Aliskiren versus Ramipril

Aliskiren versus Ramipril Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6month, randomized, double-blind trial1 Presented by Harshil Patel, Pharm. D. Candidate, 2009

Background

2

“Hypertension affects approximately 50 million people in the US�

There is a consistent link between hypertension and increased risk of heart attack, heart failure, stroke, and kidney disease Antihypertensive treatment has a clear reduction in morbidity and mortality

Diagnosis and Classification

2

Treatment Algorithm

2

Study Drugs

3 Aliskiren

Angiotensinogen Renin

Ramipril Angiotensin I ACE Angiotensin II

AT1 receptor

Aldosterone Release

Aliskiren: A new class

4,5

Investigational drug in trial MOA: Direct renin inhibitor that decreases plasma renin activity (PRA) and therefore stops the activation of RAAS. It also inhibits prorenin, which can have renin-like effects Aliskiren is first drug in class Indicated for treatment of hypertension as monotherapy or in combination with other antihypertensives

Aliskiren: A new class

4,5

Side effect profile similar to ACEI and ARBs Edema Cough Diarrhea Increased risk of hyperkalemia Hypotension

Efficacy is affected by ethnicity Role in therapy is unknown Half-life is 24 hours Metabolized by CYP3A4

6

Ramipril

Comparator drug in trial MOA: Inhibits angiotensin-converting enzyme, leading to decreased angiotensin II levels Ramipril is a commonly used ACEI On formulary at Hunterdon Medical Center Half-life: 9-17 hours Excreted renally (60%) and in feces (40%) If CrCl<40 ml/min, dose reduce to 25% of normal dose

Ramipril Well-tolerated medication, with few side effects Angioedema Cough Hyperkalemia Symptomatic hypotension

ACEI are useful in patients with specific comorbidities: Heart failure Post-MI High Coronary disease risk DM Chronic Kidney disease Recurrent stroke prevention

Hydrochlorothiazide (HCTZ) Adjunct therapy in both arms of trial MOA: Thiazide diuretic, which inhibits sodium reabsorption in distal convoluted tubule of the nephron Considered first line therapy in hypertension Maximal effect seen at 25 mg May cause potassium wasting Not recommended in patients with gout Useful in osteoporosis patients

Hydrochlorothiazide

7

Previous Aliskiren Trials

4,8

Indication for monotherapy based on 6 short-term trials showing superiority of aliskiren to placebo Short-term trials of combinations with other antihypertensive medications have also been conducted, showing improved efficacy of combination HCTZ Valsartan Amlodipine Ramipril

Many other studies are currently being conducted Optimal dosing New formulations in combination with other antihypertensives Special populations

Why this study?

1

To look into the efficacy and safety of aliskiren compared to an activecomparator in a long-term trial Current study was a 6 month trial Other trials last 6 weeks or less Study design also allowed for follow-up upon discontinuation of drug after longterm therapy

Study Overview

1

Objective: To compare the efficacy and safety of aliskiren to ramipril as monotherapy and in combination with hydrochlorothiazide in patients with hypertension 6-month multi-national, multi-center trial Funded by Novartis Pharma AG

Exclusion Criteria

1

Severe hypertension msDBP

110 mmHg or msSBP

180 mmHg

History of secondary hypertension Hypertensive neuropathy Known Keith-Wagener grade III or IV

Exclusion Criteria

1

Diabetes type I or II HbA1c>9%

History of severe cerebrovascular or cardiovascular disease Any condition that may alter the ADME of the study drugs Pregnant or nursing women

Patient Population

1

Study Design

1

Randomized, double-blind study with active and placebo controls Conducted at 92 centers in 9 countries

Looked for non-inferiority and superiority to ramipril Superiority only studied if non-inferiority achieved

Looked for superiority to placebo in withdrawal period

Study Design

1

Measurements of Efficacy Active-controlled treatment period Primary endpoint Change from baseline in msDBP at week 26

Secondary endpoints Change from baseline in msSBP at week 26 Change in msSBP and msDBP at week 6 and 12 Proportions of patients achieving BP control at weeks 6, 12, and 26 Also looked at the proportions who reached systolic BP control on weeks 6, 12, and 26

Measurement of Efficacy

1

Placebo-controlled withdrawal period Changes in blood pressure from week 26 to week 30

Safety and tolerability recorded Post-hoc analyses Obesity Metabolic Syndrome Diabetes

Statistical Analyses

1

Non-inferiority of aliskiren to ramipril Assessed using ANCOVA Comparisons done from baseline to weeks 6, 12, and 26 Non-inferiority margin 2 mmHg for msDBP and 4 mmHg for msSBP One-sided significance level P= 0.025

Statistical Analyses

1

Superiority of aliskiren to ramipril Only considered if aliskiren validated as noninferior Assessed at a two-sided significance level P=0.05

Performed based on modified ITT population Last observation carried forward (LOCF) method was used

Statistical Analyses

1

Superiority of active treatment to placebo Changes in msSBP and msDBP assessed from week 26 to 30 analyzed Two-way ANCOVA P=0.05

Secondary endpoints Measured using logistic regression at weeks 6, 12, 26, and 30

Results

1

Results of Active-Control Phase Primary Endpoint - Change from baseline in msDBP

99 87 Ramipril Aliskiren

86

Secondary Endpoints Change from baseline in msSBP

151 136 Ramipril Aliskiren

134

Secondary Endpoints Change in msSBP and msDBP at week 6 and 12

Secondary Endpoints Proportions of patients achieving blood pressure control Ramipril

*Statistically significant difference detected

Systolic blood pressures

Aliskiren

Diastolic blood pressures

Results of Withdrawal Phase Change in msSBP and ms DBP from week 26 to week 30 Mean Systolic BP

Mean Diastolic BP

Post-hoc Analyses Obesity

Metabolic Syndrome Aliskire Ramipril n (n=182) (n=168)

Drug

Aliskiren (n=184)

Ramipril (n=219)

Percent with controlled SBP

67.4

59.8

69.0

Percent with controlled overall BP

57.1

48.4

57.7

Diabetes Aliskire n (n=42)

Ramipril (n=49)

62.6

61.9

65.3

50.5

52.4

53.1

Safety and Tolerability In active-controlled period Aliskiren showed substantially higher rates in

Ramipril showed substantially higher rates in

Headaches Diarrhea Pain in extremity Bronchitis Dyspepsia Hyperkalemia

Cough URTI Increased serum creatinine

Safety and Tolerability In placebo-controlled period Aliskiren showed substantially higher rates in Hypokalemia

*Note: Each drug was compared to placebo

Ramipril showed substantially higher rates in URTI Hypokalemia Hyperkalemia

1

Discussion

Active-controlled period Significantly higher rates of systolic BP control with aliskiren Lower BP rates with aliskiren over ramipril, as monotherapy and in combination with HCTZ Fewer patients required HCTZ addition and titration with aliskiren

1

Discussion

Placebo-controlled withdrawal period Aliskirenâ&#x20AC;&#x2122;s placebo had gradual loss of effect over a month Ramiprilâ&#x20AC;&#x2122;s placebo lost effect within one week Neither active drug groups lost effect

1

Discussion

Post-hoc analysis As with the overall population, the groups studied generally showed slightly greater efficacy with aliskiren over ramipril

Safety and Tolerability The adverse effect profiles seen are consistent with prior studies Most adverse effects were mild Comparatively high incidence of headaches with aliskiren Hypokalemia attributed to HCTZ treatment

Critique and Comments Study Population There is a substantial difference in gender and race Exclusion criteria included history of cardiac disease Exclusion criteria included patients with uncontrolled diabetes

Critique and Comments Study Design Mirrored practical and likely medication use Initiation, titration, and the addition of a second medication follows treatment algorithm Each arm of study had equal titrations and drug additions

Withdrawal period provided useful safety data and validated trial results Monitoring done at appropriate and regular intervals

Critique and Comments Endpoints Primary endpoint is valid measure of hypertension However, it does not give insight into morbidity and mortality of patient Using blood pressure may lack clinical importance No translation of data to risk reduction

Secondary endpoints strengthen primary None of them considered improvement in patientâ&#x20AC;&#x2122;s QOL or morbidity in patient

Critique and Comments Endpoints Post-hoc analysis provided interesting data on patients with comorbid conditions Study was not intended to look for differences in these groups

Safety and tolerability data provided further reinforcement of known effects Reporting and linking to medication lacked unified system

Critique and Comments Statistics Trial used an modified intent-to-treat method Trial considered non-inferiority and superiority of aliskiren versus ramipril One-sided test with P-value of 0.025 used for noninferiority Two-sided test with P-value of 0.05 used for superiority

Authors did not specify studyâ&#x20AC;&#x2122;s power or n Primary endpoint data was analyzed using ANCOVA Appropriate because data measured is continuous

Critique and Comments Statistics Secondary endpoint data based on linear regression Appropriately used to combine data of all patients

No use of any hazards ratio or measurement of risk Does not provide concrete evidence to use either medication over the other

Critique and Comments Trial showed efficacy of aliskiren However, did not indicate definitive improvement over ramipril

Trial reinforced past studies Better BP control through the day has been known Longer half-life previously established

Future directions More concrete comparison of aliskiren Trials powered for recognizing differences in sub-populations Co-morbidities of the post-hoc analysis Uncontrolled diabetics Patients with cardiac disease Non-compliant patients

Analysis of drug interactions of aliskiren

Questions

References 1. Anderson K, Weinberger MH, Egan B, Constance CM, Ali MA, Jin J, Keefe DL. Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, doubleblind trial.Journal of Hypertension. 2008; 26:589-599 2. National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206 3. Zamad MA, Oparil S, Calhoun DA. Drugs Targeting Renin-Angiotensin-Aldosterone System. Nature Reviews Drug Discovery. 2002 Aug; 621-636 4. Novartis Pharma. Tekturna ® package insert. East Hanover, NJ; 2007 5. O'Brien E, Barton J, Nussberger J, Mulcahy D, Jensen C, Dicker P, Stanton A. Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an AngiotensinConverting Enzyme Inhibitor, or an Angiotensin Receptor Blocker. Hypertension. 2007; 49:276-284 6. King Pharmaceuticals. Altace ® package insert. Bristol, TN; 2007 7. Klabunde, R. Cardiovascular Pharmacology Concepts’: Diuretics. 2007 Mar. [cited 2008 Jun 6] [1 screen].

Available from: http://www.cvpharmacology.com/diuretic/nephron.gif 8. Clinicaltrials.gov Database. Search results for aliskiren. 2007 Sep [cited 2008 Jun 6] [1 screen]. Available from: www.clinicaltrials.gov

Thank you