Hawthorn and Heart Failure - Coral Rudiecoralrudie.yolasite.com/resources/Hawthorn and Heart Failure.pdf · ! 3! I. INTRODUCTION Crataegus oxycantha has been used by many cultures

Hawthorn and Heart Failure:

Will taking Hawthorn help improve the incidence of cardiac events and improve cardiac function in heart failure patients?

NST 194 Botanical Research Evaluation April 16, 2012 Coral Rudie

2

Table of Contents

I. Introduction……………………………….……..3

II. Methods……………………………….……….....3-5

a. Figure 1. Search Inclusion Criteria

b. Figure 2. Searches on PubMed and Academic Search

Complete

c. Figure 3. Primary Papers Accepted and Excluded

III. Accepted Primary Papers Overview……………6-18

IV. Quality Criteria Checklist……………………...19-29

V. Evidence Summary…………………………….30-33

VI. Conclusion Statement & Practice Guideline…..34

VII. Bibliography…………………………………..….35

3

I. INTRODUCTION

Crataegus oxycantha has been used by many cultures around the world since the first

century A.D. as a cardiac tonic. C. oxycantha is a thorny deciduous tree that is found in Europe, North America, and Western Asia. This 25-30 foot tree is a member of the Rosaceae family and has a common name hawthorn. Hawthorn’s cardiovascular protective activity is generally attributed to the high flavonoid content, more specifically the oligomeric proanthocyanidins (OPCs). These compounds are found in high concentrations in the leaves, berries, and flowers. OPCs have high vitamin P (citrin bioflavonoid) activity that works with vitamin C to support capillary stability (Crataegus oxycantha, 2010). Hawthorn contains several other constituents that may assist in cardiovascular protection: quercetin, quercetrin, triterpene saponins, vitamin C, and several cardioactive amines (Crataegus oxycantha, 2010). Hawthorn’s antioxidant content is believed to cause dilation of smooth muscles in the heart and blood vessels, lowering resistance and increasing blood flow. In vitro studies involving crataegus extract have shown to prolong the action potential and refractory period thereby showing that crataegus has anti-arrhythmic properties (Holubarsch, 2008). The following heart conditions are believed to benefit from the use of hawthorn: angina, atherosclerosis, congestive heart failure and hypertension (Carson, 2010). However, the use of Crataegus while taking digitalis, anti-hypertensive agents, and lipid-lowering medications can increase the drugs effect. Hence, lower dosage of these drugs may be necessary when taking hawthorn concurrently (Crataegus oxycantha, 2010).

The intent of this paper is to answer the question: “Will taking hawthorn help decrease the incidence of cardiac events and improve cardiac function in heart failure patients?” with evidence-based analysis. The independent variable in question is the use of crataegus extract WS 1442 (a dry extraction from hawthorn leaves with flowers) and the dependent variable is time until a cardiac event or exercise tolerance.

II. METHODS

Literature searches were conducted using PubMed database

(http://www.ncbi.nlm.nih.gov/pubmed/) and Academic Search Complete (www.ebscohost.com/academic/academic-search-complete). For the PubMed search the highlighted criteria in Figure 1 was used as limited while searching. The limits while searching Academic Search Complete included full text, scholarly (peer review) journals, publish dates of 2001-2012, and English for language. The results of relevant, non-relevant and repeated papers from the searches are shown in Figure 2. A total of six relevant papers were found and were then examine using all of the criteria in Figure 1. Five of the six primary papers were accepted; one was not accepted since it was a meta-analysis and not a clinical trial (see Figure 3).

4

Figure 1. INCLUSION CRITERIA (highlighted criteria are those included in the “limits” for Pubmed database) Language English Types of studies Clinical trials, randomized controlled trails Required sample size At least 10 in each group Minimum drop-out: ≤20% Acceptable age range Adults (19 + yr old) Gender or ethnicity of interest

Females and males; does not have to be equal proportion in sample size

Age of studies Within the last 12 years Human Studies only? Yes Required disease state/health of the subjects

Clinical sign and symptoms of chronic heart failure, New York Heart Association (NYHA) class II or III

Standardized form of herbal Capsule Method of administration Orally Database PubMed and Academic Search Complete

Figure 2. Searches on PubMed and Academic Seach Complete PubMed Search #1 Search #2 Search #3 Terms searched Hawthorn, Heart Hawthorn, Heart

Failure Crataegus, heart failure

Total Identified 9 5 5 Total relevant 3 3 3 Total irrelevant 6 2 2 Total Number of Repeat papers

0 3 – repeats from search #1

3– repeats from search #1

Academic Search Complete

Search #4 Search #5 Search #6

Terms searched Hawthorn, Heart Hawthorn, Heart failure

Crataegus, heart failure

Total Identified 21 13 14 Total relevant 4 4 4 Total irrelevant 17 9 10 Total Number of Repeat papers

1 – repeats from search #1



The total number of papers to review: 6

5

Figure 3. PRIMARY PAPERS ACCEPTED 1 Holubarsch, C. F., Colucci, W. S., Meinertz, T., Gaus, W., & Tendera, M. (2008). The

efficacy and safety of Crataegus extract WS® 1442 in patients with heart failure: The SPICE trial. European Journal Of Heart Failure, 10(12), 1255-1263. doi:10.1016/j.ejheart.2008.10.004

2 Zick, S. M., Vautaw, B., Gillespie, B., & Aaronson, K. D. (2009). Hawthorn Extract Randomized Blinded Chronic Heart Failure (HERB CHF) Trial. European Journal Of Heart Failure, 11(10), 990-999. doi:10.1093/eurjhf/hfp116

3 Zick SM, Gillespie B, Aaronson KD. The effect of Crataegus oxycantha Special Extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure. Eur J Heart Fail. 2008 Jun;10(6):587-93. Epub 2008 May 19. PubMed PMID: 18490196; PubMed Central PMCID: PMC2577845.

4 Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York Heart Association class-III heart failure. Am Heart J. 2002 May;143(5):910-5. PubMed PMID: 12040357.

5 Zapfe jun G. Clinical efficacy of crataegus extract WS 1442 in congestive heart failure NYHA class II. Phytomedicine. 2001 Jul;8(4):262-6. PubMed PMID: 11515715.

PRIMARY PAPERS EXCLUDED REASON FOR EXCLUSION 6 Tassell, M. C., Kingston, R., Gilroy, D.,

Lehane, M., & Furey, A. (2010). Hawthorn (Crataegus spp.) in the treatment of cardiovascular disease. Pharmacognosy Reviews, 4(7), 32-41. doi:10.4103/0973-7847.65324

The paper was a meta-analysis, not a clinical trial

6

III. ACCEPTED PRIMARY PAPERS OVERVIEW STUDY #1: The efficacy and safety of Crataegus extract WS® 1442 in patients with heart failure: The SPICE trial.

Background Questions

Author and complete citation

Holubarsch, C. F., Colucci, W. S., Meinertz, T., Gaus, W., & Tendera, M. (2008). The efficacy and safety of Crataegus extract WS® 1442 in patients with heart failure: The SPICE trial. European Journal Of Heart Failure, 10(12), 1255-1263. doi:10.1016/j.ejheart.2008.10.004

Study design Randomized, double-blind, placebo-controlled multicenter study

Purpose of the study The aim was to investigate the efficacy and safety of an add-on treatment with Crataegus WS® 1442 in patients with congestive heart failure

Location of the study 13 European countries

Funding of the study Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germnay

Did the funding present any potential bias?

No

Methods

Subject inclusion and exclusion criteria

Inclusion:

Participants had to be at least 18 years old Had to present with clinical signs and symptoms of chronic heart

failure, NYHA class II or III o Due to ischaemic heart disease, idiopathic dilated

cardiomyopathy, or hypertensive heart disease with left ventricular dilatation.

A wall motion index ≤1.2 (corresponding to a LVEF ≤35%) Eligible patients had to have an exercise time between 2 and 12 min

in symptom limited bicycle exercise tests at both screening and baseline, with the difference between both visits not exceeding 1 min

o Starting at 25 W workload, with a workload increase of 25 W every 2 min

There were no restrictions regarding ethnic groups. Exclusion:

Patients suffering from chronic heart failure attributable to haemodynamically significant valvular disease, with a history of cardiac arrest or symptomatic sustained ventricular tachycardia not adequately controlled by drugs or implantation of a defibrillator

Other conditions were sick-sinus-syndrome, 2nd or 3rd degree AV block not controlled by a pacemaker, congenital heart disease, hypertrophic or restrictive cardiomyopathy, left ventricular hypertrophy without dilatation, myocardial infarction, unstable angina, or cardiac surgery within 3 months before study inclusion,

7

peripheral arterial disease symptomatic at rest, as well as chronic obstructive pulmonary disease.

Patients with planned surgical or non- surgical cardiac intervention during the treatment period as well as those with diseases that might interfere with the study procedures (e. g., with the bicycle exercise test), or with inadequately controlled insulin dependent diabetes mellitus or arterial hypertension were not eligible for participation.

Study intervention (independent variables)

WS® 1442 is a dry extract from hawthorn leaves with flowers (4–6.6:1), extraction solvent: ethanol 45% (w/w). The extract is adjusted to 17.3–20.1% oligomeric procyanidins. Film-coated tablets containing 450 mg of the extract were used. Film coated placebo tablets were identically matched. During the double-blind, randomized treatment period the patients had to take 2 film-coated tablets per day corresponding to 900 mg/ day of dry extract in case of WS® 1442

Study outcomes (dependent variables)

The primary outcome measure for treatment efficacy was the number of days between baseline and the first cardiac event, defined as a composite of cardiac death (sudden cardiac death, death due to progressive heart failure, fatal myocardial infarction), non-fatal myocardial infarction, or hospitalization due to progressive heart failure. Sudden cardiac death was defined as death without warning or within 1 h of symptoms.

Secondary efficacy outcome measures included each individual endpoint contributing to a cardiac event, workload during exercise testing, echocardiographic measures, as well as quality of life and pharmacoeconomic assessments.

Conclusion: WS® 1442 had no significant effect on the primary endpoint. WS® 1442 was safe to use in patients receiving optimal medication for heart failure. In addition, the data may indicate that WS® 1442 can potentially reduce the incidence of sudden cardiac death, at least in patients with less compromised left ventricular function.

Was there good internal validity? (were all other factors, such as diet or potential confounders, the same for both groups at entry and at the end of the study)? If not, describe.

Yes

Was there good external validity? Explain

Yes. The study included a wide range of population with NYHA stage III heart failure. It also allowed participants to remain on standard medications to see if hawthorn showed any additional benefit on top of the medication.

Was the intervention duration long-enough?

Yes – the intervention time was 24 months long. The authors had made projections of it taking 24 months to desired percentages of cardiac events in each group. They predicted to see around 24% in treatment group and

8

30% in placebo group. After the 24 months, the percent of patients with cardiac events was 27.9% and 28.9% in the treatment and control groups, respectively

What was the compliance of the study?

Across the follow-up period the interquartile range for treatment compliance (assessed by medication counting) was 96.2%–102.3% for WS® 1442 and 96.3%–101.5% for placebo.

Were the validity and reliability of tools discussed?

No

Results

Sample size at entry & end of the study

Treated with WS 1442 (n=1338) Completed WS 1442 treatment as scheduled (n=960) Treated with Placebo (n=1343) Completed placebo treatment as scheduled (n=946)

Calculate % follow-up 71%; intension to treat analysis was done

If needed, was an intention-to-treat done?

Yes

Were adjustments made in the analysis for differences between groups at study entry?

Groups were similar no adjustments were needed

As best you can tell, are Author’s conclusions supported by data in text and tables

Yes

Overall impressions

Identify at least strengths of the paper

Control and treatment group were very similar in terms of baseline data

Participants and investigators were both blinded

Identify at least 2 weaknesses of the paper

Authors did not discuss possible weaknesses of the study

No power calculation was reported to address type 2 error

STUDY #2: Hawthorn Extract Randomized Blinded Chronic Heart Failure (HERB CHF) Trial.


Author and complete Zick, S. M., Vautaw, B., Gillespie, B., & Aaronson, K. D. (2009). Hawthorn

9

citation Extract Randomized Blinded Chronic Heart Failure (HERB CHF) Trial. European Journal Of Heart Failure, 11(10), 990-999. doi:10.1093/eurjhf/hfp116

Study design Randomized, double-blind, placebo-controlled trial

Purpose of the study The aim of the study was to determine whether hawthorn increases submaximal exercise capacity when added to standard medical therapy.

Location of the study University of Michigan

Funding of the study Grant to the University of Michigan Complementary and Alternative Medicine Research Center from the National Center for Complementary and Alternative Medicine Research resources were also provided by the General Clinical Research Center of the University of Michigan


No

Methods


Inclusion:

Ambulatory patients aged 18 years of age and older with a !3 months history of HF (NYHA classes II-III) and a left ventricular ejection fraction (LVEF) "40%

Patients had to be receiving standard medical therapy (in the absence of a contraindication or intolerance), defined as an angiotensin converting enzyme inhibitor or angiotensin receptor antagonist, a beta-blocker and a diuretic.

Subjects had to walk between 150 and 450 m during two 6 min walk tests, conducted 2 weeks apart (screening and baseline visits, respectively)

Exclusion:

Patients were ineligible if they had: haemodynamically severe uncorrected primary valvular disease; active myocarditis; hypertrophic cardiomyopathy; restrictive cardiomyopathy; myocardial infarction, stroke, unstable angina, coronary artery bypass graft surgery, valvular surgery, cardiac resynchronization therapy or angioplasty ≤ 3 months before randomisation.

Patients with symptomatic or sustained ventricular tachycardia not controlled by antiarrhythmic drugs or an implantable cardioverter–defibrillator

Any condition other than HF that would be expected to limit exercise (e.g., angina, peripheral vascular disease, pulmonary disease, arthritis or an orthopaedic problem severe enough to limit exercise)

Nursing mothers, pregnant women and those planning a pregnancy during the study period

10


C. oxycantha extract, Crataegus Special Extract WS 1442 (Crategutt forte, Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany), 450 mg orally twice daily, or a matching placebo


Our primary objective was to test the effect of Crataegus Special Extract WS 1442 on submaximal exercise capacity at 6 months as determined by the 6 min walk test.

The secondary objectives included:

o Physician and patient global assessment of the change in heart failure symptoms from baseline on a 7-point Likert scale

o Disease-specific QOL as determined by the Minnesota Living with Heart Failure Questionnaire (MLHFQ)

o Functional capacity as accessed by peak exercise oxygen consumption (peak VO2) and anaerobic threshold during maximal cardiopulmonary treadmill exercise testing using a modified Naughton ramp protocol

o Functional capacity as subjectively assessed by NYHA functional classification

o LVEF

o Mortality risk as determined by the Heart Failure Survival Score (HFSS)

o Neuro-hormone profile

o Oxidative stress Inflammation Global QOL

o Utility for health status [as determined by the utility component of the EQ5D (Visual Analogue Scale)

o Hospitalizations during the 6-month study period


Yes


Yes. By having the participants already taking the normal medications assigned to heart failure patients, the results are more valid since patient would likely take hawthorn on top of medications


Yes; 6 months

What was the compliance of the study?

Fifty-seven participants in the placebo group and 54 participants in the hawthorn arm completed all study visits. Adherence to study medications was high with 98% of all participants taking greater than 95% of all study medication and with no significant differences between groups.

11


Yes

Results


120 randomized 60 assigned to placebo 57 completed the trials in the placebo group 60 assigned to hawthorn 54 completed the trial in the hawthorn group

Calculate % follow-up 111/120= 92.5%


Yes


Despite the entry criteria of an LVEF "40% on a clinically indicated study obtained within the prior 12 months (see above), the baseline study radionuclide ventriculogram performed after randomization revealed an LVEF of greater than 40% in 38 study participants. Since the baseline assessment of LVEF occurred after randomization, we were not able to exclude these patients. Consequently, the effects of study drug vs. placebo on 6 min walk distance and secondary outcomes at 6 months were also evaluated by ANCOVA, adjusting for baseline value and baseline.


Yes

Overall impressions


The limitation of the study were discussed

Numerous secondary outcomes were measured to asses Hawthorn’s impact


The study had a fairly small sample size (n=120)

The study length was short (6 months)

STUDY #3: The effect of Crataegus oxycantha Special Extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure.



Zick SM, Gillespie B, Aaronson KD. The effect of Crataegus oxycantha Special Extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure. Eur J Heart Fail. 2008 Jun;10(6):587-

12

93. Epub 2008 May 19. PubMed PMID: 18490196; PubMed Central PMCID: PMC2577845.

Study design Retrospective analysis of a randomized, double-blind, placebo-controlled trial

Purpose of the study The aim of the study was to examine whether hawthorn (Crataegus Special Extract WS 1442 {CSE}) inhibits progression in heart failure (HF) patients.

Location of the study University of Michigan

Funding of the study Grant to the University of Michigan Complementary and Alternative Medicine Research Center from the National Center for Complementary and Alternative Medicine. Research resources were also provided by the General Clinical Research Center of the University of Michigan


No

Methods


Inclusion:

Ambulatory patients aged 18 years of age and older with a !3 months history of HF (NYHA classes II-III) and a left ventricular ejection fraction (LVEF) "40%

Patients had to be receiving standard medical therapy (in the absence of a contraindication or intolerance), defined as an angiotensin converting enzyme inhibitor or angiotensin receptor antagonist, a beta-blocker and a diuretic.

Subjects had to walk between 150 and 450 m during two 6 min walk tests, conducted 2 weeks apart (screening and baseline visits, respectively)

Exclusion:

Patients were ineligible if they had: haemodynamically severe uncorrected primary valvular disease; active myocarditis; hypertrophic cardiomyopathy; restrictive cardiomyopathy; myocardial infarction, stroke, unstable angina, coronary artery bypass graft surgery, valvular surgery, cardiac resynchronization therapy or angioplasty ≤ 3 months before randomisation.

Patients with symptomatic or sustained ventricular tachycardia not controlled by antiarrhythmic drugs or an implantable cardioverter–defibrillator

Any condition other than HF that would be expected to limit exercise (e.g., angina, peripheral vascular disease, pulmonary disease, arthritis or an orthopaedic problem severe enough to limit exercise)

Nursing mothers, pregnant women and those planning a pregnancy during the study period

Study intervention C. oxycantha extract, Cratae- gus Special Extract WS 1442 (Crategutt forte,

13

(independent variables) Willmar Schwabe Phar- maceuticals, Karlsruhe, Germany), 450 mg orally twice daily, or a matching placebo


The primary outcome for this analysis, progression of HF, was defined as (1) death due to HF, (2) hospitalization due to HF, or (3) sustained increase in diuretic dose for HF.


Yes




No. It would have been better if the study was longer than six months since the study was looking at heart failure progression

Briefly describe the diet tools & methods used

Fifty-seven participants in the placebo group and 54 participants in the hawthorn arm completed all study visits. Adherence to study medications was high with 98% of all participants taking greater than 95% of all study medication and with no significant differences between groups.


Yes

Results


120 randomized 60 assigned to placebo 57 completed the trials in the placebo group 60 assigned to hawthorn 54 completed the trial in the hawthorn group

Calculate % follow-up 111/120= 92.5%


Yes


No adjustments needed

As best you can tell, are Author’s conclusions

Yes

14

supported by data in text and tables

Overall impressions


Explained possible reasons for observed results and discussed study limitations

Used many statistical test to analysis the data


Retrospective analysis

The study had a fairly small sample size (n=120) and study length was short (6 months)

STUDY #4: Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York Heart Association class-III heart failure.



Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York Heart Association class-III heart failure. Am Heart J. 2002 May;143(5):910-5. PubMed PMID: 12040357.

Study design Randomized, double-blind, placebo-controlled, multicentric trial

Purpose of the study The purpose of this study was to investigate whether long-term therapy with crataegus extract WS 1442 is efficacious as add-on therapy to preexisting diuretic treatment in patients with heart failure with a more advanced stage of the disease (New York Heart Association [NYHA] class III), whether effects are dose dependent, and whether the treatment is safe and well tolerated.

Location of the study 18 centers in Germany

Funding of the study Not mentioned


Since funding was not mentioned the bias can not be assed

Methods


Inclusion:

> 40 years old with chronic congestive heart failure (NYHA class III) known for at least 6 months were eligible for participation in this study if they were previously untreated or treated with a diuretic and/or with a low dose of an angiotensin-converting enzyme (ACE) inhibitor

Have an exercise capacity of #75 watts (W) as assessed by seated

15

bicycle ergometry. Exclusion:

NYHA status I, II, or IV

Treatment with digitalis within the previous 6 months

Exercise capacity of $75 W for 2 min at the test during run-in

Unstable angina or myocardial infarction within the previous 6 months

Atrial fibrillation or ventricular arrhythrnia

Lown III Cardiac valvular disease or hypertrophic cardiomyopathy

Significant hypertension or hypotension (%60mmHg or &105mmHg diastolic or %90mmHg or $175mmHg systolic)

Electrolyte disturbances, hyperuricemia, hypovolemia Impaired renal function (creatinine $1.8 mg/dL) or hepatic function

Obstructive airways disease Insulin-dependent diabetes

Malignant or other serious disease

Hypersensitivity to study drug

Pregnancy, unreliable contraception, breast-feeding mothers

Participation in another clinical trial within the previous 6 weeks


16 weeks with either 450 mg WS 1442 bid or 900 mg WS 1442 bid, or placebo bid, in addition to the preexisting diuretic therapy, which remained unchanged


Exercise capacity was assessed by use of seated bicycle ergometry with incremental workloads.


Yes




Yes

Was compliance measured?

Yes; compliance checks were carried out by pill counting

Were the validity and reliability of tools

Yes

16

discussed?

Results


Total participants at start of trial- 209 1800mg of WS 1442- 69 900mg of WS 1442- 70 Placebo group- 70

Total participants at end of trial- 197 1800mg of WS 1442- 68 900mg of WS 1442- 63 Placebo group- 66

Calculate % follow-up 94%


Yes


No, groups were the same at entry


Yes

Overall impressions


Performed a 4 week-single blind run in phase which helps make them more comparable once they are on the treatment of placebo

Looked at more than once dose of WS 1442 to see the dose-dependent relationship of the drug


Did not discuss limitations of the study or indicate the study’s funding

P-values and Confidence intervals were not presents for findings

STUDY #5: Clinical efficacy of crataegus extract WS 1442 in congestive heart failure NYHA class II.



Zapfe jun G. Clinical efficacy of crataegus extract WS 1442 in congestive heart failure NYHA class II. Phytomedicine. 2001 Jul;8(4):262-6. PubMed PMID: 11515715.

Study design Randomized, placebo-controlled, double-blind clinical study

17

Purpose of the study The aim of the study was to investigate the clinical efficacy and safety of crataegus extract WS 1442 on patients suffering from congestive heart failure NYHA class II

Location of the study Erlangen, Germany

Funding of the study Not stated


Funding was not stated, thus the potential bias cannot be assessed

Methods


Inclusion: Chronic congestive heart failure NYHA II Age 40 to 80 years Informed consent according to German Drug Law (AMG)

Exclusion: Severe cerebral deterioration Severe organic or mental disease (e.g. addiction) Decompensated heart disease Pregnancy or lactation Severe blood pressure elevation (diastolic > 120 mmHg) Ventricular arrhythmia (> Lown class III) Cardiac infarction within the last 6 months Unstable angina pectoris Participation in other clinical trials simultaneously or with-in the last

4 weeks Degenerative joint disease or other disorder, that limits ergometric

investigation from the outset


They were treated with either 240 mg/d Crataegus extract WS® 1442 (80 mg t. i. d.) or matching placebos for 12 weeks.


The primary outcome variable was exercise tolerance determined with bicycle exercise testing Secondary outcome variable the difference of the double product was calculated


Yes


No. it is unlikely that patients will stop taking all drugs and just take hawthorn to help improve the symptoms of heart failure

Was the intervention 12 weeks – 4 months

18

duration long-enough?

Was compliance measured?

Study does not indicated if or how compliance was measured.


Yes

Results


Patients at the beginning of the trail: 40 Patients at the end of the trail: 39

Calculate % follow-up 97.5%


Yes


No, groups were comparable no adjustments were needed


Yes

Overall impressions


The study had a 7 day wash out period before initiation of the treatment

Both treatment and placebo groups were comparable in terms of baseline characteristics


Study duration was short (4 months)

Study population was small (n=40)

19

IV. QUALITY CRITERA CHECKLIST STUDY #1: The efficacy and safety of Crataegus extract WS® 1442 in patients with heart failure: The SPICE trial. RELEVANCE QUESTIONS 1. Would implementing the studied intervention or procedure (if found successful) result in

improved outcomes for the patients/clients/population group? (NA for some Epi studies) – No

Yes No

2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?

Yes No

3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dietetics practice?

Yes No

4. Is the intervention or procedure feasible? (NA for some Epidemiological studies) Yes No I f the answers to a l l o f the above Relevance Ques t ions are “Yes ,” the r epor t i s e l i g ib l e fo r

des i gnat ion wi th a p lus (+) on the Evidence Qual i ty Workshee t , depending on answers to the fo l lowing Val id i ty Ques t ions .

VALIDITY QUESTIONS 1. Was the research question clearly stated?

1.1 Was the specific intervention(s) or procedure (independent variable(s)) identified?- yes 1.2 Was the outcome(s) (dependent variable(s)) clearly indicated? – yes 1.3 Were the target population and setting specified? – yes

Yes No

2. Was the selection of study subjects/patients free from bias? 2.1 Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression,

diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? – yes

2.2 Were criteria applied equally to all study groups? –yes 2.3 Were health, demographics and other characteristics of subjects described?- yes 2.4 Were the subjects/patients a representative sample of the relevant population?- yes

Yes No

3. Were study groups comparable? 3.1 Was the method of assigning subjects/patients to groups described and unbiased?

(Method of randomization identified if RCT) – yes 3.2 Were distribution of disease status, prognostic factors and other factors (e.g.,

demographics) similar across study groups at baseline? – yes 3.3 Were concurrent controls used? (Concurrent preferred over historical controls.) – yes 3.4 If cohort study or cross-sectional study, were groups comparable on important

confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? – N/A

3.5 If case control study, were potential confounding factors comparable for cases and controls? If case series or trial with subjects serving as own control, this criterion is not applicable. Criterion may not be applicable in some cross-sectional studies. – N/A

3.6 If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., “gold standard”)?– N/A

Yes No

4. Was method of handling withdrawals described? 4.1 Were follow up methods described and the same for all groups?- yes 4.2 Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up,

attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) – yes

4.3 Were all enrolled subjects/patients (in the original sample) accounted for? – yes 4.4 Were reasons for withdrawals similar across groups?- yes 4.5 If diagnostic test, was decision to perform reference test not dependent on results of test

under study? – N/A

Yes No

5. Was blinding used to prevent introduction of bias? Yes No

20

5.1 In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?- yes

5.2 Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met)- yes

5.3 In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? – N/A

5.4 In case control study, was case definition explicit and case ascertainment not influenced by exposure status? – N/A

5.5 In diagnostic study, were test results blinded to patient history and other test results?

6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were intervening factors described? 6.1. In RCT or other intervention trial, were protocols described for all regimens studied?

– yes 6.2. In observational study, were interventions, study settings, and clinicians/provider

described? – N/A 6.3 Was the intensity and duration of the intervention or exposure factor sufficient to

produce a meaningful effect? – yes 6.4 Was the amount of exposure and, if relevant, subject/patient compliance measured? –

yes 6.5 Were co-interventions (e.g., ancillary treatments, other therapies) described?- N/A 6.6 Were extra or unplanned treatments described? – N/A the same way for all groups? – yes 6.8 In diagnostic study, were details of test administration and replication sufficient?

Yes No

7. Were outcomes clearly defined and the measurements valid and reliable? 7.1 Were primary and secondary endpoints described and relevant to the question? - yes 7.2 Were nutrition measures appropriate to question and outcomes of concern? – yes 7.3 Was the period of follow-up long enough for important outcome(s) to occur? – yes 7.4 Were the observations and measurements based on standard, valid and reliable data

collection instruments/tests/procedures? – yes 7.5 Was the measurement of effect at an appropriate level of precision? – yes 7.6 Were other factors accounted for (measured) that could affect outcomes? – yes 7.7 Were the measurements conducted consistently across groups? – yes

Yes No

8. Was the statistical analysis appropriate for the study design and type of outcome indicators? 8.1 Were statistical analyses adequately described the results reported appropriately? – yes 8.2 Were correct statistical tests used and assumptions of test not violated? – yes 8.3 Were statistics reported with levels of significance and/or confidence intervals? – yes 8.4 Was “intent to treat” analysis of outcomes done (and as appropriate, was there an

analysis of outcomes for those maximally exposed or a dose-response analysis)? – yes 8.5 Were adequate adjustments made for effects of confounding factors that might have

affected the outcomes (e.g., multivariate analyses)?- N/A 8.6 Was clinical significance as well as statistical significance reported? – yes 8.7 If negative findings, was a power calculation reported to address type 2 error? – no,

power of the study was noted but not to address type to error just to asses need study size

Yes No

9. Are conclusions supported by results with biases and limitations taken into consideration? 9.1 Is there a discussion of findings?- yes 9.2 Are biases and study limitations identified and discussed?- no

Yes No

10. Is bias due to study’s funding or sponsorship unlikely? 10.1 Were sources of funding and investigators’ affiliations described?- yes 10.2 Was there no apparent conflict of interest?- no

Yes No

The quality rating for this paper is: (+) MINUS/NEGATIVE (-): If most (six or more) of the answers to the above validity questions are “No,” the report should be designated with a minus (-) symbol on the Evidence Quality Worksheet. NEUTRAL (∅): If the answers to validity criteria questions 2, 3, 6 and 7 do not indicate that the study is exceptionally strong, the report should be designated with a neutral (∅) symbol on the Evidence Quality Worksheet. PLUS/POSITIVE (+): If most of the answers to the above validity questions are “Yes” (including criteria 2, 3, 6, 7 and at

21

least one additional “Yes”); the report should be designated with a plus symbol (+) on the Evidence Quality Worksheet.

STUDY #2: Hawthorn Extract Randomized Blinded Chronic Heart Failure (HERB

CHF) Trial.

RELEVANCE QUESTIONS

1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (NA for some Epi studies)- yes

Yes No

2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? - yes

Yes No

3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dietetics practice? - yes

Yes No

4. Is the intervention or procedure feasible? (NA for some Epidemiological studies) - yes Yes No I f the answers to a l l o f the above Rel evance Ques t ions are “Yes ,” the r epor t i s e l i g ib l e fo r des i gnat ion wi th a p lus (+) on the Evidence Qual i ty Workshee t , depending on answers to the fo l lowing Val id i ty Ques t ions .

VALIDITY QUESTIONS

1. Was the research question clearly stated? 1.1 Was the specific intervention(s) or procedure (independent variable(s)) identified?- yes 1.2 Was the outcome(s) (dependent variable(s)) clearly indicated? - yes 1.3 Were the target population and setting specified? - yes

Yes No


diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? - yes

2.2 Were criteria applied equally to all study groups? - yes 2.3 Were health, demographics and other characteristics of subjects described? - yes 2.4 Were the subjects/patients a representative sample of the relevant population? - yes

Yes No


(Method of randomization identified if RCT)- yes 3.2 Were distribution of disease status, prognostic factors and other factors (e.g.,

demographics) similar across study groups at baseline?- yes 3.3 Were concurrent controls used? (Concurrent preferred over historical controls.) – yes 3.4 If cohort study or cross-sectional study, were groups comparable on important

confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? - n/a

3.5 If case control study, were potential confounding factors comparable for cases and controls? If case series or trial with subjects serving as own control, this criterion is not applicable. Criterion may not be applicable in some cross-sectional studies. - n/a

3.6 If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., “gold standard”)?- n/a

Yes No

4. Was method of handling withdrawals described? 4.1 Were follow up methods described and the same for all groups?- yes 4.2 Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up,

attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)- - yes

4.3 Were all enrolled subjects/patients (in the original sample) accounted for? - yes 4.4 Were reasons for withdrawals similar across groups? - yes 4.5 If diagnostic test, was decision to perform reference test not dependent on results of test

under study? - n/a

Yes No

22

5. Was blinding used to prevent introduction of bias? 5.1 In intervention study, were subjects, clinicians/practitioners, and investigators blinded

to treatment group, as appropriate? –yes 5.2 Were data collectors blinded for outcomes assessment? (If outcome is measured using

an objective test, such as a lab value, this criterion is assumed to be met) – yes 5.3 In cohort study or cross-sectional study, were measurements of outcomes and risk

factors blinded? - n/a 5.4 In case control study, was case definition explicit and case ascertainment not influenced

by exposure status? - n/a 5.5 In diagnostic study, were test results blinded to patient history and other test results? -

n/a

Yes No


- yes 6.2. In observational study, were interventions, study settings, and clinicians/provider

described? 6.3 Was the intensity and duration of the intervention or exposure factor sufficient to

produce a meaningful effect? –yes 6.4 Was the amount of exposure and, if relevant, subject/patient compliance measured? -

yes 6.5 Were co-interventions (e.g., ancillary treatments, other therapies) described? - n/a 6.6 Were extra or unplanned treatments described? - n/a 6.7 Was the information for 6d, 6e, and 6f assessed the same way for all groups? - yes 6.8 In diagnostic study, were details of test administration and replication sufficient? - n/a

Yes No

7. Were outcomes clearly defined and the measurements valid and reliable? 7.1 Were primary and secondary endpoints described and relevant to the question? - yes 7.2 Were nutrition measures appropriate to question and outcomes of concern? - no 7.3 Was the period of follow-up long enough for important outcome(s) to occur? –yes 7.4 Were the observations and measurements based on standard, valid and reliable data

collection instruments/tests/procedures? - yes 7.5 Was the measurement of effect at an appropriate level of precision? - yes 7.6 Were other factors accounted for (measured) that could affect outcomes? - yes 7.7 Were the measurements conducted consistently across groups? - yes

Yes No

8. Was the statistical analysis appropriate for the study design and type of outcome indicators? 8.1 Were statistical analyses adequately described the results reported appropriately? - yes 8.2 Were correct statistical tests used and assumptions of test not violated? - yes 8.3 Were statistics reported with levels of significance and/or confidence intervals? - yes 8.4 Was “intent to treat” analysis of outcomes done (and as appropriate, was there an

analysis of outcomes for those maximally exposed or a dose-response analysis)? - yes 8.5 Were adequate adjustments made for effects of confounding factors that might have

affected the outcomes (e.g., multivariate analyses)? - yes 8.6 Was clinical significance as well as statistical significance reported?- yes 8.7 If negative findings, was a power calculation reported to address type 2 error?- no

Yes No

9. Are conclusions supported by results with biases and limitations taken into consideration? 9.1 Is there a discussion of findings?- yes 9.2 Are biases and study limitations identified and discussed?- yes

Yes No

10. Is bias due to study’s funding or sponsorship unlikely? 10.1 Were sources of funding and investigators’ affiliations described?- yes 10.2 Was there no apparent conflict of interest? – yes

Yes No

The quality rating for this paper is: ( +) MINUS/NEGATIVE (-): If most (six or more) of the answers to the above validity questions are “No,” the report should be designated with a minus (-) symbol on the Evidence Quality Worksheet.

23

NEUTRAL (∅): If the answers to validity criteria questions 2, 3, 6 and 7 do not indicate that the study is exceptionally strong, the report should be designated with a neutral (∅) symbol on the Evidence Quality Worksheet. PLUS/POSITIVE (+): If most of the answers to the above validity questions are “Yes” (including criteria 2, 3, 6, 7 and at least one additional “Yes”); the report should be designated with a plus symbol (+) on the Evidence Quality Worksheet.

STUDY #3 The effect of Crataegus oxycantha Special Extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure. RELEVANCE QUESTIONS

1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (NA for some Epi studies) - yes

Yes No


Yes No


Yes No

4. Is the intervention or procedure feasible? (NA for some Epidemiological studies) - yes Yes No I f the answers to a l l o f the above Relevance Ques t ions are “Yes ,” the r epor t i s e l i g ib l e fo r des i gnat ion wi th a p lus (+) on the Evidence Qual i ty Workshee t , depending on answers to the fo l lowing Val id i ty Ques t ions .

VALIDITY QUESTIONS

1. Was the research question clearly stated? 1.1 Was the specific intervention(s) or procedure (independent variable(s)) identified? - yes 1.2 Was the outcome(s) (dependent variable(s)) clearly indicated? - yes 1.3 Were the target population and setting specified? - yes

Yes No




Yes No


(Method of randomization identified if RCT) –yes 3.2 Were distribution of disease status, prognostic factors and other factors (e.g.,

demographics) similar across study groups at baseline? ) –yes 3.3 Were concurrent controls used? (Concurrent preferred over historical controls.) ) –yes 3.4 If cohort study or cross-sectional study, were groups comparable on important

confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? –n/a

3.5 If case control study, were potential confounding factors comparable for cases and controls? If case series or trial with subjects serving as own control, this criterion is not applicable. Criterion may not be applicable in some cross-sectional studies. –n/a

3.6 If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., “gold standard”)? –n/a

Yes No

4. Was method of handling withdrawals described? 4.1 Were follow up methods described and the same for all groups? –yes 4.2 Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up,

attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) –yes

4.3 Were all enrolled subjects/patients (in the original sample) accounted for? –yes 4.4 Were reasons for withdrawals similar across groups? –yes

Yes No

24

4.5 If diagnostic test, was decision to perform reference test not dependent on results of test under study? –n/a


to treatment group, as appropriate? –yes 5.2 Were data collectors blinded for outcomes assessment? (If outcome is measured using

an objective test, such as a lab value, this criterion is assumed to be met) –yes 5.3 In cohort study or cross-sectional study, were measurements of outcomes and risk

factors blinded? –n/a 5.4 In case control study, was case definition explicit and case ascertainment not influenced

by exposure status? –n/a 5.5 In diagnostic study, were test results blinded to patient history and other test results? –

n/a

Yes No


–yes 6.2. In observational study, were interventions, study settings, and clinicians/provider

described? –n/a 6.3 Was the intensity and duration of the intervention or exposure factor sufficient to

produce a meaningful effect? –yes 6.4 Was the amount of exposure and, if relevant, subject/patient compliance measured? –

yes 6.5 Were co-interventions (e.g., ancillary treatments, other therapies) described? –n/a 6.6 Were extra or unplanned treatments described? –n/a 6.7 Was the information for 6d, 6e, and 6f assessed the same way for all groups? 6.8 In diagnostic study, were details of test administration and replication sufficient? –n/a

Yes No

7. Were outcomes clearly defined and the measurements valid and reliable? 7.1 Were primary and secondary endpoints described and relevant to the question? –yes 7.2 Were nutrition measures appropriate to question and outcomes of concern? –yes 7.3 Was the period of follow-up long enough for important outcome(s) to occur? –no 7.4 Were the observations and measurements based on standard, valid and reliable data

collection instruments/tests/procedures? –yes 7.5 Was the measurement of effect at an appropriate level of precision? –yes 7.6 Were other factors accounted for (measured) that could affect outcomes? –no 7.7 Were the measurements conducted consistently across groups? –yes

Yes No

8. Was the statistical analysis appropriate for the study design and type of outcome indicators? 8.1 Were statistical analyses adequately described the results reported appropriately? –yes 8.2 Were correct statistical tests used and assumptions of test not violated? –yes 8.3 Were statistics reported with levels of significance and/or confidence intervals? –yes 8.4 Was “intent to treat” analysis of outcomes done (and as appropriate, was there an

analysis of outcomes for those maximally exposed or a dose-response analysis)? –yes 8.5 Were adequate adjustments made for effects of confounding factors that might have

affected the outcomes (e.g., multivariate analyses)? –no 8.6 Was clinical significance as well as statistical significance reported? –yes 8.7 If negative findings, was a power calculation reported to address type 2 error?- no

Yes No

9. Are conclusions supported by results with biases and limitations taken into consideration? 9.1 Is there a discussion of findings? –yes 9.2 Are biases and study limitations identified and discussed? –yes

Yes No

10. Is bias due to study’s funding or sponsorship unlikely? 10.1 Were sources of funding and investigators’ affiliations described? –yes 10.2 Was there no apparent conflict of interest? –yes

Yes No

The quality rating for this paper is: (+) MINUS/NEGATIVE (-): If most (six or more) of the answers to the above validity questions are “No,” the report should be designated with a minus (-) symbol on the Evidence Quality Worksheet.

25

NEUTRAL (∅): If the answers to validity criteria questions 2, 3, 6 and 7 do not indicate that the study is exceptionally strong, the report should be designated with a neutral (∅) symbol on the Evidence Quality Worksheet. PLUS/POSITIVE (+): If most of the answers to the above validity questions are “Yes” (including criteria 2, 3, 6, 7 and at least one additional “Yes”); the report should be designated with a plus symbol (+) on the Evidence Quality Worksheet.

Study #4 Efficacy and safety of crataegus extract WS 1442 in comparison with

placebo in patients with chronic stable New York Heart Association class-III heart

failure.

RELEVANCE QUESTIONS

1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (NA for some Epi studies)- yes

Yes No


Yes No


Yes No

4. Is the intervention or procedure feasible? (NA for some Epidemiological studies) - yes Yes No I f the answers to a l l o f the above Relevance Ques t ions are “Yes ,” the r epor t i s e l i g ib l e fo r des i gnat ion wi th a p lus (+) on the Evidence Qual i ty Workshee t , depending on answers to the fo l lowing Val id i ty Ques t ions .

VALIDITY QUESTIONS

1. Was the research question clearly stated? 1.1 Was the specific intervention(s) or procedure (independent variable(s)) identified? - yes 1.2 Was the outcome(s) (dependent variable(s)) clearly indicated? - yes 1.3 Were the target population and setting specified? - yes

Yes No




Yes No


(Method of randomization identified if RCT) - yes 3.2 Were distribution of disease status, prognostic factors and other factors (e.g.,

demographics) similar across study groups at baseline? - yes 3.3 Were concurrent controls used? (Concurrent preferred over historical controls.) - yes 3.4 If cohort study or cross-sectional study, were groups comparable on important

confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? -n/a

3.5 If case control study, were potential confounding factors comparable for cases and controls? If case series or trial with subjects serving as own control, this criterion is not applicable. Criterion may not be applicable in some cross-sectional studies. -n/a

3.6 If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., “gold standard”)? -n/a

Yes No

4. Was method of handling withdrawals described? 4.1 Were follow up methods described and the same for all groups? - yes 4.2 Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up,

attrition rate) and/or response rate (cross-sectional studies) described for each group?

Yes No

26

(Follow up goal for a strong study is 80%.) - yes 4.3 Were all enrolled subjects/patients (in the original sample) accounted for? - yes 4.4 Were reasons for withdrawals similar across groups? - yes 4.5 If diagnostic test, was decision to perform reference test not dependent on results of test

under study? -n/a


to treatment group, as appropriate? - yes 5.2 Were data collectors blinded for outcomes assessment? (If outcome is measured using

an objective test, such as a lab value, this criterion is assumed to be met) - yes 5.3 In cohort study or cross-sectional study, were measurements of outcomes and risk

factors blinded? -n/a 5.4 In case control study, was case definition explicit and case ascertainment not influenced

by exposure status? -n/a 5.5 In diagnostic study, were test results blinded to patient history and other test results? -

n/a

Yes No


- yes 6.2. In observational study, were interventions, study settings, and clinicians/provider

described? -n/a 6.3 Was the intensity and duration of the intervention or exposure factor sufficient to

produce a meaningful effect? –yes 6.4 Was the amount of exposure and, if relevant, subject/patient compliance measured? -

yes 6.5 Were co-interventions (e.g., ancillary treatments, other therapies) described? -n/a 6.6 Were extra or unplanned treatments described? -n/a 6.7 Was the information for 6d, 6e, and 6f assessed the same way for all groups? - yes 6.8 In diagnostic study, were details of test administration and replication sufficient? -n/a

Yes No

7. Were outcomes clearly defined and the measurements valid and reliable? 7.1 Were primary and secondary endpoints described and relevant to the question? - yes 7.2 Were nutrition measures appropriate to question and outcomes of concern? - yes 7.3 Was the period of follow-up long enough for important outcome(s) to occur? –yes 7.4 Were the observations and measurements based on standard, valid and reliable data

collection instruments/tests/procedures? - yes 7.5 Was the measurement of effect at an appropriate level of precision? - yes 7.6 Were other factors accounted for (measured) that could affect outcomes?- no 7.7 Were the measurements conducted consistently across groups? - yes

Yes No

8. Was the statistical analysis appropriate for the study design and type of outcome indicators? 8.1 Were statistical analyses adequately described the results reported appropriately? - no 8.2 Were correct statistical tests used and assumptions of test not violated? - yes 8.3 Were statistics reported with levels of significance and/or confidence intervals? - no 8.4 Was “intent to treat” analysis of outcomes done (and as appropriate, was there an

analysis of outcomes for those maximally exposed or a dose-response analysis)? - yes 8.5 Were adequate adjustments made for effects of confounding factors that might have

affected the outcomes (e.g., multivariate analyses)? - no 8.6 Was clinical significance as well as statistical significance reported? - yes 8.7 If negative findings, was a power calculation reported to address type 2 error?- - no

Yes No

9. Are conclusions supported by results with biases and limitations taken into consideration? 9.1 Is there a discussion of findings? - yes 9.2 Are biases and study limitations identified and discussed? - no

Yes No

10. Is bias due to study’s funding or sponsorship unlikely? Yes No

27

10.1 Were sources of funding and investigators’ affiliations described? - no 10.2 Was there no apparent conflict of interest? - no

The quality rating for this paper is: (+) MINUS/NEGATIVE (-): If most (six or more) of the answers to the above validity questions are “No,” the report should be designated with a minus (-) symbol on the Evidence Quality Worksheet. NEUTRAL (∅): If the answers to validity criteria questions 2, 3, 6 and 7 do not indicate that the study is exceptionally strong, the report should be designated with a neutral (∅) symbol on the Evidence Quality Worksheet. PLUS/POSITIVE (+): If most of the answers to the above validity questions are “Yes” (including criteria 2, 3, 6, 7 and at least one additional “Yes”); the report should be designated with a plus symbol (+) on the Evidence Quality Worksheet.

Study #5 Clinical efficacy of crataegus extract WS 1442 in congestive heart failure

NYHA class II.

RELEVANCE QUESTIONS

1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (NA for some Epi studies)

Yes No

2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?

Yes No

3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dietetics practice?

Yes No

4. Is the intervention or procedure feasible? (NA for some Epidemiological studies) Yes No I f the answers to a l l o f the above Relevance Ques t ions are “Yes ,” the r epor t i s e l i g ib l e fo r des i gnat ion wi th a p lus (+) on the Evidence Qual i ty Workshee t , depending on answers to the fo l lowing Val id i ty Ques t ions .

VALIDITY QUESTIONS

1. Was the research question clearly stated? 1.1 Was the specific intervention(s) or procedure (independent variable(s)) identified? – yes 1.2 Was the outcome(s) (dependent variable(s)) clearly indicated? – yes 1.3 Were the target population and setting specified? – yes

Yes No


diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? – yes

2.2 Were criteria applied equally to all study groups? – yes 2.3 Were health, demographics and other characteristics of subjects described? – yes 2.4 Were the subjects/patients a representative sample of the relevant population? – yes

Yes No


(Method of randomization identified if RCT) – yes 3.2 Were distribution of disease status, prognostic factors and other factors (e.g.,

demographics) similar across study groups at baseline? – yes 3.3 Were concurrent controls used? (Concurrent preferred over historical controls.) – yes 3.4 If cohort study or cross-sectional study, were groups comparable on important

confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? – n/a

3.5 If case control study, were potential confounding factors comparable for cases and controls? If case series or trial with subjects serving as own control, this criterion is not applicable. Criterion may not be applicable in some cross-sectional studies. – n/a

3.6 If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., “gold standard”)? – n/a

Yes No

4. Was method of handling withdrawals described? Yes No

28

4.1 Were follow up methods described and the same for all groups? – yes 4.2 Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up,

attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)– yes

4.3 Were all enrolled subjects/patients (in the original sample) accounted for? – yes 4.4 Were reasons for withdrawals similar across groups? – no 4.5 If diagnostic test, was decision to perform reference test not dependent on results of test

under study? – n/a 5. Was blinding used to prevent introduction of bias?

5.1 In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? – yes

5.2 Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met) – yes

5.3 In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? – n/a

5.4 In case control study, was case definition explicit and case ascertainment not influenced by exposure status? – n/a

5.5 In diagnostic study, were test results blinded to patient history and other test results?-n/a

Yes No

6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were intervening factors described? 6.1. In RCT or other intervention trial, were protocols described for all regimens studied? –

yes 6.2. In observational study, were interventions, study settings, and clinicians/provider

described? – n/a 6.3 Was the intensity and duration of the intervention or exposure factor sufficient to

produce a meaningful effect? –yes 6.4 Was the amount of exposure and, if relevant, subject/patient compliance measured? – no 6.5 Were co-interventions (e.g., ancillary treatments, other therapies) described? – no 6.6 Were extra or unplanned treatments described? – no 6.7 Was the information for 6d, 6e, and 6f assessed the same way for all groups? – yes 6.8 In diagnostic study, were details of test administration and replication sufficient? – n/a

Yes No

7. Were outcomes clearly defined and the measurements valid and reliable? 7.1 Were primary and secondary endpoints described and relevant to the question? – yes 7.2 Were nutrition measures appropriate to question and outcomes of concern? – yes 7.3 Was the period of follow-up long enough for important outcome(s) to occur? –yes 7.4 Were the observations and measurements based on standard, valid and reliable data

collection instruments/tests/procedures? – yes 7.5 Was the measurement of effect at an appropriate level of precision? – yes 7.6 Were other factors accounted for (measured) that could affect outcomes? – no 7.7 Were the measurements conducted consistently across groups? – yes

Yes No

8. Was the statistical analysis appropriate for the study design and type of outcome indicators? 8.1 Were statistical analyses adequately described the results reported appropriately? – yes 8.2 Were correct statistical tests used and assumptions of test not violated? – yes 8.3 Were statistics reported with levels of significance and/or confidence intervals? – no 8.4 Was “intent to treat” analysis of outcomes done (and as appropriate, was there an analysis

of outcomes for those maximally exposed or a dose-response analysis)? – yes 8.5 Were adequate adjustments made for effects of confounding factors that might have

affected the outcomes (e.g., multivariate analyses)? – n/a 8.6 Was clinical significance as well as statistical significance reported? – yes 8.7 If negative findings, was a power calculation reported to address type 2 error? – no

Yes No

9. Are conclusions supported by results with biases and limitations taken into consideration? 9.1 Is there a discussion of findings? – yes 9.2 Are biases and study limitations identified and discussed? – no

Yes No

10. Is bias due to study’s funding or sponsorship unlikely? 10.1 Were sources of funding and investigators’ affiliations described? – no

Yes No

29

10.2 Was there no apparent conflict of interest? – no The quality rating for this paper is: (∅) MINUS/NEGATIVE (-): If most (six or more) of the answers to the above validity questions are “No,” the report should be designated with a minus (-) symbol on the Evidence Quality Worksheet. NEUTRAL (∅): If the answers to validity criteria questions 2, 3, 6 and 7 do not indicate that the study is exceptionally strong, the report should be designated with a neutral (∅) symbol on the Evidence Quality Worksheet. PLUS/POSITIVE (+): If most of the answers to the above validity questions are “Yes” (including criteria 2, 3, 6, 7 and at least one additional “Yes”); the report should be designated with a plus symbol (+) on the Evidence Quality Worksheet.

30

V. EVIDENCE SUMMARY Study #1: (+)The e f f i cacy and safe ty o f Crataegus extract WS® 1442 in pat ients with heart fa i lure : The SPICE tr ial . - Holubarsch, C. F. et al. SUMMARY:

This randomized, double blind, placebo-controlled multicenter study looked at the efficacy and safety of Crataegus extract in patients with heart failure. The study population included 2681 adults who presented clinical signs and symptoms of chronic heart failure, NYHA class II or III. The treatment consisted of taking two capsules daily of 450mg of WS 1442 or 0mg of WS 1442 for 24 months. Participants were allowed to continue use of some heart medications at clinically appropriate doses such as β-Blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics, and digoxin or digitoxin. The primary outcome measured was the number of days been baseline and first cardiac event. The secondary outcome assessed consisted of each individual endpoint contributing to a cardiac event. An intention-to-treat analysis was used, which had an 83% completion rate. The total number of patients with a cardiac event during the 24 months was 373 (27.9%) from the treatment group and 388 (28.9%) in the control groups. These findings were not clinically nor statistically significant with an α> 0.05. The use of Crataegus was not shown to reduce the risk of cardiac events in all patients. However, the subgroup of patients with left ventricle function >25% had a lower incidence of sudden cardiac death, which was statistically significant. Strengths of this study include large sample size, study design, and length of study. One weakness of the study was that the limitations of the study were not discussed. Funding of study was stated and no potential bias was found.

Conclusion: C. F. et al concluded that WS 1442 was safe for patients to take in conjunction with optimal medications for heart failure. WS 1442 did not show any significant effect on the primary endpoints across of all cardiac patients. However, the data indicates that’s the treatment can potentially reduce the incidence of sudden cardiac death in patients with left ventricle function >25%. Study #2: (+) Hawthorn Extract Randomized Blinded Chronic Heart Fai lure (HERB CHF) Trial . - Zick et a l . SUMMARY:

This randomized, double blind, placebo-controlled study looked at the impact that Hawthorn has on submaximal exercise capacity when added to standard medical therapy. The study population included 120 ambulatory adults who presented clinical signs and symptoms of chronic heart failure, NYHA class II or III and a left ventricular ejection fraction (LVEF) <40%. Standard medical therapy is described as an angiotensin converting enzyme inhibitor or angiotensin receptor antagonist, a β-Blocker and a diuretic. The treatment consisted of taking two capsules daily of 450mg of WS 1442 or 0mg of WS 1442 for 6 months. The primary outcome measured was the submaximal exercise capacity at 6 months as determined by the 6 minute walk test. The secondary outcome assessed consisted of: (i) physician and patient global assessment of the change in heart failure symptoms from baseline on a 7-point Likert scale; (ii) disease-specific QOL as determined by the Minnesota

31

Living with Heart Failure Questionnaire (MLHFQ); (iii) functional capacity as accessed by peak exercise oxygen consumption (peak VO2) and anaerobic threshold during maximal cardiopulmonary treadmill exercise testing; (iv) functional capacity as subjectively assessed by NYHA functional classification; (v) LVEF; (vi) mortality risk as determined by the Heart Failure Survival Score (HFSS); (vii) neuro-hormone profile; (viii) oxidative stress Inflammation Global QOL; (ix) utility for health status [as determined by the utility component of the EQ5D; and (x) hospitalizations during the 6 month study period. An intention-to-treat analysis was used and the study had a 98% adherence rate. The study results showed no significant change in submaximal exercise capacity during the six-minute walk test (p=0.61). Additionally none of the secondary outcomes assessed showed statistical significance, all had p-values greater than 0.05. Since the findings were not clinically or statistically significant, the use of hawthorn was not shown to increase submaximal exercise capacity. Strengths of this study include study design, numerous outcomes measured, and discussion of study limitations. Some weaknesses of the study include small sample size and short study duration. Funding of study was stated and no potential bias was found.

Conclusion: Zick et al concluded that hawthorn provides no symptomatic or functional benefit for patients when taken in conjunction with standard medical therapy. Study #3: (+) The e f f e c t o f Crataegus oxycantha Spec ial Extract WS 1442 on c l ini cal progress ion in pat ients with mild to moderate symptoms of heart fa i lure . - Zick et al. SUMMARY:

This study was a secondary data analysis of the HERB CHF trial (a randomized, double blind, placebo-controlled study) looking at the impact of Hawthorn on the progression of heart failure. The study population included 120 ambulatory adults who presented clinical signs and symptoms of chronic heart failure, NYHA class II or III and a left ventricular ejection fraction (LVEF) <40%, and standard medical therapy. Standard medical therapy is described as an angiotensin converting enzyme inhibitor or angiotensin receptor antagonist, a β-Blocker and a diuretic. The treatment consisted of taking two capsules daily of 450mg of WS 1442 or 0mg of WS 1442 for 6 months. The primary outcome measured was time progression of heart failure in terms of heart failure death, hospitalization, or sustained increase in diuretics. The study had a 92% follow-up rate. The progression of heart failure was evident in 46.6% of the treatment group and 43.3% in the placebo group. The difference in outcomes between these two groups was not statistically significant (p=0.86). The treatment has more heart failure death (3.3% vs. 1.6%) and hospitalization (18.3% vs. 10%) but less frequent need for increased diuretic (25% vs. 31.6%) compared to the placebo group. The non-proportional Cox model of regression analysis showed that the risk of having heart failure progression in the group taking the hawthorn supplement was HR=3.2 (95%, CI=1.3, 8.3, p=0.02) times higher than in the placebo group. Strengths of this study include study several statistical test and discussion of study limitations. Some weaknesses of the study include study design, small sample size, and short study duration. Funding of study was stated and no potential bias was found.

32

Conclusion: Zick et al. concluded that hawthorn does not reduce the risk of heart failure progression in individuals with heart failure. Additionally, Hawthorn may increase early risk of heart failure progression for those who are ill and have left ventricular ejection fraction (LVEF) <35%. Study #4: (+) Eff i cacy and safe ty o f crataegus extract WS 1442 in comparison with placebo in pat ients with chronic s table New York Heart Assoc iat ion c lass-III heart fa i lure . - Tauchert , M. SUMMARY:

This randomized, double blind, placebo-controlled multicenter study investigated the impact and effectiveness of long-term therapy with cratargus extract WS 1442 as an add-on therapy to pre-existing diuretic treatment in patients with more advance stages of heart failure. The study population included 209 adults > 40 years old with chronic congestive heart failure (NYHA class III) known for at least 6 months, previously untreated or treated with diuretic and/or low dose of an angiotensin-converting enzyme and had an exercise capacity of <75 watts as assessed by seat bicycle ergometry. The treatment consisted of a 4 week single blind run in phase, in which all participants took placebo tablets twice daily in addition to of taking a combination of 50mg of triamterene and 25mg of hydroclorothiazide once daily in the morning. After the 4 weeks of the placebo the participants were randomized into two treatment groups and one placebo group where they and followed the treatment for 16 weeks and took the capsules twice daily: 69 took the 1800mg of WS 1442, 70 took 900mg of WS 1442, and 70 in the placebo group. During the trial, participants were not permitted to take digitalis, ACE-inhibitors, sympathomimetics, antiarrhythmics, vasodilators, and diuretics other than triamterene/ hydrochlorothiazide. The primary outcome measured was measured three times (run in phase, week 6, and week 16) using the symptom-limited bicycle exercise test that started at an initial work load of 25 watts and increased by 25 watts every two minutes. An intention-to-treat analysis was used, the study had a 94% completion rate. The treatment groups showed a statistically significant increase (1800mg WS 1442, p= 0.013; 900mg WS 1442, p=0.01) in the maximal workload tolerated in comparison to the placebo. The treatment also showed a statistically significant reduction in typical symptoms and complaints of heart failure compared to the placebo. The efficacy, tolerability and incidence of adverse events were lowest in the 1800mg WS 1442 group. Strengths of this study include study design and having wash out period. Some weaknesses of the study include lack of p-values and confidence intervals for all findings, small sample size, and short study duration. Funding of study was not stated therefore potential bias could not be assessed. Conclusion: This study showed WS 14422 to be tolerated and safe and have a dose-dependent effect of WS 1442 on exercise capacity of patients with heart failure.

33

Study #5: (∅ ) Clinical e f f i cacy o f crataegus extract WS 1442 in congest ive heart fa i lure NYHA class II - G. Zepfe jun. SUMMARY:

This randomized, double blind, placebo-controlled study investigated the clinical efficacy and safety of cratargus extract WS 1442 in outpatients suffering from congestive heart failure NYHA class II. The study population included 40 adults aged 40-80 suffering from mild to chronic heart failure. The treatment consisted of a 7-day wash out period for participants that were taking a medication not allowed during the trial such as cardiac glycosides, diuretics, calcium antagonists, ACE inhibitors and other hawthorn preparations. The participants were randomized into treatment and placebo groups where they followed the treatment for 12 weeks, taking the capsules twice daily: 80mg of WS 1442 (n=20), 0mg of WS 1442 (n=20). The primary outcome was measured five times using the symptom-limited bicycle exercise test that started at an initial work load of 25 watts and increased by 25 watts every two minutes. An intention-to-treat analysis was used, the study had a 97.5% completion rate. In the treatment group the exercise tolerance increased by 66.3 W x min (616.3 W x min at the start of the study to 682.5 W x min by the end). In the placebo group, the exercise tolerance decreased by 105.3 W x min over the 12-week study duration (623.8 W x min to 527.6 W x min). The change in exercise tolerance had a p-value of 0.06 compared to the placebo group. The drug was well tolerated by study participants. Strengths of this study include study design and having wash out period. Some weaknesses of the study include small sample size, and short study duration. Funding of study was not stated therefore potential bias could not be assessed.

Conclusion: The study concludes that cratargus extract WS 1442 in effective at improving exercise tolerance in patients suffering from congestive heart failure.

34

VI. CONCLUSION STATEMENT AND PRACTICE GUIDELINE Conclusion Statement: Consumption of 450mg of Hawthorn (WS 1442) twice a day is safe and tolerated in heart failure (NYHA III) patients; no harm and limited benefit was shown for patients taking or not taking standard medical therapy for heart failure. However one study showed potential harm in patients that are ill and have left ventricular ejection fraction (LVEF) <35%. (Grade III: Limited) Practice Guideline: If the patient asks about hawthorn, then the dietitian should tell the patient that there is insufficient evidence to support its use in preventing heart failure progression. (Conditional)

35

VII. BIBLIOGRAPHY Carson, Tara. "Health Benefits of Hawthorn Tea." LIVESTRONG.COM. 21 Oct. 2010.

Web. 10 Apr. 2012. <http://www.livestrong.com/article/285852-health-benefits-of-hawthorn-tea/>.

Crataegus oxycantha (Hawthorn) Monograph. (2010). Alternative Medicine Review, 15(2), 164-

167. Holubarsch, C. F., Colucci, W. S., Meinertz, T., Gaus, W., & Tendera, M. (2008). The

efficacy and safety of Crataegus extract WS® 1442 in patients with heart failure: The SPICE trial. European Journal Of Heart Failure, 10(12), 1255-1263. doi:10.1016/j.ejheart.2008.10.004

Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in

patients with chronic stable New York Heart Association class-III heart failure. Am Heart J. 2002 May;143(5):910-5. PubMed PMID: 12040357.

Zapfe jun G. Clinical efficacy of crataegus extract WS 1442 in congestive heart failure

NYHA class II. Phytomedicine. 2001 Jul;8(4):262-6. PubMed PMID: 11515715. Zick SM, Gillespie B, Aaronson KD. The effect of Crataegus oxycantha Special Extract WS

1442 on clinical progression in patients with mild to moderate symptoms of heart failure. Eur J Heart Fail. 2008 Jun;10(6):587-93. Epub 2008 May 19. PubMed PMID: 18490196; PubMed Central PMCID: PMC2577845.

Zick, S. M., Vautaw, B., Gillespie, B., & Aaronson, K. D. (2009). Hawthorn Extract

Randomized Blinded Chronic Heart Failure (HERB CHF) Trial. European Journal Of Heart Failure, 11(10), 990-999. doi:10.1093/eurjhf/hfp116

Documents

Hawthorn and Heart Failure - Coral Rudiecoralrudie.yolasite.com/resources/Hawthorn and Heart Failure.pdf · ! 3! I. INTRODUCTION Crataegus oxycantha has been used by many cultures