Losartan Potassim combination

Clinical Management of Patientsof Hypertension (with or without co-morbidities)with A2A Combination : 

Clinical Management of Patientsof Hypertension (with or without co-morbidities)with A2A Combination FROM: DR. MUHAMMAD SAADAT BUSINESS MANAGER, SQUARES, HIMONT PHARMACEUTICALS (PVT) LTD., KARACHI, PAKISTAN.

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Hypertension even today is a triple paradox which is : Easy to diagnose OFTEN remains undetected Simple to treat OFTEN remains untreated Despite availability of potent drugs, treatment all too OFTEN is ineffective

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Large amount of attention is given to the treatment of Hypertension : Hypertension is a major cardiovascular risk factor that contributes to MI, CHF, stroke and PREMATURE MORTALITY. The last 3 decades have shown through clinical trials (HOT & UKPDS) that AGGRESSIVE pharmacological treatment of moderate and even mild Hypertension leads to better survival and less cardiovascular morbidity. The JNC VI & WHO-ISH (1999) guidelines reinforce these findings

Hypertension : A Multifactorial Entity : 

Hypertension : A Multifactorial Entity Hypertension is a multifactorial entity, it is therefore not surprising that there is heterogeneity in responsiveness to treatment. Today, there is no simple way of predicting which patients will respond to which class of antihypertensive agents. - Journal of Human Hypertension 1995 ; 9 : S33-S36

Why combination therapy : 

Why combination therapy Multiple mechanisms involved in the pathogenesis of hypertension Effectiveness of monotherapy limited by stimulation of counter-regulatory mechanisms Effective BP control seen in only 50% of patients on monotherapy; combination therapy results in a much higher responder rate (>80%) BP goals difficult to attain with monotherapy in patients with diabetes or target organ damage

Combination therapy for hypertension – Recommended by JNC-VI guidelines and 1999 WHO-ISH guidelines : 

Combination therapy for hypertension – Recommended by JNC-VI guidelines and 1999 WHO-ISH guidelines With any single drug, not more than 25–50% of hypertensives achieve adequate blood pressure control J Hum. Hypertens 1995; 9:S33–S36 For patients not responding adequately to low doses of monotherapy Increase the dose of drug. This, however, may lead to increased side effects Substitute with another drug from a different class Add a second drug from a different class (Combination therapy) Add second drug from different class (Combination therapy) If inadequate response obtained

American Heart Association : 

American Heart Association “Starting with combination therapy may be the best way to get hypertensive patients’ blood pressure down to goal levels.”

Hypertension Treatment Focus : 

Effective BP lowering End organ Protection Evidence Hypertension Treatment Focus

AII Antagonist Scientific/Clinical Publications : 

*Current Contents Database Updated 8/06 AII Antagonist Scientific/Clinical Publications Cumulative Total 6559 1414 920 944 214 346 182 Cumulative Total Publications* EVIDENCE

EFFICACY OF AIIA COMBINATION : 

EFFICACY OF AIIA COMBINATION This question of efficacy is potentially very important because if there are real and clinically meaningful differences in antihypertensive efficacy within the AIIA class , physicians would need to be aware of such differences to optimize therapeutic decision making

EFFICACY OF AIIAS : 

EFFICACY OF AIIAS Independent interpretation of available clinical data is confounded by : Small trials Often conducted by Pharmaceutical manufacturers with a study design potentially set up in its favor. Differences in methodology in describing blood pressure reductions Lack of sufficient large , well designed independent head to head comparative studies.

EFFICACY OF AIIAs : 

EFFICACY OF AIIAs In the absence of optimal studies an alternative way to objectively assess the antihypertensive efficacy of AIIA is to pool all of the existing randomized clinical trials and conduct a meta analysis

DATA SOURCE : 

DATA SOURCE No of trials: 43 ( RCT) No of patients: 11,281 Types of Data: Trials comparing Various AIIAs with other established classes of AHT (ACE-1, CCBs,BBs) AIIA + HCTZ with established classes. Direct AIIA efficacy comparison trials.

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Weight Average Reduction in Blood Pressure AIIA Combination Conlin et al. Am J Hypertens 2000 mmHg Meta-Analysis of 43 published double-blind, randomized, controlled trials

Mean reduction in S & DBP from baseline as observed from ARBs Combination Clinical Trials. : 

DBP 17 mmHg Mean reduction in S & DBP from baseline as observed from ARBs Combination Clinical Trials. SBP 30 mmHg LIIFE Study Lancet, 2002 50 - 100 Losartan + 25 HCTZ EFFICACY

Hypertension Treatment Focus : 

Hypertension Treatment Focus END ORGAN PROTECTION Brain

RENAAL: Primary Hypothesis : 

RENAAL: Primary Hypothesis In type 2 diabetic patients with nephropathy, losartan compared to placebo will increase the time to the first event of the composite endpoint of: Doubling of serum creatinine (sCr) ESRD (need for chronic dialysis or transplantation) Death (all cause mortality)

RENAAL: Secondary Hypotheses : 

RENAAL: Secondary Hypotheses In type 2 diabetic patients with nephropathy, losartan compared to placebo will: Renal Reduce the rate of progression of renal disease, as measured by the slope of 1/sCr Reduce proteinuria during the course of the study Cardiovascular Increase the time to the first event of the composite endpoint of cardiovascular morbidity/mortality (cardiovascular death, MI, stroke, first hospitalization for heart failure, first hospitalization for unstable angina, peripheral and coronary revascularization)

RENAAL Impact of Losartan on Secondary Endpoints : 

RENAAL Impact of Losartan on Secondary Endpoints 10% risk reduction in the secondary composite endpoint* (P=0.26) 32% risk reduction in first hospitalization for heart failure (P=0.005) 35% average reduction in the level of proteinuria (P<0.001 for the overall treatment effect) 18% reduction in the decline of renal function (P=0.01) 15.2% reduction in the estimated decline in the glomerular filtration rate (P=0.01) *Composite of cardiovascular morbidity & mortality, including myocardial infarction, stroke, first hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, or death from cardiovascular causes Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.

RENAAL Summary of Important Findings : 

RENAAL Summary of Important Findings In patients with type 2 diabetes and nephropathy: Losartan, in combination with other antihypertensive therapy (non-ACE or ARB), delayed the onset of the primary composite endpoint* (P=0.02) and delayed progression to end stage renal disease (P=0.002) Losartan reduced proteinuria (P<0.001) and the rate of decline in renal function (P=0.01) Losartan reduced the incidence of first hospitalization for heart failure (P=0.005) These benefits were above and beyond those attributable to blood pressure reduction alone *Composite of a doubling of serum creatinine, end stage renal disease, or death Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.

CV Outcome Trials in Hypertension with AIIA Combination : 

CV Outcome Trials in Hypertension with AIIA Combination Losartan vs atenolol = LIFE Hypertensive patients with LVH n = 9,193 over 4.8 y PEP = cardiovascular morbidity and mortality Valsartan vs amlodipine = VALUE Hypertensive patients at high CV risk n = 15,245 over 4.2 y PEP = cardiac morbidity and mortality Candesartan vs placebo = SCOPE Elderly hypertensive patients n = 4,964 over 3.7 y PEP = cardiac morbidity and mortality PEP: Primary Endpoint

LIFE: Primary Composite Endpoint : 

LIFE: Primary Composite Endpoint Study Month 0 6 12 18 24 30 36 42 48 54 60 66 Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 Adjusted Risk Reduction 13.0%, p=0.021 Unadjusted Risk Reduction 14.6%, p=0.009 Number at Risk -13% (p=0.021)

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VALUE: Primary Composite Endpoint CV morbidity and mortality 14 12 10 8 6 4 2 0 Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 Proportion of Patients With First Event (%) Valsartan-based regimen Amlodipine-based regimen HR = 1.03; 95% CI = 0.94–1.14; P = 0.49 Julius S et al. Lancet. June 2004;363. Number at risk Valsartan Amlodipine 7596 7649 7469 7459 7424 7407 7267 7250 7117 7085 6772 6732 6955 6906 6576 6536 5959 5911 3725 3765 1474 1474 6391 6349 NS

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Cand Control (n) (n) 2477 2460 2454 2423 2371 2333 2262 2230 1587 1542 406 401 0 6 12 18 24 30 36 42 48 54 60 Months Proportion of patients with first event (%) Candesartan Control 0 2 4 6 8 10 12 14 16 Risk Reduction = 10.9% p = 0.19 Difference in BP reduction3.2 / 1.6 mmHg SCOPE: Primary Composite Endpoint Major CV event (CV death, non-fatal MI, non-fatal stroke) NS Lithell – Hypertension 2003

LIFE: Stroke : 

LIFE: Stroke Losartan+ HCTZ Atenolol+ HCTZ Adjusted Risk Reduction 24.9%, p=0.001 Unadjusted Risk Reduction 25.8%, p=0.0006 Study Month 0 6 12 18 24 30 36 42 48 54 60 66 Dahlöf B et al Lancet 2002;359:995-1003. Losartan 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925 Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897 Proportion of patients with first event (%) Number at Risk -25% (p=0.001)

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VALUE: Fatal and Non-fatal Stroke Julius S et al. Lancet. June 2004;363. Number at risk Valsartan Amlodipine 7596 7649 7499 7494 7455 7448 7334 7312 7195 7170 6918 6877 7055 7022 6744 6692 6163 6093 3846 3859 1532 1516 6587 6515 6 5 4 3 2 1 0 Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 Proportion of Patients With First Event (%) Valsartan-based regimen Amlodipine-based regimen HR = 1.15; 95% CI = 0.98–1.35; P = 0.08 NS

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SCOPEPrimary and secondary outcomes candesartan placebo RR p (n= 2477 ) (n= 2460 ) (%) Primary composite 10.9% ns CV mortality 141 150 ns Stroke 89 115 21% ns MI Total mortality Cognitive Funct (MMSE) 28.0 27.9 diff. : 0.15 ns New Onset DM 20% ns Non fatal stroke 68 93 28% 0.04 Lithell – Hypertension 2003

New-Onset Diabetes : 

Intention-to-Treat New-Onset Diabetes Losartan+ Atenolol+ Study Month Adjusted Risk Reduction 25 %, p<0.001 Unadjusted Risk Reduction 25 %, p<0.001 B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002. Endpoint Rate 25% RR

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Incidence of New-onset Diabetes New-Onset Diabetes (% of patients in treatment group) Julius S et al. Lancet. June 2004;363. 0 2 4 6 8 10 12 14 Valsartan-based Regimen (n = 7649) Amlodipine-based Regimen (n = 7596) 13.1% 16.4% 23% Risk Reduction With Valsartan 16 18 P < 0.0001

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SCOPEPrimary and secondary outcomes candesartan placebo RR p (n= 2477 ) (n= 2460 ) (%) Primary composite 10.9% ns CV mortality 141 150 ns Stroke 89 115 21% ns MI Total mortality Cognitive Funct (MMSE) 28.0 27.9 diff. : 0.15 ns New Onset DM 20% ns Non fatal stroke 68 93 28% 0.04 Lithell – Hypertension 2003

Losartan Significantly Reduced the Risk of New-Onset AF by 33% : 

Losartan Significantly Reduced the Risk of New-Onset AF by 33% HR = hazard ratio; CI = confidence interval Adapted from Wachtell et al J Am Coll Cardiol 2005;45:712–719.

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0 6 12 18 24 30 36 42 48 54 60 66 Study month Proportion of patients (%) Adjusted risk reduction = 38.7%; p=0.002 Unadjusted risk reduction = 40.1%; p=0.001 Number at risk Losartan 586 579 573 572 566 558 552 543 533 513 265 136 Atenolol 609 604 592 582 576 566 552 537 529 495 232 113 Diabetic Patients: Total Mortality Adapted from Lindholm LH et al Lancet 2002;359:1004–1010.

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Diabetic Patients: Sudden Cardiac Death Adapted from Lindholm LH et al Lancet 2003;362:619–620. Proportion of patients (%) Number at risk Losartan 609 592 575 550 525 198 Atenolol 586 573 566 552 533 234 Study month p=0.027 51%

Is it a “CLASS EFFECT”? : 

Is it a “CLASS EFFECT”?

Testosterone / Estrogen Molecular Structure : 

Testosterone / Estrogen Molecular Structure Cecil Textbook of Medicine 21st edition, 2000

Yes … it Matters How …………!! : 

Yes … it Matters How …………!!

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Thank You

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