# Presentation: 337905

## Preventive Cardiology Pharmacotherapy Update

**Joseph J. Saseen, Pharm.D., FCCP, BCPS**
- Associate Professor
- Clinical Pharmacy and Family Medicine
- University of Colorado Health Sciences Center
- joseph.saseen@uchsc.edu

## Objectives

- Compare and contrast recent evidence evaluating hypertension pharmacotherapy, and dyslipidemia pharmacotherapy with contemporary consensus guidelines
- Describe antihypertensive classes that have proven benefits in reducing CV events
- Identify the benefit of intensive LDL lowering in patients with diabetes and/or established CHD

## Cardiovascular Disease (CVD) in the U.S. (1999-2000)

***American Heart Association. Heart Disease and Stroke Statistics — 2005 Update. ***

## 2004 Top Prescribed Drugs (#)

- Hydrocodone/APAP 92,719,975
- Lipitor 		69,766,431
- Lisinopril 		46,206,563
- Atenolol 		44,162,229
- Synthroid 		44,056,176
- Amoxicillin 		41,393,538
- HCTZ 		41,345,733
- Zithromax 		37,171,754
- Furosemide 		36,508,251
- Norvasc 		34,729,004

- Toprol XL 		2,794,562
- Alprazolam 		32,404,743
- Albuterol 		31,219,862
- Zoloft 		29,877,707
- Zocor 		27,234,005
- Metformin		25,472,580
- Ibuprofen 		25,188,051
- Triamterene/HCTZ 	24,616,014
- Ambien 		24,494,669
- Cephalexin 		23,665,172

***http://www.rxlist.com/top200.htm***

## Major Cardiovascular Risk Factors

- Age (> 55 for men, 65 for women)
- Hypertension
- Cigarette smoking
- Dyslipidemia
- Diabetes mellitus

- Family history of premature CVD (men <55 or women <65)
- Obesity (BMI >30 kg/m2)
- Physical inactivity
- Microalbuminuria or estimated GFR <60 mL/min

***Hypertension 2003;42:1206.***

## AHA/NHLBI Scientific Statement

**Diagnosis and Management of the Metabolic Syndrome**
**An American Heart Association/National Heart, Lung, and Blood Institute**
**Scientific Statement**
**Executive Summary**

***Circulation. 2005;112:e285-e290***

**AHA/NHLBI Scientific Statement**

## AHA/NHLBI Scientific StatementMetabolic Syndrome Diagnostic Criteria

***Circulation. 2005;112:e285-e290***

| Measure 
(3 of 5 constitutes diagnosis) | Categorical 
Cut Points |
| --- | --- |
| Elevated waist circumference (in) | ≥ 40 (men), ≥ 35 (women) |
| Elevated TGs (mg/dL) |  150 
or drug therapy |
| Reduced HDL-C (mg/dL) | < 40 (men), < 50 (women) or drug therapy |
| Elevated BP (mm Hg) |  130/85 
or drug therapy |
| Elevated fasting glucose (mg/dL) |  100 
or drug therapy |

## Risk for CHD and Diabetes Based on Number of Metabolic Syndrome Criteria

**CHD**

**0**

**Diabetes**

***Circulation 2003;108:414-419***

**1**

**2**

**3**

**4 or 5**

**1**

**Hazard Ratio**

**1.79**

**2.25**

**3.19**

**3.65**

**1**

**2.36**

**4.50**

**7.26**

**24.40**

**0**

**5**

**10**

**15**

**20**

**25**

**No. of  factors:**

## AHA/NHLBI Scientific StatementLifestyle Modifications

***Circulation. 2005;112:e285-e290***

## AHA/NHLBI Scientific Statement

- Components that may be targeted with pharmacotherapy:

***Circulation. 2005;112:e285-e290***

## Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

- Primary Goal:  morbidity and mortality
- Target organ disease
- Heart, brain, kidney, periphery, eyes
- Surrogate Goal: Treat to a target BP
- <140/90 mm Hg for most
- <130/80 mm Hg for Diabetes or Chronic Kidney Disease (CKD)

***Hypertension. 2003;42:1206–1252***

## Antihypertensive Agents

- Primary Agents
- Supported by Outcomes data:
- Diuretics
- ACE Inhibitors
- Angiotensin Receptor Blockers (ARBs)
- Calcium Channel Blockers (CCBs)
- Beta-blockers
- Alternative Agents
- Alpha-blockers, Arterial vasodilators, Centrally acting agents, Reserpine

## Algorithm for Hypertension

**Initial Drug Choices**

**With Compelling ****Indications**

**Without Compelling ****Indications**

***Hypertension. 2003;42:1206–1252***

## Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

- 	**Objective:****	**Compare amlodipine, doxazosin 			and lisinopril to chlorothalidone
- Prospective, double-blind, randomized trial
- 42,448 patients with hypertension for 4 to 9 yrs
- Mean age was 67 yrs
- Atenolol, reserpine, or clonidine allowed as add-on if BP was not controlled, then hydralazine
- Primary Endpoint: nonfatal MI + CHD death

***JAMA 2002;288:2981-97***

## Results

- Primary Endpoint: Nonfatal MI + CHD death
- Secondary Endpoints:

|  | 6-yr event rate (%)  | RR  (95% CI)  |
| --- | --- | --- |
| Chlorthalidone | 11.5  | -- |
| Lisinopril  | 11.4  | 0.99 (0.91-1.08) |
| Amlodipine  | 11.3  | 0.98 (0.90-1.07)  |

***JAMA 2002;288:2981-97***

|  | RR  (95% CI) |  |
| --- | --- | --- |
|  | Heart Failure | Stroke |
| Lisinopril vs Chlorthalidone | 1.38 
(1.25-1.52) | 1.15
(1.02-1.30) |
| Amlodipine vs Chlorthalidone | 1.19 
(1.07-1.31) | 0.93
(0.82-1.06) |

## ASCOT-Blood Pressure Lowering Arm

**	****Objective:****	**Compare atenolol +/-				bendroflumethiazide  vs. 				amlodipine +/- perindopril
- Prospective, double-blind, randomized trial
- 19,257 patients with hypertension and 3 other CV risk factors treated for 5.5 yrs
- Mean age was 63 yrs
- Primary Endpoint: nonfatal MI + CHD death

***Lancet 2005; 366: 895–906***

## ASCOT-Blood Pressure Lowering Arm

***Lancet 2005;366:895–906***

***includes silent MI**

- p=0.11

- p=0.0003

- p=0.007

**0**

**5**

**10**

**15**

**20**

**Primary: Non-fatal MI**

**+ fatal CHD***

**Secondary: All**

**Coronary Events**

**Secondary: Stroke**

- Rate per 1000

**Amlodipine-based**

**Atenolol-based**

## ASCOT-Blood Pressure Lowering Arm

- After multivariate adjustments for BP and other differences (e.g., cholesterol):
- No statistical difference in all coronary events
- No statistical difference in stroke

***Lancet 2005;366:907–13***

|  | Mean SBP (mmHg) | Mean DBP
(mmHg) |
| --- | --- | --- |
| Amlodipine-based | 136.1 | 77.4 |
| Atenolol-based  | 137.7 | 79.2 |

- p<0.0001

- p<0.0001

## Beta-Blockers for “Primary Hypertension”

- In 2004, a meta analysis of 9 atenolol-based clinical trials demonstrated no decrease in  all cause mortality, CV mortality or MI
- In 2005, a newer meta analysis evaluated:
- 13 randomized controlled trials (n=105,951) comparing beta-blockers to other agents
- 7 randomized controlled trials (n=27,433) comparing beta-blockers to placebo

***Lancet 2004;364:1684–1689***
***Lancet 2005;366:1545-1553***

## 2005 Meta Analysis Results

- Authors Interpretation:
- Beta-blockers should not remain first choice in the treatment of primary hypertension

***Lancet 2005;366:1545-1553***

|  | Relative Risk (95% CI) |  |  |
| --- | --- | --- | --- |
|  | Beta-Blocker vs
placebo | Beta-Blocker vs
other agents | Atenolol vs
other agents |
| Stroke | 0.81 (0.71-0.93) | 1.16 (1.04–1.30) | 1.26 (1.15-1.38) |
| MI  | 0.93 (0.83-1.04)  | 1.02 (0.93–1.12) | 1.05 (0.91-1.21) |
| Total Mortality | 0.95 (0.86-1.04) | 1.03 (0.99–1.08) | 1.08 (1.02-1.14) |

## Comparison of Beta-Blockers

|  | Daily Frequency | Half life (hr) | Lipid Solubility | Cardio-selectivity | Alpha Blockade |
| --- | --- | --- | --- | --- | --- |
| Atenolol (generic) | 1-2 | 6-7 | Low | Yes | No |
| Carvedilol (Coreg) | 2 | 6-10 | High | No | Yes |
| Metprolol 
Succinate (Toprol XL) | 1 | n/a | Moderate to High | Yes | No |
| Metoprolol Tartarate
(generic) | 2 | 3-7 | Moderate to High | Yes | No |

## JNC 7: Compelling Indications

- Diuretic with
- ACE Inhibitor

- Beta-Blocker

- ACE Inhibitor or
- ARB

- Diuretic with
- ACE Inhibitor

- ACE Inhibitor or
- ARB

- Beta-Blocker

- ACE Inhibitor or CCB or
- Diuretic

- Diuretic

- ARB or Aldosterone Antagonist

- Aldosterone Antagonist

- Beta-Blocker or
- CCB

***First-line***

***Second-line***

***Third-line***

**Heart**
**Failure**

**Post **
**Myocardial**
**Infarction**

**High**
**Coronary**
**Disease**
**Risk**

**Diabetes**

**Chronic**
**Kidney**
**Disease**

**Recurrent**
**Stroke**
**Prevention**

***Goal BP***

- <140/90 mmHg

- <130/80 mmHg

## Morbidity and Mortality after Stroke (MOSES)

- 1405 patients with cerebrovascular disease
- Randomized to eporsartan or nitredipine regimens for 2.5 yrs
- Primary end point:
- Composite of total mortality and all vascular events
- BP decreases:
- Eprosatan      151/84 to 138/81
- Nitrendipine   152/87 to 136/80

***Stroke 2005;36:1218-1226***

- p=0.014

## NCEP Report:July 2004 Update

**NCEP Report:****July 2004 Update**

## ATP III: 2004 Update

**ATP III: 2004 Update**

| Risk Category | LDL-C Goal (mg/dL)  | Initiate TLC (mg/dL)  | Drug Therapy (mg/dL)  |
| --- | --- | --- | --- |
| High
CHD or equivalents
(10 yr risk > 20%) | < 100 
(Therapeutic 
Option, < 70) | ≥ 100 |  100
(<100: drug optional)  |
| Moderately-High
2+ risk factors 
(10 yr risk 10-20%) | < 130 
(Therapeutic 
Option, < 100)  | ≥ 100 |  130
(100-129: drug optional)  |
| Moderate
2+ risk factors 
(10 yr risk < 10%)  | < 130 | ≥ 130 | ≥ 160 |
| Lower
0 to 1 risk factors  | < 160 | ≥ 160 |  190
(160-189: drug optional)  |

## AHA/NHLBI Scientific Statement:Metabolic Syndrome Goal Values

- Primary target: 		LDL-C goal
- Secondary target: 	Non-HDL-C goal
- Only if LDL-C goal met and if TG ≥ 200 mg/dL
- Always 30 mg/dL higher than LDL-C goal
- Tertiary target: 		HDL-C
- Only after LDL-C and non-HDL-C goals are met
- Raise to extent possible with standard therapy, ≥ 40 mg/dL (men), ≥ 50 mg/dL (women)

***Circulation. 2005;112:e285-e290***

## ATP III: 2004 Update Standard Statin Doses toAttain 30-40% LDL-C Reductions

| Drug | Dose (mg/d) | LDL-C reduction (%) |
| --- | --- | --- |
| Atorvastatin | 10 | 39 |
| Lovastatin | 40 | 31 |
| Pravastatin | 40 | 34 |
| Simvastatin | 20-40 | 35-41 |
| Fluvastatin | 40-80 | 25-35 |
| Rosuvastatin | 5-10 | 39-45 |

***Circulation 2004; 110:227-239***

## Lipid-Lowering Therapies

***JAMA 2001;285:2486.    Zetia [package insert]  Merck-Shering-Plough Pharmaceuticals; 2003. ***
***Crestor [package insert] Astra-Zeneca; 2003***

|  | LDL-C | HDL-C | TG |
| --- | --- | --- | --- |
| Statins 
(atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin) |  18-63% |  5-15% |  7-30% |
| Bile Acid Sequestrants
(colesevelam, cholestyramine, colestipol) |  15-30% |  3-5% | 0 or  |
| Nicotinic  Acid  |  5-25% |  15-35% |  20-50% |
| Fibric Acid Derivatives
(gemfibrozil, fenofibrate) |  5-20 or  |  10-20% |  20-50% |
| Cholesterol Absorption Inhibitor (ezetimibe) |  18% |  1% |  7% |

**Notes:**
NCEP ATP III guidelines recommend therapeutic lifestyle changes (TLC) as an essential component of lipid-lowering.
Diet
Reduced intake of saturated fat (<7% of total calories)
Reduced intake of cholesterol (<200 mg/d)
Use of plant stanols/sterols
Use of soluble fiber
Weight reduction
Increased physical activity
Patients at high risk are likely to require both TLC and pharmacologic therapy.
Statins
Fibrates
Niacin
Bile acid sequestrants
These agents target different aspects of lipid metabolism and have been shown to reduce the risk of CAD.

## Cholesterol Treatment Trialists’ Collaborators

- Meta-analysis,14 randomized controlled trials (n=90,056)

***Lancet 2005;366:1267-1278***

****p<0.001***

- Cancer incidence
- RR 1.00 (0.95-1.06)
- Rhabdomyolysis
- Statin: 9 of 39,884 (0.023%)
- Control: 6 of 39,817 (0.015%)
- P=0.4

## Collaborative AtoRvastatin Diabetes Study (CARDS)

**Collaborative AtoRvastatin Diabetes Study (CARDS)**

- 37% reduction

- p=0.001

**Placebo**

**Primary Endpoint: Major CV Event (%)**

- ARR = 3.2%
- NNT = 31

- 2838 primary prevention patients with type 2 diabetes randomized to placebo or atorvastatin 10 mg daily for 3.9 yrs
- Mean baseline LDL 118 mg/dL decreased to 77 mg/dL

***Lancet 2004;364:685-696***

**Atorvastatin 10 mg**

## Treat to New Targets (TNT) Trial

- ARR = 2.2%
- NNT = 45

***N Engl J Med. 2005;352:1425-1435***

**10 mg atorvastatin**
**Mean LDL = 101 mg/dL**

**80 mg atorvastatin**
**Mean LDL = 77 mg/dL**

- 10,001 patients with CHD and LDL-C 	<130mg/dL randomized to atorvastatin 10 mg or 80 mg daily for 5 yrs

- 22% reduction

- p<0.001

***includes stroke**

## Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL)

- 8888 patients with a past history of MI
- Randomized, to open-label high dose atorvastatin or standard dose simvastatin x 4.8 yrs
- Blinded endpoint evaluations
- Mean LDL-C (mg/dL):
- Simvastatin    104
- Atorvastatin     81

- p=0.07

- p<0.001

- p=0.02

***JAMA 2005;294:2437-2445***

***does not include stroke**

**0**

**10**

**20**

**30**

**40**

**Primary:**

**Major**

**Coronary**

**Event***

**Secondary:**

**Major CV**

**Event**

**Secondary:**

**Any CV Event**

**Incidence of Endpoint (%)**

**Atrovastatin 80 mg/d**

**Simvastatin 20 mg/d**

## Combination therapy often used in diabetes 
3,339 case reports of rhabdomyolysis with statins from 1990-2002; 38% were associated with concurrent fibrate therapy
Statin/Fibrate:
Controlled clinical trials (n=600): 1% incidence of elevated CK (>3 x ULN); no cases of rhabdomyolysis
Interaction most problematic with gemfibrozil
Statin/Niacin:
Lower risk for myopathy than statin/fibrate

- 3,339 case reports of rhabdomyolysis with statins from 1990-2002; 38% were associated with concurrent fibrate therapy
- Statin/Fibrate:
- Controlled clinical trials (n=600): 1% incidence of elevated CK (>3 x ULN); no cases of rhabdomyolysis
- Interaction most problematic with gemfibrozil
- Statin/Niacin:
- Lower risk for myopathy than statin/fibrate

***JAMA 2003;289:1681-1690***
***J Am Col Cardiol 2002;40(3):568-579***

**Dyslipidemia Combination Therapy**

## Statin/Fibrate Interaction

- Facts about gemfibrozil:
- Known to  risk of rhabdomyolysis with statins
- Inhibits hepatic glucuronidation of certain statins
- Reduced maximum statin dose in combination:
- Lovastatin 20 mg daily
- Rosuvastatin 10 mg daily
- Simvastatin 10 mg daily
- Fenofibrate does not inhibit glucuronidation

***JAMA 2003;289:1681-1690***

## Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)

- 9795 patients with type 2 diabetes
- Randomized, double-blind to placebo or micronized fenofibrate 200 mg daily x 5 yrs
- Primary endpoint:
- CHD death +nonfatal MI
- Baseline values:
- LDL-C 	119 mg/dL
- TG	184 mg/dL
- HDL	42 mg/dL

***Lancet 2005; 366: 1849–1861***

***Total CV events**

- p=0.16

- p=0.35

## Conclusions