Pharmacotherapy the CVD Patient - CEConsultants,...

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Pharmacotherapy &

the CVD Patient

Joel C. Marrs, Pharm.D., FNLA, BCPS (AQ Cardiology), CLS Assistant Professor

University of Colorado Skaggs School of Pharmacy and PharmaceuFcal Sciences

Clinical Pharmacy Specialist Denver Health Medical Center

Disclosure

Joel C. Marrs Reports no relevant financial relationships

Learning Objectives

  Describe clinical controversies related to the treatment of hypertension and dyslipidemia.

  Review current guidelines for the management of hypertension and dyslipidemia in the metabolic syndrome patient.

  Identify how clinical trials evidence may drive potential changes to come in the JNC 8 and NCEP ATP IV guidelines.

  Evaluate the safety and efficacy of pharmacologic treatment of hypertension and dyslipidemia

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Brunzell JD et al. Diabetes Care. 2008; 31:811-‐22.

↑Lipids ↑BP ↑Glucose

Smoking, Physical Inactivity, Unhealthy Eating

Hypertension Inflammation, Hypercoagulation

Age, Race, Gender, Family History

Overweight/Obesity

Abnormal Lipid Metabolism

•  LDL-C ↑ •  ApoB ↑ •  HDL-C ↓ • Triglycerides ↑

Age Genetics

Hypertension – Guidelines

  2003: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7). JAMA. 2003; 289:2560-71.

  2008: AHA Scientific Statement: Resistant Hypertension: Diagnosis, Evaluation, and Treatment. Circulation. 2008;117:e510-e526.

  2011: ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly. JACC. 2011; 57:2037-114.

  2013: JNC-8 (public comment period and official release?)

JNC 7 Goal

Primary Goal: ↓ CV morbidity & mortality

Blood Pressure Goals:   <140/90 mm Hg for most patients   <130/80 mm Hg for Diabetes or CKD

Chobanian AV, et al. Hypertension. 2003;42:1206–1252

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2013 ADA Standards of Care

“People with diabetes and hypertension should be treated to a systolic blood pressure goal of <140 mmHg.” (B)

“Lower systolic targets, such as <130 mmHg, may be appropriate for certain individuals, such as younger paTents, if it can be achieved without undue treatment burden.” (C)

“PaTents with diabetes should be treated to a DBP of <80 mmHg.” (B)

Diabetes Care. 2013 Jan;36 Suppl 1:S11-‐66.

Hypertension Landmark Clinical Trials (Published since JNC 7)

  ACCOMPLISH •  Benazepril + amlodipine vs benazepril + Hydrochlorothiazide

  ACCORD Blood Pressure Study •  SBP < 120 mm Hg vs < 140 mm Hg in DM patients

  ASCOT BPLA •  Amlodipine + ACE-Inhibitor vs atenolol + thiazide •  Subanalysis of resistant HTN patients

  HYVET •  Indapamide + ACE-Inhibitor in patients > 80 years old

  ONTARGET •  Ramipril vs telmisartan vs the combination

  VALUE •  Amlodipine vs valsartan

Effects of Intensive Blood Pressure Control on Cardiovascular Events in

Type 2 Diabetes Mellitus: The Action to Control Cardiovascular Risk in Diabetes

(ACCORD) trial

  Randomized, double-blind, controlled trial •  Glucose control: stopped early •  Blood pressure: Goal 140 mmHg vs. 120 mmHg •  Lipid: statin + fenofibrate or statin alone

  1° endpoint: Nonfatal MI, nonfatal stroke, or CV death

Cushman WC, et al. N Eng J Med. 2010;362:1575–85.

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ACCORD Design

Intensive Glycemic Control 5128

Standard Glycemic Control 5123

Lipid BP

Placebo Fibrate Intensive Standard

2371 2362 2753 2765

1383 1374

1391 1370

1193

1178 1184

1178

10,251

4733* 5518 * 94% power for 20% reducTon in event rate, assuming standard group rate of 4% / yr and 5.6 yrs follow-‐up.


Systolic Pressures

Average a9er 1st year: 133.5 Standard vs. 119.3 Intensive, 14.2

Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3


Primary & Secondary Outcomes

Intensive Events (%/yr)

Standard Events (%/yr)

HR (95% CI) P

Primary 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20

Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55

Cardiovascular Deaths

60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74

Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25

Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03

Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01

Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the primary outcome, revascularizaUon and unstable angina (HR=0.95, p=0.40)


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Resistant Hypertension

  American Heart Association (AHA) Definition: •  “Blood pressure that remains above goal in spite

of the concurrent use of 3 antihypertensive agents of different classes. Ideally, one of the 3 agents should be a diuretic and all agents should be prescribed at optimal dose amounts.”

•  Also refers to BP controlled with > 4 medications

Calhoun DA, et al. Hypertension. 2008;51:1403-‐19.

Treatment Approaches   Optimize Diuretic Therapy   Add Aldosterone Antagonist Therapy   Optimize Combination Therapy   Alternative Add-on Therapy

Hypertension. 2008;51:1403-‐19.

Classification of Adults with HTN in the United States (NHANES 2003-2008)

ClassificaTon N All HTN

% (SE) Drug treated HTN

% (SE)

Uncontrolled and not treatment

1520 30.7 (1.2)

Controlled on < 3 anThypertensives

2035 40.8 (1.1) 58.9 (1.2)

Uncontrolled on < 2 anThypertensives

1136 19.6 (0.8) 28.3 (1.1)

Resistant HTN 539 8.9 (0.6) 12.8 (0.9)

Resistant HTN = uncontrolled on > 3 anThypertensives or on > 4 anThypertensives

Persell SD. Hypertension. 2011; 57:1076-‐80.

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HCTZ vs Chlorthalidone (meta-analysis)

Ernest ME, et al. Am J Hypertens. 2010; 23:440-‐6.

Change in SBP* (± SD)

Change in K** (± SD)

Dose Range (mg/day) HCTZ CHL HCTZ CHL

12.5 < 25 -14 (4.1) -24 (6.7)† -0.24 (0.09) -0.39 (0.07)†

25 < 37.5 -16 (4.7) -26 (0.0)† -0.50 (0.35) -0.50 (0.00)

37.5 < 60 -18 (5.8) -20 (6.6)† -0.43 (0.16) -0.60 (0.19)†

*Values reported in mmHg; ** Values reported in mEq/L; SBP = systolic blood pressure; K = serum potassium; HCTZ = hydrochlorothiazide; CHL = chlorthalidone † p < 0.05 for comparison of HCTZ vs chlorthalidone

Aldosterone Antagonists in Patients with Resistant Hypertension

  Spironolactone •  5 prospective trials (2 RCT; 3 OL) •  1 retrospective study

  Spironolactone vs Eplerenone •  1 prospective trial (RCT) in primary aldosteronism and

HTN   Eplerenone

•  1 prospective trials (OL)   Amiloride (1 RCT)

•  Amiloride vs Spironolactone vs Combination J Hypertens. 2011;29:980–90. Hypertension. 2005;48:481-‐7. Ann Pharmacother. 2010;44:1762-‐9. J Am Soc Hypertens. 2010;4:290-‐4. J Am Soc Hypertens. 2008;2:463-‐8.

Spironolactone Trials Trial Design Dose* (mean) Δ in SBP† Δ in DBP†

Nishizaka, et al (2003)

OL, UC, 6 mo (n = 76)

12.5-‐50 (30.8) -‐25.0 (2.3) -‐12.0 (1.4)

Chapman, et al (2007)

R,O, 1.3 yrs (n = 1411)

25-‐50 (45) -‐21.9 (0.6) -‐9.5 (0.4)

Lane, et al (2007)

OL, O, 3 mo (n = 119)

25-‐100 (median 25)

-‐21.7 (2.2) -‐8.5 (1.4)

De Souza, et al (2010)

OL, O,12 mo (n = 175)

25-‐100 (median 50)

-‐16.0 (14) -‐9.0 (9)

Engback, et al (2010)

RET, UC, 6 mo (n = 296)

25-‐50 (37.1) -‐25.5 (2.7) -‐10.5 (1.5)

Vaclavick, et al (2011)

R, DB, PC, 2 mo (n = 117)

25 (25) -‐13.8 (11.8)## -‐4.2 (7.0)##

OL = open label, UC = uncontrolled; R = randomized; O = observaTonal; RET = retrospecTve; DB = double-‐blind; PC = placebo controlled; * values reported in mg; † values reported in mmHg; ## 24 hour ambulatory blood pressure monitor (ABPM) values

Václavík J, et al. Hypertension. 2011;57:1069-‐75. Marrs JC. Ann Pharmacother. 2010;44:1762-‐9. Engbaek M, et al. J Am Soc Hypertens. 2010;4:290-‐4.

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Does it matter what time of day patients take their antihypertensive medication?

MAPEC Study

  Trial Design •  Prospective, randomized,

placebo-controlled trial   Study Arms:

•  All BP medications in AM •  At least 1 BP medications

in PM   Eligible patients:

•  Type 2 Diabetes and HTN   Primary Endpoint (5.4 yrs):

•  Total cardiovascular events

P < 0.001

10.6%

29.3%

Hermida RC, et al. Diabetes Care. 2011; 34:1270-‐6

N = 448

2013 ADA Standards of Care

•  Administer one or more anThypertensive medicaTons at bedTme. (A)

•  MulTple anThypertensive medicaTons (two or more agents at maximal doses) is generally required to achieve blood pressure targets. (B)


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Dyslipidemia – Guidelines

  2001: National Cholesterol Education Panel (NCEP) Adult Treatment Panel III (ATP III). JAMA. 2001; 285:2486-97.

  2004: NCEP ATP III implications. Grundy SM et al. Circulation. 2004; 110:227-39.

  2008: ADA/ACCF Consensus Statement on Lipoprotein Management in Patients With Cardiometabolic Risk. Diabetes Care 2008;31: 811-22.

  2012: AACE Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract. 2012;18(Suppl 1).

  2013: NCEP ATP IV (Public comment period and official release?)

CVD or Diabetes

High Risk <100 mg/dL, <70 mg/dL is opTonal if Very High Risk

Yes

Lower Risk <160 mg/dL

Moderate Risk

<130 mg/dL

High Risk <100 mg/dL

No ≥2 major CV risk factors*

10-‐20% <10%

No Yes

NCEP ATP III: LDL-C Goal Values

Moderately High Risk

<130 mg/dL, <100 mg/dL is opTonal

>20%

*Major risk factors: Age (≥45yrs men, ≥55yrs women), hypertension, smoking, family history of premature CHD, HDL-C <40 mg/dL

10-‐year CHD risk: Framingham Score

Grundy SM et al. Circulation. 2004; 110:227-39.

Diabetes Care 2008;32:811-22.

Goals LDL-‐C (mg/dL)

Non-‐HDl-‐C (mg/dL)

ApoB (mg/dL)

Very High Risk < 70 < 100 < 80

Established CVD

DM and > 1 major CVD RF’s*

High Risk < 100 < 130 < 90

Established CVD and > 2 major CVD RF’s*

DM and no major CVD RF’s* * Includes dyslipidemia, smoking, hypertension, and family history of premature CAD

Lipoprotein Management in PaFents with Cardiometabolic Risk

Consensus Statement American Diabetes AssociaTon and the American College of Cardiology FoundaTon

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AACE LDL-C Treatment Goals

Risk Category PaFent populaFon LDL-‐C (mg/dL)

Very High Risk Established or recent hospitalizaTon for coronary, caroTd, or peripheral

vascular disease

< 70

Diabetes with > 1 addiTonal risk factor

High Risk > 2 major risk factors and FRS> 20% < 100

CHD risk equivalent

Moderately High Risk > 2 major risk factors and FRS 10-‐20% < 130

Moderate Risk > 2 major risk factors and FRS < 10% < 130

Low Risk < 1 risk factor < 160

FRS = 10 year Framingham risk score; CHD risk equivalent = diabetes, peripheral artery disease, abdominal aorTc aneurysm, and caroTd artery disease

American AssociaTon of Clinical Endocrinologists (AACE)

Endocr Pract. 2012;18(Suppl 1).

2013 ADA Standards of Care •  LDL-‐C goal < 100 mg/dL without CVD (B) and LDL-‐C < 70 mg/dL

with CVD (B) •  StaTn therapy should be added to lifestyle therapy, regardless of

baseline lipid levels, for diabeTc paTents with overt CVD, or without CVD if >40 yrs with ≥ 1 other CVD risk factors. (A)

•  If targets not reached on maximal tolerated staTn therapy, a reducTon in LDL-‐C of 30-‐40% from baseline is an alternaTve. (B)

•  Triglycerides <150 mg/dL and HDL-‐C >40 mg/dL in men and >50 mg/dL in women, are desirable (C); However, LDL-‐C–targeted staTn therapy remains the preferred strategy (A)

•  CombinaTon therapy has been shown not to provide addiTonal cardiovascular benefit above staTn therapy alone and is not generally recommended. (A)


Evolution of NHLBI Supported Guidelines

NCEP ATP I 1988

NCEP ATP II 1993

NCEP ATP III 2001

NCEP ATP III 2004 Update

NCEP ATP IV

2013?

AHA/ACC 2° PrevenTon Guidelines

2006

AHA/ACCF 2° PrevenTon Guidelines

Update 2011*

Framingham MRFIT

LCR-‐CPPT CDP

Helsinki Heart CLAS

Angiographic Trials (FATS, POSCH, SCOR, STARS, Ornish,

MARS) Meta-‐analyses

4S WOSCOPS CARE LIPID

AFCAPS/ TexCAPS

HPS PROVE-‐IT ASCOT-‐LLA PROSPER ALLHAT-‐LLT

TNT IDEAL

CTT meta-‐analysis

NHLBI = NaTonal Heart, Lung, and Blood InsTtute NCEP ATP = NaTonal Cholesterol EducaTon Panel Adult Treatment Panel AHA = American Heart AssociaTon ACC = American College of Cardiology ACCF = American College of Cardiology FoundaTon

*The wriFng commifee anFcipates that the recommendaFons will be reviewed when the updated ATP IV guidelines are released.

SPARCL JUPITER

ACCORD Lipid SHARP

AIM-‐HIGH

More Intensive Treatment RecommendaFons

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Dyslipidemia Landmark Clinical Trials (Published since NCEP ATP III)

  SPARCL •  High dose atorvastatin post stroke/TIA

  TNT •  High vs low dose atorvastatin in stable ischemic heart disease

  ACCORD Lipid •  Simvastatin + fenofibrate or placebo in T2DM

  JUPITER •  Rosuvastatin in patients with LDL-C <130 mg/dL and hsCRP >2 mg/

dL   AIM-HIGH

•  Simvastatin + niacin ER or placebo in established CVD   SHARP

•  Simvastatin + ezetimibe in CKD (1/3 dialysis and 2/3 pre-dialysis)

ACCORD Study: Combination Lipid Therapy

  5518 patients with type 2 diabetes treated with open-label simvastatin randomized to fenofibrate or placebo for 4.7 yr

  Primary outcome: nonfatal MI, nonfatal stroke, or CV death

Ginsberg HN, et al. N Engl J Med. 2010; 362:1563-1574.

Baseline End of Study

Fenofibrate Placebo LDL-‐C (mg/dL) 100.6 81.1 80.0

HDL-‐C (mg/dL) 38.1 41.2 40.5

Triglycerides (mg/dL) 162 122 144

ACCORD Study: Results

2.4 2.2

0

1

2

3

4

Placebo Fenofibrate

Ann

ual R

ate of Primary En

dpoint (%

)   Subgroup analyses: •  Possible benefit for

men and possible harm for women

•  Possible benefit in patients with both high baseline triglycerides (≥204) and a low baseline HDL-C (≤34) •  P=0.057 for interaction

P=0.32

Ginsberg HN, et al. N Engl J Med. 2010; 362:1563-1574.

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Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH)

  Double-blind trial in 3414 patients with a history of CVD treated with statin therapy to an LDL-C of 40-80 mg/dL

  Randomized to placebo or extended-release niacin (1500-2000 mg daily)

  Primary endpoint: Composite CV events   Clinical trial was stopped at 3 years, 18 months earlier

than planned

Boden WE, et al. N Engl J Med 2011;365:2255-‐67.

AIM-HIGH: Results

  Incidence of Primary Endpoint •  Statin plus placebo: 16.2% •  Statin plus niacin: 16.4% p=0.80

Baseline

At Year 3

Niacin Placebo LDL-‐C (mg/dL) 75.8 65.2 68.3

HDL-‐C (mg/dL) 35.3 44.1 39.1

Triglycerides (mg/dL) 162 120 152

Boden WE, et al. N Engl J Med 2011;365:2255-‐67.

FDA Statin Safety Updates

  New labeling to statins per (February 2012) FDA Safety announcement

•  “Increases in HgbA1C and fasting serum glucose have been reported with statin therapy”

•  “Healthcare professionals should perform liver enzyme tests before initiating statin therapy in patients and as clinically indicated thereafter”

•  “Rare post-marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use

FDA Drug Safety CommunicaTon: Important safety label changes to cholesterol-‐lowering staTn drugs. February 28, 2012. htp://www.fda.gov/Drugs/DrugSafety/ucm293101.htm#data

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Statin and Risk of Diabetes

  2010 meta-analysis of 13 trials (n=91,140) •  4,278 developed diabetes (2,226 with statins vs. 2,052 with

control) over a mean 4 yrs •  9% increased risk (p<0.05) •  NNH was 255 patients

  2011 meta-analysis of 5 trials (n=32,752) •  2,749 developed diabetes (1,449 with intensive-dose statin vs.

1,300 with moderate-dose statin) over a mean 1.9 yrs •  12% increased risk (p<0.05) •  NNH was 498; but, NNT for CV events was 155

Sattar N, et al. Lancet 2010; 375: 735–42. Priess D, et al. JAMA. 2011;305(24):2556-2564.

Benefits and Diabetes Risk in JUPITER

  17,603 patients, randomized to placebo or rosuvastatin 20 mg for up to 5 years •  Stratified based on presence of major risk factors for developing

diabetes*

Ridker PM, et al. Lancet 2012; 380: 565–71.

# of Diabetes Risk Factors*

Placebo vs. Rosuvastatin # Primary CV Endpoints # New Diabetes Cases

0 (n=6,095)

91 vs. 44 (p<0.0001) 12 vs. 12 (p=0.99) 86 primary events avoided with no new cases of diabetes

≥ 1 (n=11,508)

157 vs. 96 (p<0.0001) 204 vs. 258 (p=0.01) 134 primary events avoided for every 54 new cases of diabetes

*BMI ≥30 kg/m², metabolic syndrome, impaired fasting glucose, glycated haemoglobin A1c ≥6%

Key Concepts

  Targeting a systolic blood pressure of less than 140 mm Hg in patients with diabetes is appropriate based on recent clinical trials and guideline updates

  Optimal pharmacotherapy for resistant hypertension should include assuring appropriate diuretic therapy, aldosterone antagonist use and appropriate use of combination therapy

  Statin therapy in combination with a fibrate or niacin can improve mixed dyslipidemia, but are not proven to reduce risk of cardiovascular events

  Statin therapy has been shown to increase the risk of diabetes, but cardiovascular benefits of statins outweigh the small increased glycemic risk

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HPI: BR is a 45 year old male who is presenTng to clinic for a follow-‐up on his hypertension and cholesterol he had checked last week. He has been on simvastaTn 40 mg daily for the last 3 months. He hopes his cholesterol is beter today so he can stop taking the simvastaTn PMH: Hypertension (x 6 years)

Gout (x 2 years) Diabetes mellitus (x 2 years) Dyslipidemia (diagnosed 3 months ago)

Social Hx: (+) tobacco 1 ppd smoker x 15 years; (+) ETOH (1-‐2 beers daily); low fat/cholesterol and low sodium diet, exercises 3 Tmes a week (staTonary bike)

Vignette

Vignette Current medications include: Metoprolol succinate 50 mg po daily Allopurinol 200 mg po daily Simvastatin 40mg po qhs (started 3 months ago) Lisinopril 40 mg po daily Amlodipine 10 mg po daily Aspirin 81 mg po daily Metformin 1000 mg po twice daily

Medication allergies: Sulfa-hives

Vignette Vitals today at clinic are as follows:

BP 140/88 mmHg and 138/86 mmHg, HR 62, RR 22, BMI 28 kg/m2; waist circumference 39 inches

Labs from 1 week ago: SCr = 1.2 mg/dL; K+ = 4.2 mEq/L; A1C = 7.6%

TC = 150 mg/dL; LDL-C = 84 mg/dL; HDL-C = 36 mg/dL; TG = 150 mg/dL

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QuesTon 1

  Which of the following recommendaTons is most appropriate to manage his hypertension?

Add spironolactone 12.5 mg daily

Change metoprolol 50 mg daily to carvediolol 12.5 mg twice daily

Change HCTZ 25 mg daily to chlorthalidone 25 mg daily

ConTnue present anThypertensive regimen unchanged

B

A

D

C

QuesTon 2

  Which of the following recommendaTons is most appropriate to manage his dyslipidemia ?

ConTnue SimvastaTn 40 mg daily

Change simvastaTn to atorvastaTn 40 mg daily

ConTnue simvastaTn and add niacin ER 1 gram daily

ConTnue simvastaTn and add fenofibrate 145 mg daily

B

A

D

C

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