| |
Rosi/Pioglitazone: new study published in Diabetes Care reports risk for heart attack, see text from published article below
|
| |
| |
UK research finds Avandia, Actos double heart attack risk
26/07/2007
www.pharmatimes.com
from study: ".....Biological basis of the reaction: The development of heart failure is a class effect of the thiazolidinediones, mediated through increased plasma volume, rather than through a direct effect on the myocardium. (9, 17, 28) A recent meta-analysis of RCTs found the odds ratio for edema with thiazolidinediones to be 2.26 [95% CI 2.02-2.53],(14) similar to our estimates of heart failure. Fluid retention due to thiazolidinediones may trigger (clinically apparent) episodes of heart failure in susceptible individuals, or may unveil the disease in those with latent heart failure (no previous cardiac history). This theory is supported by echocardiographic evaluation of heart failure patients where no deterioration in left ventricular function was found with thiazolidinedione therapy. (5) (17). Similarly, a 52-week study of rosiglitazone did not show any decline in the left ventricular ejection fraction. (29). Fluid retention appears to be mediated through increased sodium reabsorption by the renal PPAR gamma dependent pathway in the collecting tubules, suggesting a possible therapeutic role for amiloride, rather than loop diuretics for which resistance has been reported (30)....."
Just as GlaxoSmithKline's diabetes drug Avandia (rosiglitazone) is preparing Monday to face a US Food and Drug Administration advisory panel on concerns over possible links to cardiovascular adverse events, new research coming out of the UK suggests that Avandia and Eli Lilly/Takeda's Actos (pioglitazone) double the risk of heart failure, with fluid retention caused by the drugs providing the trigger.
The findings are based on a meta-analysis of more than 78,000 patients, which estimates that one in every 50 patients taking the drugs over a 26-month period will require hospital admission due to heart failure. "This means that the diabetes drugs could have caused thousands of additional cases of heart failure, creating a substantial burden on hard-pressed health services," said Dr Yoon Loke, a clinical pharmacologist at UEA's School of Medicine, Health Policy and Practice. The results are published in the August edition of the journal Diabetes Care.
In the UK, prescriptions for the drugs, known as thiazolidinediones, have doubled over the last three years and they were taken by more than 1.5 million people in England alone last year.
The new research was undertaken by Loke, working with colleagues at Wake Forest University in the US. In the UK, Avandia and Actos are recommended for use on the country's National Health Service, but Loke now says: "I think NICE [the UK's cost-effectiveness body, the National Institute for Health and Clinical Excellence] should re-evaluate their decision to recommend these diabetes drugs."
The researchers also looked in detail at more than 200 cases of patients with heart failure related to the diabetes drugs and found that the problem developed even in patients taking low doses of the drugs. Furthermore, around 25% of cases occurred in people under the age of 60, even without a history of cardiovascular disease. "Most patients in the studies did not have heart failure prior to starting on treatment with these drugs," said Dr Loke. "There doesn't seem to be a group of patients who are safe from these side effects."
"These drugs are taken by more than seven million diabetic patients in the US alone, suggesting that several thousand could be harmed," said co-author Dr Sonal Singh of Wake Forest University.
GSK statement
"The risk of heart failure in diabetes patients and with use of these medicines is well recognised and is clearly identified in prescribing information to doctors in the UK," said Alastair Benbow, European Medical Director, GlaxoSmithKline.
The analysis does not include the results from either the ADOPT or RECORD studies study, two recently published long-term prospective studies in which the risk of heart failure is assessed in patients taking rosiglitazone. In ADOPT the same number of congestive heart failure serious adverse events were reported for rosiglitazone versus metformin in a drug naive diabetic population. Meanwhile, in the RECORD interim analysis, rosiglitazone was associated with significantly more cases of CHF when compared with patients on control - metformin and sulphonylurea. Despite the increase in CHF however, the primary outcome of cardiovascular hospitalizations and death showed no significant difference between the rosiglitazone group and the metformin/sulphonylurea group.
GSK finished: "It is important for physicians to use rosiglitazone in appropriate patients in line with the European Summary of Product Characteristics, which states that rosiglitazone should not be used in patients with CHF. GSK is confident in the overall safety profile of rosiglitazone when used appropriately."
Thiazolidinediones and Heart Failure: A Teleo-Analysis
Diabetes Care In Press, published online May 29, 2007
Received for publication 23 January 2007 and accepted in revised form 18 May 2007.
Running Title: Thiazolinediones and heart failure
Sonal Singh MD1 *
Yoon K Loke MBBS MD 2*
Curt D Furberg MD PhD 3
1 Internal Medicine, Wake Forest University School of Medicine, NC
2 School of Medicine, Health Policy and Practice, University of East Anglia, UK
3. Division of Public Health Sciences, Wake Forest University School of Medicine, NC
ABSTRACT
OBJECTIVE-Thiazolidinediones are known to increase the risk of heart failure in patients with type 2 diabetes. We aimed to evaluate the magnitude of the risk of heart failure with thiazolidinediones and classify this adverse effect under the novel Dose-Time-Susceptibility system.
RESEARCH DESIGN AND METHODS - Evidence from randomized trials, controlled observational studies, anecdotal case reports, case-series and spontaneous reports in the Canadian Adverse Events Database (CADRMP) were analyzed in a teleo-analysis.
RESULTS-Random effects meta-analysis of 3 randomized controlled trials showed an odds ratio of 2.1 (95% CI: 1.08 - 4.08; p = 0.03) for the risk of heart failure in patients randomized to thiazolidinediones compared to placebo. 4 observational studies, revealed an odds ratio of 1.55 (95% CI: 1.33 - 1.80; p <0.00001) for heart failure with thiazolidinediones. A Dose-Time-Susceptibility analysis of 28 published reports, and 214 spontaneous reports from the CADRMP database showed that heart failure was more likely to occur after several months, with median treatment duration of 24 weeks after initiation of therapy. Heart failure occurred equally at high and low doses. The adverse reaction was not limited to the elderly, with 42/ 162 (26%) of the reported cases occurring in patients below the age of 60 years.
CONCLUSIONS- Our teleo-analysis confirms the increased magnitude of the risk of heart failure with thiazolidinediones. We estimate the Number-Needed-to-Harm with thiazolidinediones to be around 50 over 2.2 years. Existing guidelines and package inserts may have to be revised to incorporate these risk-characteristics of thiazolidinediones.
RESULTS
Randomized Controlled Trials: We identified 3 trials of 10,731 patients that provided numerical information on heart failure events. (10, 17, 18) (Table 1)The pooled odds ratio for heart failure was 2.1 (95% CI: 1.08 - 4.08; p = 0.03). (Figure 1) There is moderate heterogeneity around this estimate (I2 = 59 %) - attributable to the different populations, and varying criteria for ascertaining heart failure events.
Observational Studies 4 observational studies of 67,382 patients were included. (19)(20)(21)(22) (Table 2a). The pooled odds ratio for heart failure with thiazolidinediones was 1.55 (95% CI: 1.33 - 1.80; p <0.00001). (Figure 1) Moderate heterogeneity was found (I2 = 47%), due to the differences in population and co-existing morbidity. Sensitivity analysis shows the heterogeneity to have an I2 of 0% if we excluded Inzucchi's study (which focused on diabetic patients after myocardial infarction, rather than diabetic patients in general). (21)
Excluded observational studies Two observational studies were excluded as they did not fulfill the selection criteria (Table 2 (b)) (23, 24) Masoudi looked at readmission rates for patients on thiazolidinediones who already had a recent admission for heart failure (23). Rajagopalan's study compared the rates of heart failure solely between patients on pioglitazone and insulin (24). Our selection criteria were based on patients potentially being able to receive other oral hypoglycemic agents, with or without insulin. The use of a control group comprising patients on insulin is particularly prone to confounding, as patients with the most severe type 2 diabetes are the ones likely to receive insulin.
Case Reports: Age: A DoTs analysis of 162 analyzable cases showed that the age ranged from 31 - 88 years with the median age at 67 years. The adverse effect was not limited to the elderly as 42/ 162 cases (26%) were below the age of 60 years.
Dose and Duration: Among 99 analyzable cases, the median duration for the onset of heart failure was 24 weeks (range 1 - 260 weeks), suggesting that the reaction is a delayed or late-onset in nature (Figure 2). Patients on low doses were also at risk of developing heart failure soon after starting treatment. One patient on pioglitazone and 9 patients on rosiglitazone developed heart failure in the first four weeks of low-dose therapy defined as pioglitazone 15 mg or below or rosiglitazone 4mg or below. Heart failure did not develop much earlier in those receiving thiazolidinediones in the high dose
range (Figure 3). Heart failure due to thiazolidinediones use also did not occur as a function of the cumulative ingested dose.
Heart failure can occur even at doses below those used for therapeutic benefit, and the relatively low daily doses of pioglitazone 15-mg or rosiglitazone 2 mg are already at the top end of the dose-effect curve for triggering off episodes of heart failure.
Susceptibility: We were unable to identify any particular susceptibility factors. Heart failure occurred equally among 110 males and 88 females. Death occurred in 9 patients.
Discussion
Our teleo-analysis provides useful clinical information on the increased risk of heart failure with thiazolidinediones. This evidence on the increased risk of heart failure should be judged in the context of a recent systematic review of pioglitazone which found little evidence for beneficial effects on hard clinical endpoints. (25)
25. Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev (4):CD006060, 2006
Diabetes and the use of any therapy for the treatment of diabetes is associated with an increased risk of heart failure. (26) The background incidence of heart failure in patients with diabetes is approximately 1.9% over 2.2 years (27).The estimated number-needed-to-harm (NNH) with thizaolidinediones, based on an odds ratio of 2.10, would be 50 over a 2.2 year follow-up period.
Biological basis of the reaction: The development of heart failure is a class effect of the thiazolidinediones, mediated through increased plasma volume, rather than through a direct effect on the myocardium. (9, 17, 28) A recent meta-analysis of RCTs found the odds ratio for edema with thiazolidinediones to be 2.26 [95% CI 2.02-2.53],(14) similar to our estimates of heart failure. Fluid retention due to thiazolidinediones may trigger (clinically apparent) episodes of heart failure in susceptible individuals, or may unveil the disease in those with latent heart failure (no previous cardiac history). This theory is supported by echocardiographic evaluation of heart failure patients where no deterioration in left ventricular function was found with thiazolidinedione therapy. (5) (17). Similarly, a 52-week study of rosiglitazone did not show any decline in the left ventricular ejection fraction. (29). Fluid retention appears to be mediated through increased sodium reabsorption by the renal PPAR gamma dependent pathway in the collecting tubules, suggesting a possible therapeutic role for amiloride, rather than loop diuretics for which resistance has been reported (30).
The rosiglitazone package insert warns against the use of rosiglitazone in NYHA Stage III and IV heart failure patients and cautions about the increased risk of heart failure in combination with insulin. (31) Similarly, the package insert of pioglitazone cautions against this increased risk of heart failure. (32) However, this increased risk is not confined to patients on insulin. None of the patients were on Insulin in the DREAM trial (10), only one-third of patients required Insulin in PROActive. (18) We were unable to obtain information on concomitant medications in GSK-211 (17) (Table 1)
A consensus review in 2003 by the American Heart Association and the American Diabetic Association rightly recommend that thiazolidinediones be avoided in patients with New York Heart Association (NYHA) Stage III and IV heart failure (as RCTs of thiazolidinediones excluded these patients).(9) However, they also recommend that thiazolidinedione therapy be initiated at low dose, and slowly increased and closely monitored in diabetic patients with Stage NYHA I and II heart failure, those with depressed ejection fractions (<40%), and 1 or more cardiac risk factors without heart disease. (9) Recommendations for their use even at low-doses in NYHA Stage 1 and II heart failure patients, and in those with risk factors for heart failure may need to be carefully revaluated as heart failure occurred even among patients with no history of heart failure in the DREAM trial and observational studies. Heart failure also occurred at the lowest dose range for thiazolidinediones in spontaneous reports and at both the low (4 mg) and high (8 mg) doses of rosiglitazone used in clinical trials. The occurrence of heart failure several months after initiation of thiazolidinediones suggests a long-term effect of the drug, which may not be avoided by slow dose titration, and mandates the need for long-term vigilance.
Further research studies should evaluate intra-class differences in the risk of heart failure between the thiazolidenediones, and optimal management strategies in patients experiencing heart failure on thiazolidinediones, including immediate withdrawal and the role of diuretics such as amiloride or spironolactone. (33) Studies need to distinguish between the heart failure requiring hospitalization versus that which can be managed as an outpatient (the severity of heart failure) are also needed.
Limitations: There are a number of limitations to our study. The diagnosis of heart failure is challenging and may require subjective clinical interpretation of symptoms, signs and additional investigations (such as chest radiographs, or echocardiography). Inconsistent diagnostic criteria across studies may have led to some heterogeneity. Patients with progressive pedal edema from fluid retention could potentially have been erroneously classified as heart failure cases. This seems unlikely here though, as all 3 included RCTs were designed from the start to actively seek out cases of heart failure, and heart failure information in two of the large published studies was subjected to independent masked adjudication based on prespecified criteria (Table 1). Moreover, three of the four observational studies used fairly stringent criteria in that the patients required hospital admission due to heart failure.
Anecdotal case reports may not be entirely representative of the population, were often incomplete, and were not necessarily causal as they cannot rule out the role of concomitant medicines (metformin, insulin) in exacerbating heart failure. Case reports are subject to publication bias, which was minimized by the use of spontaneous reports from the CADRMP database. Spontaneous reports and case reports represent the observation of the individual health professionals and layperson and should not be used for numerically estimating the risk of ADR as the denominator is unknown. We used data from RCTs and observational studies to statistically determine the association between thiazolidinediones and heart failure. Observational studies are susceptible to confounding. We corroborated observational data with results from RCTs, and the risk of heart failure was consistent in magnitude and direction.
Conclusions: Our teleo-analysis confirms the increased magnitude of the risk of heart failure with thiazolidinediones. The Number-Needed-to-Harm with thiazolidinediones was estimated to be around 50 over 2.2 years. Heart failure can occur at both high and low doses, usually weeks to months after initiation of thiazolidinediones. It can occur in the absence of insulin, even in patients without a history of heart failure. Existing guidelines and package inserts may have to be revised to incorporate these risk-characteristics of thiazolidinediones.
|
|
| |
| |
|
|
|
