ebm team a final

7/30/2019 EBM Team a Final

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Group 7A

2012/2013


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1. Case Summary

2. PICO Application

3. Clinical Question

4. Search Strategy

5. Research Objective

6. Comment On The Article7. Application to Clinical Practice

Outline


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52 years old Malay man, a known case of Diabetes

Mellitus type 2, Hypertension and Hyperlipidaemiapresented for follow-up at Klinik Kesihatan Bandar PasirMas (KKBPM).

1 year ago he presented to KKBPM for complaint ofchronic cough and haemoptysis for 4 days. He was thendiagnosed of having PTB.

Case Summary


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Incidental findings of physical examination showed

high blood pressure and high Random Blood Sugar

(RBS). He was then also diagnosed to haveHypertension and Diabetes Mellitus Type II.

On further history, he complained often feelingthirsty, unusual hunger and increased frequency of

urination. Otherwise, there were no blurring ofvision, chest pain, cloudy urine, or reduced urineoutput.


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He was alert, conscious. Not in pain and not in

respiratory distress.

BP: 144/87 mmHg. PR: 82 bpm, regular rhythm, good volume.

General: Hand was pink, CRT


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Case Summary

24/7/11 3/11/118/9/11

154/90mmHg

16.2mmol/L(RBS)

Tx

Metformin1g BDLovastatin20mg ONAmlodipin5mg OD

150/90

mmHg14.8mmol/L(RBS)

150/90mmHg

7.6mmol/L(RBS)

TxTx

Metformin1g BDLovastatin20mg ONAmlodipine10mg OD

Gliclazide40mg BD


Gliclazide40mg BD

13/12/11

154/91mmHg

5.7mmol/L(RBS)

Tx


Gliclazide40mg BD


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Case Summary

8/2/12 30/4/12

3/4/12

148/89mmHg

8.2mmol/L(FBS)

Tx

152/95mmHg

6.2mmol/L(RBS)

150/94mmHg

9.3mmol/L(RBS)

TxTx


Gliclazide40mg BD


Gliclazide40mg BD

29/5/12

147/88mmHg

6.6mmol/L(RBS)

Tx


Gliclazide40mg BD


Gliclazide40mg BD


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Case Summary24/7/12 6/11/1218/9/12

165/92mmHg5.7

mmol/L(FBS)6.6% HbA1c

Tx

152/92mmHg

5.3mmol/L(FBS)

144/87mmHg

5.1mmol/L(RBS)

TxTx


Gliclazide40mg BD


Gliclazide40mg BD


Gliclazide40mg BD


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Diabetes mellitus equivalent to IHD.

Target BP control with DM, 120/75 mmHg.

Will combination of amlodipine and valsartanprovide better blood pressure control compared tousing amlodipine alone in mild to moderatehypertension?

Clinical Question


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Patient : Hypertension

Intervention : Amlodipine

Comparision : Amlodipine + Valsartan

Outcome : Blood pressure reduction

PICO


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Search engine : PubMed

Keyword : Amlodipine AND Valsartan ANDCombination Therapy AND Hypertension

Clinical study categories : Therapy

Language : English

Date : 2001-2012

Search resullt : 75 articles

Article selected:

Two Multicenter, 8-Week, Randomized, Double-Blind,Placebo-Controlled, Parallel-Group Studies Evaluating the Efficacy andTolerability of Amlodipine and Valsartan in Combination and asMonotherapy in Adult Patients with Mild to Moderate Essential

Hypertension

SEARCH STRATEGIES


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1. To compare the efficacy of amlodipine and

valsartan in combination and as monotherapy in

adult patients with mild to moderate essentialhypertension.

2. To compare the tolerability of amlodipine andvalsartan in combination and as monotherapy in

adult patients with mild to moderate essentialhypertension.

Research Objectives


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Two Multicenter, 8-Week, Randomized, Double-

Blind, Placebo-Controlled, Parallel-Group StudiesEvaluating the Efficacy and Tolerability ofAmlodipine and Valsartan in Combination and asMonotherapy in Adult Patients with Mild toModerate Essential Hypertension.

Article

Thomas Philipp, MD1

; Timothy R. Smith, MD, RPh2

; Robert Glazer, MD3

;Margaret Wernsing, BS3;Joseph Yen, PhD3;JamesJin, PhD3; Helmut Schneider,M D4; and Rainer Pospiech, MD 51Department of Nephrology, University Hospital Essen, Essen, Germany; 2Mercy HealthResearch, Washington University School of Medicine, St. Louis, Missouri; 3NovartisPharmaceuticals Corporation, East Hanover, New Jersey; 4Practice for General Medicine,

Messkirck, Germany; and SPractice for Internal Medicine/Cardiology, Berlin, Germany


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Original article.

Study design:

Randomized, Double- Blind, Placebo- Controlled, Parallel- GroupTrials.

Study Duration:

Study 1: Conducted between January 2003 and February 2004.

Study 2: Conducted between January 2004 and July 2004.

Journal type:

The International Peer-Reviewed Journal of Drug Therapy.

Design overview


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Authors: Thomas Philipp, MD1; Timothy R. Smith, MD,RPh2; Robert Glazer, MD3; Margaret Wernsing, BS3;JosephYen, PhD3;JamesJin, PhD3; Helmut Schneider, M D4; andRainer Pospiech, MD 5.

Sites: Study 1 : At 169 centers in 6 countries (Belgium, Canada,

France, Germany, Mexico and the United States)

Study 2 : At 133 centers in 10 countries (Egypt, France,Germany, Korea, Malaysia, Norway, Peru, Portugal, Spain, andTaiwan)

The trials were conducted according to the good clinical

practice guidelines and applicable local regulations(including European Directive 91/507/EEC and US 21 Codeof Federal Regulations parts 50 and 56) and in compliancewith the Declaration of Helsinki.


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Study design: Multinational, multicenter, 8-week,

randomized, double blind, placebo controlled,

parallel-group trials. Setting:

Study 1: January 2003 February 2004 (Belgium,Canada, France, Germany, Mexico and the US).

Study 2: January 2004- July 2004(Egypt, France,Germany, Korea, Malaysia, Norway, Peru, Portugal,Spain and Taiwan).

Sample size: 1911 patients.

Method


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Inclusion criteria:

o Male and female patients aged >18 years withmild to moderate essential hypertension(MSDBP >95 and


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Exclusion criteria:

o Severe hypertension (MSDBP >110 mm Hg or mean sitting

SBP [MSSBP]>180 mm Hg).o Secondary hypertension.

o A history of hypertensive encephalopathy.

o Cerebrovascular accident or transient ischemic attack.

o Myocardial infarction / any type of revascularizationprocedure.

o Heart failure.

Method (cont.)


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Exclusion Criteria (cont.):

o Second or third degree heart block / Significant

arrhythmia.o Angina pectoris.

o Valvular heart disease.

o Significant renal, hepatic, or pancreatic disease.

o Diabetes requiring insulin treatment or poorly

controlled type 2 diabetes (fasting glycosylatedhemoglobin >8% at visit 1).

o Concomitant use of medications known tosignificantly affect BP.

Method (cont.)


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The designs of both study included a 2-week washout period,

then followed by a single-blind placebo run-in period for twoweeks. After that continue with double-blind treatment for 8weeks.

The washout and placebo run-in periods allowed determineeligibility for the double-blind treatment period.

Patients in study 1 were randomized to 1 of 15 groups. (refer

figure 1) Patients in study 2 were randomized to 1 of 6 groups. (refer

figure 2)

Randomization was performed using a validated automatedsystem.

Method (cont.)


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Figure 1


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Figure 2


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A standard aneroid or mercury sphygmomanometer

and cuff of an appropriate size.

BP was measured at the beginning of placebo run-inperiod and after weeks, 1,2,4,6 and 8 of treatment.

Sitting SBP and DBP were measured 3 times at 1 to 2minutes interval and mean of measurements were

obtained. A single standing BP a was taken.

Blood Pressure

Measurements


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Efficacy of both studies were assessed by:

- Change from baseline in MSDBP.

- Change from baseline in MSSBP.- Response rates (the proportion of patients achieving an

MSDBP


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Primary population for analysis in both studies are

all randomized patients who had a baseline BP

measurement and at least 1 post baseline efficacymeasurement.

Safety population was defined as all randomizedpatients who received at least 1 dose of double-blind

study medication.

Statistical Analysis


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For studies 1 &2, respective samples of 110 and 150 completedpatients per treatment group (total of 1650 and 900 patientsrespectively) were required to detect a difference of 3.5 and 3.3mmHg in the change of baseline in MSDBP between 2

treatment groups with 90% power at a 2 sided significancelevel of 0.05, assuming an SD of 8 mmHg for each treatmentgroup.

Qualitative (Categorical) variables were summarized usingcontingency tables.

Descriptive statistics were used to summarize quantitative(continuous) variables.

Treatment comparability was examined using Cochran-Mantel-Haenszel x tests for qualitative variables and 2 way analysis ofvariance F tests with treatment and region as factors for

quantitative variables.


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Analysis of covariance model, with amlodipine, valsartan,and

region as 3 factors and baseline as a independent variable wereused for global assessment of the contribution of monotherapiesto the overall BP lowering effect of combination treatment,MSDBP and MSSBP.

Test for each term; amlodipine, valsartan, region,and valsartan-by-amlodipine interaction was performed at the 2 sidedsignificance level of 0.05.Pattern of interaction was further

examined using least square means. If both test for amlodipineand valsartan term were significant in BP reduction, then bothmonotherapies were considered to have contributed to theeffect of combination treatment.


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Response rate: The proportion of patients achieve MSDBP


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StudyGroup

CombinationTherapy

Amlodipine

+ Valsartan(n)

MonotherapyValsartan

(n)

MonotherapyAmlodipine

(n)

Placebo (n)

Total(N)

1 1022 507 254 128 1911

2 419 415 207 209 1250

Table 1: Number of patients randomized to receive combinationtherapy, their individual components or placebo in Study 1 and 2.


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StudyGroup

Age,years

Mean

Weight, kgMean (SD)

Sex, No (%)Male Female

Sitting BP, mmHgMean (SD)

1 54.4 88.8 (19.3) 1022(53.5)

889(46.5)

152.8/99.3

2 56.9 79.7 (15.7) 629(50.3)

621(49.7)

156.7/99.1

Table 2: Patient characteristics and baseline blood pressure (BP) inStudy 1 and 2.


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Study 1

Combination Therapy

Reduction of

MSDBP(mmHg)

Reduction of MSSBP

(mmHg)

Amlodipine 5mg + valsartan 320mg 15.9 * 22.7 *




Amlodipine 2.5mg + valsartan 320mg 14.2 * 18.3 *

Amlodipine 2.5mg + valsartan 160mg 13.3 * 16.7 *

Amlodipine 2.5mg + valsartan 80mg 13.4 * 17.0 *Amlodipine 2.5mg + valsartan 40mg 10.8 * 15.5 *

Table 3:Reduction of MSDBP and MSSBP among patients oncombination therapy in Study 1.

*P


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Study 1

MonotherapyReduction of

MSDBP(mmHg)

Reduction ofMSSBP(mmHg)

Amlodipine 5mg 11.5 * 15.1 *

Amlodipine 2.5mg 9.3 * 12.4 *

Valsartan 320mg 13.4 * 15.7 *

Valsartan 160mg 11.0 * 15.1 *

Valsartan 80mg 9.7 * 12.9 *

Valsartan 40mg 10.1 * 11.8 *

Table 4: Reduction of MSDBP and MSSBP among patients onmonotherapy in Study 1.

*P


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Study 2 Reduction ofMSDBP(mmHg)

Reduction ofMSSBP(mmHg)

Amlodipine 10mg + valsartan320mg

18.6 * 28.4 *

Amlodipine 10mg + valsartan160mg

17.6 * 27.8 *

Amlodipine 10mg 15.6 * 24.1*

Valsartan 320mg 13.3 * 19.8 *

Valsartan 160mg 13.3 * 20.2 *

Table 5:Reduction of MSDBP and MSSBP among patients oncombination therapy and monotherapy in Study 2.

*P


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Table 6: Proportions of responders (MSDBP


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Combination treatments were associated with

significantly greater reductions in mean sitting

diastolic blood pressure (MSDBP) compared withtheir individuals components and placebo (P


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The response and control rates were significantly

higher in both combination therapy of amlodipine10mg + valsartan 160mg and amlodipine 10mg +valsartan 320mg than those with valsartanmonotherapy (P


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Table 7: Demographic characteristics of the combined safetypopulation.

T bl 8 Ad t ( [%]) i i 1% f ti t i th l di i +


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Table 8: Adverse events (no[%]) occuring in 1% of patients in the amlodipine +valsartan group in the combined safety population, regardless of the

relationship to treatment.


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Figure 1: Incidence of peripheral edema and headache, regardless ofrelationship to treatment, in the combined safety population.

*P


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Compares the overall side effects rates across combined

safety population.

The most common side effects encountered forcombination therapy were peripheral edema (5.4%) andheadache (4.3%).

The amlodipine + valsartan combination was associated

with a significant reduction on the incidence of peripheraledema compared with amlodipine monotherapy (5.4% vs8.7% with P=0.014). Yet, this combination was associatedwith higher incidence of peripheral edema compared tovalsartan monotherapy (5.4% vs 2.1% with P


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Combination therapy with amlodipine + valsartan was

associated with enhanced efficacy relative to the individual

mono therapies. In each of the studies, both amlodipine and valsartan

contributed to the overall BP-lowering effect ofcombination therapy.

One of the studies was designed to evaluate the lower dose

range of the combination of amlodipine + valsartan, andthe other was designed to evaluate the higher dose range.

All dose combinations of amlodipine + valsartan wereassociated with significantly greater reductions in MSDBPand MSSBP compared with placebo (P < 0.001).

Discussion


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The combinations of amlodipine + valsartan were

also associated with significantly greater reductions

in MSDBP and MSSBP than their individualcomponents (P < 0.05).

In addition to effectiveness, tolerability is animportant factor in the success of anti-hypertensive

treatment that may be improved through the use ofcombination therapy.

Discussion (cont.)


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The combination of amlodipine + valsartan was

associated with a smaller increase in ankle-foot volume

compared with amlodipine monotherapy (1371.6 VS1582.2 mL, respectively; P < 0.05).

The amlodipine + valsartan combination was associatedwith a significant reduction in the incidence ofperipheral oedema compared with amlodipinemonotherapy (5.4% vs 8.7%, respectively; P = 0.014),although the incidence of peripheral oedema wassignificantly higher with combination therapy comparedwith valsartan monotherapy (2.1%; P < 0.001).

Discussion (cont.)


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Many patients with hypertension will require >2

medications to control BP elevation.

Patients may become non-adherent to multidrugregimens, however, and there is evidence suggestingthat the use of fixed dose combinations may promotecompliance and thereby increase the likelihood of

achieving BP targets.

Discussion (cont.)


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In adult patients with mild to moderate essential

hypertension, the combination of amlodipine + valsartan

was associated with significantly greater BP reductionsfrom baseline compared with both amlodipine andvalsartan monotherapy and placebo.

The combination was generally well tolerated and was

associated with a lower incidence of peripheral edemacompared with amlodipine monotherapy.

Conclusion


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Critical appraisal


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Well-defined key word(mild to moderateessential hypertension)

Good sample size


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Clear-stated objectives


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Well-defined inclusionand exclusion criteria


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RCT is a suitable studydesign for testinginterventions concernedwith treatment. Besidesthat, this study was

multinational andmulticenter

Patients and theclinicians were keptblinded to treatmentgiven and until the end

of the study

Randomization used avalidated automatedsystem


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Clear information on how

data was collected


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Drop out < 10%


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Clear-stated reasons of

drop out


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p value< 0.05


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Discussion relevant toobjectives


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Strong Points

Clear stated objectives

Well defined inclusion and exclusion criteria

Study design is suitable (RCT) Study is multinational, multicenter

Double-blinded study

Placebo controlled

Wash out period for two weeks. Proper randomisation using validated system


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Comparing between 15 groups in Study 1 and 6

groups in Study 2. (different doses of combination)

Method of BP measurement was clearly stated (meanof 3 measurements).

Clear information on how data was obtained.

Thorough safety profile.

Low dropout rate (


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Did not state how the sample size was calculated.

Lack of a formal analysis of compliance or adherence

with the drug regimens (compliance was onlyassessed by capsule count at scheduled visit.

Wide exclusion criteria.

Safety profile during the wash out period was not

explained.

Weak Points


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Relative proportion of Asians in the study is low.

Response and control rates did not differ

significantly between both combination therapy ofamlodipine 10mg monotherapy, amlodipine 10mg +valsartan 160mg and amlodipine 10mg + valsartan320mg.

Weak Points (cont.)

A li ti T Cli i l


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This study can help the treatment plan of this patient

because since patient is on Amlodipine and his blood

pressure is not well control.Valsartan is a new drug and proven to reduce blood

pressure significantly. It is also one of the main drugrecommended to be use by hypertensive patient withconcurrent diabetes mellitus.

In chronic diseases, it is usually recommended togive combination therapy rather than increasing thedose of monotherapy drug as this may increase therisk of developing side effect.

Application To Clinical

Practice

A li ti T Cli i l


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This study gives strong evidence that combination of

amlodipine and valsartan provides greater BP

reduction and are well tolerated by patients.However, response and control rates did not differ

significantly between both combination therapy ofamlodipine 10mg monotherapy, amlodipine 10mg +valsartan 160mg and amlodipine 10mg + valsartan320mg.

Nevertheless, the use of combination therapy areassociated with significantly lower side effects.


Practice (cont.)

A li ti T Cli i l


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Therefore, the combination therapy of amlodipine +

valsartan may not help in reducing the blood

pressure of this patient significantly. If patient had any side effect from the high dose

monotherapy, the combination of amlodipine andvalsartan may be considered.

Combination with other medication such as ACEinhibitor might be helpful in managing this patient.

Attention must also be paid to other factors that mayhelp in BP control e.g. exercise, diet control.


Practice (cont.)


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The combination of amlodipine + valsartan was

associated with significantly greater BP reductions

from baseline compared with both amlodipine andvalsartan monotherapy and placebo.

However, when comparing with monotherapyAmlodipine 10mg (patient on this drug), responseand control rates did not differ significantly.

Therefore, it is not recommended to be used on thispatient.

Other drug can be considered t o be used in thebi ti th

Conclusion

ebm team a final

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