The aim of the critique is to determine if the results and conclusions of the study are meaningful and realistic and have relevance to clinical practice of a naturopath.
Should examine methodology, inclusion and exclusion criteria for the study groups, material used including the way the drug(s) are administered, standardization, dosage, frequency of dosage.
Whether confounding factors are excluded or recorded and accounted for in results and conclusion plus relevance to hypothesis.
References will need to encompass modern sources on herbal medicine, medical texts on disease state, drug information guides.
In the intro need to provide complete reference of the paper being analyzed
Make use of headings to break up critique in distinct sections, base headings on headings employed in the original study.
Need to explain the relevance of CI and P value under Results on pg 1.
Define and reference the New York Heart Association’s 4 classes of heart failure,
Look at method and retrospective analysis.
Explain what Crataegus special extract WS 1442 is.
Critique progression of heart failure as result of intervention on pg 4.
Elaborate on the SPICE trial.
Explain the graphs on pg 9 – need to understand what was done with Crataegus.
Break down the demographics.
Were participants properly informed, paid? Was it an ethical trial.
Critique of research paper: The Effect of Crataegus oxycantha Special Extract WSS 1442 on Clinical Progression in Patients with Mild to Moderate Symptoms of Heart Failure. Zick SM, Gillespie B, Aaronson KD. Eur J Heart Fail. 2008 June: 10(6): 587-593.
The article “The effect of Crataegus oxycantha Special Extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure” is a 2008 publication in the European Journal of Heart Failure, volume 10 issue number 6 from page 587 to 593. This article evaluates how WSS 1442 extract from C. oxycantha works in patients who have mild to moderate symptoms of heart failure. This retrospective study assessed the time it took patients to develop heart failure. The study identified that since intake of C. oxycantha extract leads to faster progression to heart failure, the extract is not effective in reducing heart failure progression and instead it seems to exacerbate the progression.
Drawing from a review of literature that examines advances in treatment of heart failure (HF), Zick et al () identify that progression of heart failure has been inevitable despite the existence of pharmacological treatments. This study is therefore based on the need to curtail HF progression thus reducing prevalence of the condition. Zick et al mention that there exists a theoretical possibility of reducing progression of HF using anti-inflammatory drugs since they interfere with inflammatory signaling as well as oxidative stress which are thought to regulate HF progression. It is for this reason that the authors of this study how effective Crataegus oxycantha extracts can be in reducing progression of HF. Despite the evidence that Crataegus Special Extract WS 1442 enhances quality of life in heart failure-related symptoms, Zick et al observe that there is paucity of studies on effectiveness of Crataegus Special Extract WS 1442 in reduction of HF progression. This is what this study does using secondary data in a randomized, double-blind placebo-controlled trial.
This study was a retrospective analysis of 120 heart failure patients who had participated in HERB CHF trial. In this trial, the Crataegus Special Extract WS 1442 had been tested among patients who had class II to IV symptoms of the New York Heart Association (NYHA).
Zick et al () studied patients with a positive diagnosis of HF (NYHA classes II-IV) and the diagnosis had to have lasted for more than three months with the patient having left ventricular ejection fraction (LVEF). All the patients who participated in the study were at least 18 years old and eligible participants had to have been receiving an indicated diuretic, beta blocker, angiotensin receptor blocker or an ACE inhibitor. For patients who had NYHA class III symptoms, they must were supposed to get spironolactone for them to qualify as participants. For all patients, they had to demonstrate more than three months stability on the drugs with stability for diuretics only being at least one month.
Different classes of patients were excluded from the study. For instance patients who displayed various heart conditions less than three months prior to randomization were excluded. Such conditions included hypertrophic cardiomyopathy, valvular surgery, unstable angina, active myocarditis, myocardial infarction and angioplasty among others. If a patient exhibited sustained ventricular tachycardia or symptomatic tachycardia and was not receiving any treatment were excluded from the study. Pregnant and nursing women were also exempted from the study as was the case with conditions that had potential to interfere with exercise other than HF were also excluded. Such conditions included orthopedic complications and pulmonary disease among others.
This study involved human subjects and therefore ethical guidelines had to be followed. The researchers followed the guidelines provided under the declaration of Helsinki (EXPLAIN) in addition to approval of the University of Michigan Medical School Institutional Review Board (Explain need for IRB’s). To ensure total adherence to the ethical guidelines, a Data Safety Monitoring Board was available as an independent overseer. A written informed consent was also obtained from all the subjects.
It is important to remember that this was a secondary retrospective study. To screen for eligible participants, patients were required to walk for six minutes and those who managed a distance of 150 to 450 meters within the six minutes attended a baseline visit. The ethicality of the study was maintained since participants gave written consent prior to the baseline visit. Stable patients during the baseline study did another six-minute walk and those who managed a distance of 150 and 450 meters were recruited and randomized with all the others being classified as ineligible.
Randomization was done into two groups with one group receiving 450mg twice a day of Crataegus Special Extract WS 1442. The second group received a placebo of the same. To ensure consistency of results, the researchers used one batch of C. oxycantha extract. The pacebo was made of glucose and this was assessed using HPLC.
Ziock et al () ensured that baseline characteristics were taken by recording their means and standard deviations (for continuous variables). Categorical variables were recorded in terms of percentages and number counts. It is evident that the baseline characteristics for both the treatment and placebo group did not differ considerably thus enabling competent comparison of results. To analyze the primary outcome i.e. HF progression, the researchers determined the relative risks as well as the 95% confidence intervals using Cochran-Mantel-Haenszel statistical techniques. A Kaplan-Meier survival estimate was constructed to analyze the time taken to progress to HF in the treatment group. The lo-rank test was then used to test the estimates. Cox modeling was used to determine how various factors affected prognosis of HF. Such factors included NYHA functional class, age, HF cause, sex and LVEF among others. A backward stepwise regression assessed the most parsimonious approach with an alpha value of ≤ .05 being classified as significant. Using the above statistical procedures and parameters, it was possible to obtain a power of 84% in detecting a hazard of at least 2.0. For the LVEF subgroup, there existed an 81% power of detecting a hazard ration of at least 2.6.
Socio-demographic and clinical characteristics
It was observed that the demographic and clinical characteristics of the subjects were not different thereby guaranteeing uniformity and consistency of results. During the study, it was observed that 38 participants exhibited an LVEF greater than 40% and these were supposed to be excluded from the study since eligibility required an LVEF ≤ 40%. This may have affected the results since the baseline characteristics differed in 38 patients.
Participation and completion of the study can be rated high among both the placebo and treatment groups. Among the total 120 participants who were recruited, only 9 patients failed to competed the six months study for various reasons. Among the 60 placebo subjects, only 3 patients dropped from the study due to death, pneumonia and heart transplant (UNOS status 1). For the C. oxycantha extract group, a larger number (6) of patients failed to complete the study with three deaths being reported (2 due to HF and 1 due to aplastic anemia). The other three patients dropped due to complications such as Grave’s disease, thyomas and heart transplant (UNOS status 1).
Progression of heart failure
There was HF progression in 46.6% of patients who received Crataegus Special Extract WS 1442 compared to 43.3% among placebo group. Since the p value was greater than .05 (i.e. p = .86), this difference was termed as non significant. There was a detection hazard of 1.14 as far as progression of HF was concerned as portrayed by the odds ratio. The confidence interval was not wide as both values were positive (95% CI = 0.56 – 2.35). There were more deaths and hospitalizations among Crataegus Special Extract WS 1442 group (3.3% and 18.3% respectively) compared to the placebo group (1.6 and 10.0% respectively). The number of those who needed increased diuretic was however higher among placebo group that the treatment group (19 versus 15 patients respectively).
According to the Kaplan-Meier curve for both treatment groups, it was evident that hazards changed over time. This was demonstrated by a crossing pattern that was observed at different time periods of therapy. Although hazard for Crataegus Special Extract WS 1442 was slightly lower than that of placebo, there was crossing at around 180 and 220 days of therapy showing that the hazard was equal for both groups of treatments at the crossing points. A Cox regression was performed to find risk of heart failure progression over time. There was a significant change in risk (p = .047) in both groups over time. It was demonstrated that the risk of HF progression among Crataegus Special Extract WS 1442 was 3.9 times higher than that of the placebo. This difference was significant and a fairly large number of population had the risk (95% CI = 1.0 – 13.7; p = .035). There was a decrease in hazard ratio for WS 1443 group with time and at 6 months, there was no increase in HF progression due to Crataegus Special Extract WS 1442. However, this change was not significant (HR = 0.63, 95% CI = 0.29 – 1.47; p = .72).
It was also observed that there was an increased risk of HF progression at baseline for the treatment group and this risk was significant HR = 6.4 (95% CI = 1.5 – 26.5; p = .011) compared to the placebo group. Progression of HF at six months due to Crataegus Special Extract WS 1442 was non-significant relative to the placebo group (HR = 0.41, 95% CI = 0.14 – 1.08: p = .64).
The increase in time taken to reach primary endpoint for a subgroup of 68 subjects who had a LVEF ≤ 35% was non-significant (p = .48) with an odds ratio of 1.42 (95% CI 0.55 – 3.69) for the treatment group ac compared to the placebo group. Risk of HF progression over time was also shown to change over time according to Kalplan-Meier analysis with the interaction being non-significant (p = .13). Adjustment in various factors that affect HF progression led to a significant increase in hazard risk among the treatment group relative to the placebo (HR = 3.2; 95% CI = 1.3 – 8.3: p =.02).
Discussion & Conclusion
It was observed that C. oxycantha does not reduce the risk of HF progression. Instead, HF progression counts seemed to increase at baseline for the C. oxycantha group. A subgroup analysis of patients with LVEF ≤ 35% showed increased HF progression risk throughout the study. Zick et al () attribute the high risk of HF progression in the treatment group to chance given that the study was a limited in terms of power due to a small sample size and secondary data was used. Even the subgroup analysis that had sicker patients was more limited in power since the sample size was very small (n = 68). Paucity of studies examining effect of C. oxycantha on HF progression made it impossible to make comparisons in the results. The only available study cited by the authors of this study is the Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in Congestive Heart Failure (SPICE). However, the study had not been published by the time Zick et al conducted this study. The SPICE clinical trial involved almost 3,000 HF subjects whose LVEF was less than or equal to 35% and progression was monitored over a period of 24 months. The same extract (Crataegus Special Extract WS 1442) was used at the same dosage and baseline characteristics same as this current study. The unpublished SPICE trial results indicated a non-significant HF progression difference for treatment and placebo groups but the progression in Zick et al study was higher. It was impossible to compare relative risk over time using the SPICE trial since Kaplan-Meier curves were not available. Herb-drug interactions were cited as possible causes of an increase in HF progression risk for the treatment group in patients with LVEF ≤ 35%. Possible drug interactions may have resulted among patients who were using digoxin, which interacted with flavinoids from the C. oxycantha extracts.
Among the limitations for this study included a small sample size which led to reduced power of detecting hazard ratios, the study was a secondary data analysis, and hence monitoring HF progression may have been limited. Despite these limitations, Zick et al cautioned use of C. oxycantha extracts in treatment of HF progression where close monitoring should be done. This study concluded that Crataegus Special Extract WS 1442 is not effective in reducing HF progression for mild and moderate heart failure. Instead, there is likelihood that the treatment exacerbates the risk at an early phase of HF progression.
The NYHA heart failure classification can is classified into four classes depending on how severe the symptoms are as well as functionality. Class I HF does not limit physical activity and normal physical activity rarely causes fatigue. Class II HF is characterized by some impaired physical activity but the patient feels comfortable while resting. Normal activities however lead to fatigue or dyspnea. In Class III HF, phsycial activity is limited to a large extent and though the patient may feel comfortable when resting, even less than ordibnary activities may lead to fatigue. Class IV HF patients perform all activities with discomfort and symptoms are exhibited even at rest (Greenberg et al).
Management of Heart Failure
By Barry Greenberg, Denise Barnard, Sanjiv Narayan. John Wiley and Sons, 2010. ISBN 047075379X, 9780470753798