.6%)
Sabatine MS et al. N Engl J Med May 4;376(18):

42. FOURIER: Author Conclusions
Patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.
Sabatine MS et al. N Engl J Med May 4;376(18):

43. PCSK9 inhibitor Criticism
Cost
~ $1100/month
How low can we go (LDL)

44. What does this mean?
ACC Statement: ECDP will be updated in response to FOURIER Trial
Likely making stronger statements for PCSK9 inhibitors
Likely returning to goals

45. Patient Case
54-year-old man with a past medical history of dyslipidemia and hypertension. Six weeks ago, presented to the emergency room with a chief complaint of chest pain that radiated to the jaw, and he was diagnosed with chronic stable angina. He was also started on atorvastatin 80 mg daily at that time.
Meds:
metoprolol succinate 100 mg po daily
nitroglycerin 0.4 mg SL prn
aspirin 81 mg po daily
atorvastatin 80 mg po daily
Vital Signs: BP = 136/86; HR = 82 beats/min; Wt = 230 lbs; ht = 75
Lipid Panel (mg/dL): TC = 175; HDL-C = 35; TG = 150; LDL-C = 110
Diet:  cholesterol/fat diet
Exercise: Very little
SHx: non-smoker; social ethanol use infrequently

47. Navigating Conflicting Recommendations: Hypertension and Dyslipidemia
Liza Wilson, PharmD, BCACP
Assistant Professor
University of Colorado Anschutz Medical Campus