Menopausal Hormone Therapy and Coronary Heart Disease: Reconciling Divergent Findings from Observational Studies and Clinical Trials

Randomized clinical trials of menopausal hormone therapy have shown increased risks of coronary heart disease in the first few years after randomization, and neutral or increased risk over the full trial period. These results diverge substantially from the protective associations of menopausal hormone use with coronary heart disease found in observational studies. In common with many other studies, conventional analyses in the Women’s Health Initiative Observational Study cohort of estrogen plus progestin users showed an association with reduced risk of coronary heart disease even after adjustment for potential confounders. However, upon allowing risk to vary by time since initiation, the hazard ratios did not differ significantly from those observed in the clinical trial. In analyses combining clinical trial and observational data the hazard ratios were 1.58 (1.12, 2.24) within the first 2 years after initiation, 1.19 (0.87, 1.63) between 2 and 5 years, and 0.63 (0.59, 1.26) after 5 years. Similar analyses for estrogen alone also reconciled trial and observational data. These findings were confirmed in novel re-analyses of the Nurses’ Health Study when investigators for the first time included outcomes occurring in the interval between the biennial study cycles. The key towards understanding the underestimation of coronary heart disease in observational studies of menopausal hormone therapy appears to lie in the time-dependent nature of coronary heart disease risk rather than differences in study populations. Observational studies typically do not capture early events in current users and the data mostly reflect the experience of long-term users who have survived the early risk, while clinical trials by design capture early events very efficiently and mainly reflect short-term use.     

Clinical trials in systemic sclerosis: lessons learned and outcomes

The pathogenesis of systemic sclerosis (SSc) is complex and largely unclear. The clinical heterogeneity of the disease and its progression over a number of years makes the choice of endpoints in the design of clinical trials difficult. The overwhelming need in this disease is to diagnose it early and identify those patients who will benefit most from early, aggressive treatment that potentially can alter the clinical disease course. To achieve this, innumerable challenges must be overcome. This article reviews data from recent clinical trials and the lessons derived from retrospective observational studies, databases, and patient registries. Taken together, these observations will help to improve our understanding of the diverse clinical course of SSc and permit refinement of existing outcome measures for the design of future clinical trials, in which the likelihood of observing a positive treatment effect with the drugs at our disposal will be maximized.     

COX-2: Where are we in 2003? - Distinction from NSAIDs becoming blurred

The distinction between cyclooxygenase-2-selective inhibitors (CSIs) and nonsteroidal anti-inflammatory drugs ultimately must be clinical and must be clinically and economically relevant. This distinction needs to be demonstrated in a substantial and clinically relevant difference in the respective rates of serious adverse reactions of the upper gastrointestinal tract. Event-driven, randomized, blinded, controlled trials with sufficient power are required to resolve uncertainties concerning the relative risk of thrombotic cardiovascular events in patients taking CSIs who have risk factors for these events. Patients and situations more representative of those in primary-care practice - elderly, comorbidities, comedication - need to be included in larger studies to provide a better understanding of the risks and benefits of CSIs.     

Withdrawal of cerivastatin from the world market

Cerivastatin was recently withdrawn from the market because of 52 deaths attributed to drug-related rhabdomyolysis that lead to kidney failure. The risk was found to be higher among patients who received the full dose (0.8 mg/day) and those who received gemfibrozil concomitantly. Rhabdomyolysis was 10 times more common with cerivastatin than the other five approved statins. We address three important questions raised by this withdrawal. Should we continue to approve drugs on surrogate efficacy? Are all statins interchangeable? Do the benefits outweigh the risks of statins? We conclude that decisions regarding the use of drugs should be based on direct evidence from long-term clinical outcome trials.     

The Effect of Ginger (Zingiber officinale) on Platelet Aggregation: A Systematic Literature Review

BackgroundThe potential effect of ginger on platelet aggregation is a widely-cited concern both within the published literature and to clinicians; however, there has been no systematic appraisal of the evidence to date.MethodsUsing the PRISMA guidelines, we systematically reviewed the results of clinical and observational trials regarding the effect of ginger on platelet aggregation in adults compared to either placebo or baseline data. Studies included in this review stipulated the independent variable was a ginger preparation or isolated ginger compound, and used measures of platelet aggregation as the primary outcome.ResultsTen studies were included, comprising eight clinical trials and two observational studies. Of the eight clinical trials, four reported that ginger reduced platelet aggregation, while the remaining four reported no effect. The two observational studies also reported mixed findings.DiscussionMany of the studies appraised for this review had moderate risks of bias. Methodology varied considerably between studies, notably the timeframe studied, dose of ginger used, and the characteristics of subjects recruited (e.g. healthy vs. patients with chronic diseases).ConclusionThe evidence that ginger affects platelet aggregation and coagulation is equivocal and further study is needed to definitively address this question.     

Combining parametric and nonparametric models to estimate treatment effects in observational studies

Performing causal inference in observational studies requires we assume confounding variables are correctly adjusted for. In settings with few discrete-valued confounders, standard models can be employed. However, as the number of confounders increases these models become less feasible as there are fewer observations available for each unique combination of confounding variables. In this paper, we propose a new model for estimating treatment effects in observational studies that incorporates both parametric and nonparametric outcome models. By conceptually splitting the data, we can combine these models while maintaining a conjugate framework, allowing us to avoid the use of Markov chain Monte Carlo (MCMC) methods. Approximations using the central limit theorem and random sampling allow our method to be scaled to high-dimensional confounders. Through simulation studies we show our method can be competitive with benchmark models while maintaining efficient computation, and illustrate the method on a large epidemiological health survey.     

Stroke in the female: role of biological sex and estrogen

Women are protected from stroke relative to men until the years of menopause. Because stroke is the leading cause of serious, long-term disability in the United States, modeling sex-specific mechanisms and outcomes in animals is vital to research. Important research questions are focused on the effects of hormone replacement therapy, age, reproductive status, and identification of sex-specific risk factors. Available research relevant to stroke in the female has almost exclusively utilized rodent models. Gender-linked stroke outcomes are more detectable in experimental studies than in clinical trials and observational studies. Various estrogens have been extensively studied as neuroprotective agents in women, animals, and a variety of in vitro models of neural injury and degeneration. Most data in animal and cell models are based on 17 beta estradiol and suggest that this steroid is neuroprotective in injury from ischemia/reperfusion. However, current evidence for the clinical benefits of hormone replacement therapy is unclear. Future research in this area will need to expand into stroke models utilizing higher order, gyrencephalic animals such as nonhuman primates if we are to improve extrapolation to the human scenario and to direct and enhance the design of ongoing and future clinical studies and trials.     

Increasing efficiency and reducing bias when assessing HPV vaccination efficacy by using nontargeted HPV strains

Studies of vaccine efficacy often record both the incidence of vaccine-targeted virus strains (primary outcome) and the incidence of nontargeted strains (secondary outcome). However, standard estimates of vaccine efficacy on targeted strains ignore the data on nontargeted strains. Assuming nontargeted strains are unaffected by vaccination, we regard the secondary outcome as a negative control outcome and show how using such data can (i) increase the precision of the estimated vaccine efficacy against targeted strains in randomized trials and (ii) reduce confounding bias of that same estimate in observational studies. For objective (i), we augment the primary outcome estimating equation with a function of the secondary outcome that is unbiased for zero. For objective (ii), we jointly estimate the treatment effects on the primary and secondary outcomes. If the bias induced by the unmeasured confounders is similar for both types of outcomes, as is plausible for factors that influence the general risk of infection, then we can use the estimated efficacy against the secondary outcomes to remove the bias from estimated efficacy against the primary outcome. We demonstrate the utility of these approaches in studies of HPV vaccines that only target a few highly carcinogenic strains. In this example, using nontargeted strains increased precision in randomized trials modestly but reduced bias in observational studies substantially.     

Estimated benefit of increased vitamin D status in reducing the economic burden of disease in western Europe

Vitamin D has important benefits in reducing the risk of many conditions and diseases. Those diseases for which the benefits are well supported and that have large economic effects include many types of cancer, cardiovascular diseases, diabetes mellitus, several bacterial and viral infections, and autoimmune diseases such as multiple sclerosis. Europeans generally have low serum 25-hydroxyvitamin D [25(OH)D] levels owing to the high latitudes, largely indoor living, low natural dietary sources of vitamin D such as cold-water ocean fish, and lack of effective vitamin D fortification of food in most countries. Vitamin D dose–disease response relations were estimated from observational studies and randomized controlled trials. The reduction in direct plus indirect economic burden of disease was based on increasing the mean serum 25(OH)D level to 40 ng/mL, which could be achieved by a daily intake of 2000–3000 IU of vitamin D. For 2007, the reduction is estimated at €187,000 million/year. The estimated cost of 2000–3000 IU of vitamin D3/day along with ancillary costs such as education and testing might be about €10,000 million/year. Sources of vitamin D could include a combination of food fortification, supplements, and natural and artificial UVB irradiation, if properly acquired. Additional randomized controlled trials are warranted to evaluate the benefits and risks of vitamin D supplementation. However, steps to increase serum 25(OH)D levels can be implemented now based on what is already known.     

Mechanisms of NSAID-induced ulcerogenesis: structural properties of drugs, focus on the microvascular factors, and novel approaches for gastro-intestinal protection.

The multifactorial ulcer-producing actions of non-steroidal anti-inflammatory drugs (NSAIDs) are briefly reviewed and the main actions highlighted as the focus for potential strategies for reducing the ulcerogenic effects of these drugs. While some clinical benefits are evident from long-term clinical studies from application of PG analogues (misoprostol) and H+/K(+)-ATP-ase inhibitors (omeprazole) these are, ultimately, expensive approaches. Chemical structural properties of the NSAIDs underlying differences in their ulcerogenicity are analyzed with the objective of establishing the reasons for the low ulcerogenicity of some of these drugs (e.g. azapropazone). These studies serve as a basis for developing less gastrotoxic drugs in the future. In the studies we have undertaken analysis of the benefits of micronutrients and of modulating eicosanoid metabolism have been considered. The results of some clinical trials with micronutrients have proven encouraging. These and other approaches and pitfalls reported give further encouragement to explore the mechanisms of the protective effects of these latter agents and serve as a basis for future developments.     

Menopausal hormone therapy and women’s health: An umbrella review

BackgroundThere remains uncertainty about the impact of menopausal hormone therapy (MHT) on women’s health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes.Methods and findingsWe searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412).ConclusionsMHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.

In an umbrella review, Guo-Qiang Zhang and colleagues comprehensively summarize evidence on the benefits and harms of menopausal hormone therapy across diverse health outcomes.     

Common harms from amoxicillin: a systematic review and meta-analysis of randomized placebo-controlled trials for any indication

Background:When prescribing antibiotics for common indications, clinicians need information about both harms and benefits, information that is currently available only from observational studies. We quantified the common harms of the most frequently prescribed antibiotic, amoxicillin, from randomized placebo-controlled trials.Methods:For this systematic review, we searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials, without language restriction, for any randomized, participant-blinded, placebo-controlled trials of amoxicillin or amoxicillin–clavulanic acid for any indication, in any setting. Our main outcome was any reported adverse event.Results:Of 730 studies identified, we included 45 trials: 27 involving amoxicillin, 17 involving amoxicillin–clavulanic acid and 1 involving both. The indications for antibiotic therapy were variable. The risk of bias was low, although only 25 trials provided data suitable for assessment of harms, which suggested under-reporting. Diarrhea was attributed to amoxicillin only in the form of amoxicillin–clavulanic acid (Peto odds ratio [OR] 3.30, 95% confidence interval [CI] 2.23–4.87). The OR for candidiasis (3 trials) was significantly higher (OR 7.77, 95% CI 2.23–27.11). Rashes, nausea, itching, vomiting and abnormal results on liver function tests were not significantly increased. The results were not altered by sensitivity analyses, nor did funnel plots suggest publication bias. The number of courses of antibiotics needed to harm was 10 (95% CI 6–17) for diarrhea with amoxicillin–clavulanic acid and 27 (95% CI 24–42) for candidiasis with amoxicillin (with or without clavulanic acid).Interpretation:Diarrhea was caused by use of amoxicillin–clavulanic acid, and candidiasis was caused by both amoxicillin and amoxicillin–clavulanic acid. Harms were poorly reported in most trials, and their true incidence may have been higher than reported. Nevertheless, these rates of common harms associated with amoxicillin therapy may inform decisions by helping clinicians to balance harms against benefits.Most antibiotics are prescribed by primary care clinicians for common infections, particularly acute respiratory infections.¹ However, for most acute respiratory infections, antibiotics provide only marginal benefits, and an inevitable consequence of this injudicious use is the prospect of antibiotic resistance. One way to reduce antibiotic prescribing in primary care is to explain to patients how little these drugs help for many common infections and to apply a process of shared decision-making during the consultation.²The practice of shared decision-making requires not just an explanation of the paucity of benefits of antibiotics in most primary care situations, but also an explanation of the potential harms. Serious harms are probably sufficiently rare to be discounted by most clinicians and their patients.³ Yet when the decision to use or not use antibiotics relates to a self-remitting illness, for which the benefits are likely to be modest at best, the more common, mild harms of antibiotics become important. Unfortunately, common harms from antibiotics are poorly quantified, and clinicians cannot talk to patients with confidence about their likelihood.Current understanding of the common harms of antibiotics is derived largely from observational studies. However, estimates of common harms from such studies may be biased, principally because it is difficult to distinguish adverse drug reactions from disease-related symptoms. One approach to addressing this problem is to investigate common harms encountered in randomized controlled trials of antibiotic against placebo. This study design controls for disease-related symptoms, allowing for better quantification of antibiotic-related adverse effects.The most common antibiotic used in primary care is amoxicillin, either alone or in combination with clavulanic acid. “Common harms” can be defined as those frequent enough to be observable in the patient samples of most randomized trials and occurring during the recording of primary outcomes in such studies (with recognition that some of the adverse effects will occur later).Accordingly, we systematically reviewed all published placebo-controlled randomized trials of amoxicillin or amoxicillin–clavulanic acid for any indication, with the rationale that the risks of drug-induced harms are independent of the condition being treated.⁴     

Adoption of prasugrel into routine practice: rationale and design of the Rijnmond Collective Cardiology Research (CCR) study in percutaneous coronary intervention for acute coronary syndromes

Background

Platelet inhibition is crucial in reducing both short- and long-term atherothrombotic risks in patients with acute coronary syndromes (ACS) managed with percutaneous coronary intervention (PCI). Based on randomised trials, recent recommendations in the current guidelines include the endorsement of prasugrel as a first-choice adenosine diphosphate receptor inhibitor. Yet, there is limited experience with the use of prasugrel in routine practice.

Methods

The Rijnmond Collective Cardiology Research (CCR) registry is a prospective, observational study that will follow-up 4000 PCI-treated ACS patients in the larger region of Rotterdam, the Netherlands. Based on recently implemented hospital protocols, all patients will receive prasugrel as first-choice antiplatelet agent, unless contraindicated, in accordance with European guidelines, and will be followed for up to 1 year post-discharge for longitudinal assessment of outcomes and bleeding events. This registry exemplifies a collaborative study design that employs a regional PCI registry platform and provides feedback to participating sites regarding their practice patterns, thereby supporting and promoting improvement of quality of care.

Conclusion

The CCR registry will evaluate the adoption of prasugrel into routine clinical practice and thus, will provide important evidence with regard to the benefits and risks of real-world utilisation of prasugrel as antiplatelet therapy in PCI-treated ACS patients.     

Equivalence and noninferiority trials - are they viable alternatives for registration of new drugs? (III)

The scientific community's reliance on active-controlled trials is steadily increasing, as widespread agreement emerges concerning the role of these trials as viable alternatives to placebo trials. These trials present substantial challenges with regard to design and interpretation as their complexity increases, and the potential need for larger sample sizes impacts the cost and time variables of the drug development process. The potential efficacy and safety benefits derived from these trials may never be demonstrated by other methods. Active-controlled trials can develop valuable data to inform both prescribers and patients about the dose- and time-dependent actions of any new drug and can contribute to the management and communication of risks associated with the relevant therapeutic products.     

Levamisole and 5-fluorouracil therapy for resected colon cancer: a new indication.

OBJECTIVE: To evaluate the benefits and risks of postoperative treatment with levamisole plus 5-fluorouracil (5-FU) in patients with colon cancer. DESIGN: Computerized searches of MEDLINE and CANCERLIT were performed, and the reference list of each retrieved article was checked. Only randomized trials of therapy with levamisole alone or combined with 5-FU for colon cancer without distant metastases were included. The studies were then evaluated with the use of four criteria. RESULTS: We reviewed six randomized trials, of which three satisfied our criteria. Two studies demonstrated a significant improvement in the survival rate with levamisole plus 5-FU among patients with colon cancer and pathologically confirmed metastases to adjacent lymph nodes (Dukes'' stage C). A subgroup analysis in another study demonstrated a similar benefit. The toxic effects of the drugs were generally mild. The three other studies showed no difference in survival rates between the treatment groups; however, the samples were too small to detect a clinically or statistically important difference. CONCLUSIONS: Because many patients with colon cancer will suffer a relapse we recommend that they be offered the opportunity to participate in clinical trials of adjuvant therapy. For those with stage C disease not entering a clinical trial levamisole plus 5-FU is appropriate adjuvant therapy.     

Complications of Laparoscopic Versus Open Bariatric Surgical Interventions in Obesity Management

With the epidemic of obesity fast spreading its grasp throughout the world, the medical professionals of diverse facilities need to be called on for better management to prevent its further progression. In particular, the gastroenterologists have a major role to play in all aspects of obese patient care. They should be able to recognize and treat obesity and associated disorders through the understanding and assessment of the various benefits and risks linked with a particular type of obesity treatment option. While treating these problems, a better understanding of the physiologic and anatomic alterations that might be associated with the treatment procedure and the weight loss-linked problems in association with the method of surgical intervention need to be weighed. Morbid obesity has been efficaciously treated by bariatric surgery promoting weight loss considerably and reducing the obesity-associated risks such as certain cancers, diabetes, cardiovascular disease, and all-cause mortality. Bariatric surgery has been performed traditionally through open method or, the more recent and popular form, laparoscopically that involves only a small incision in the abdomen. The laparoscopic bariatric surgery has become the surgical method of choice since its introduction in 1993 and has immediately crossed open surgery in terms of popularity. Drastic numbers came out when the two methods were compared for their applicability during a 3-year period in the United States. Only 6,000 reported open gastric bypass surgeries were recorded, but the number soared to nearly 16,000 for laparoscopic gastric bypass surgeries. The laparoscopic method has been found to be associated with much reduced complications and hospital stay along with lower cases of mortality as suggested by small randomized controlled trials and observational studies. However, these facts need to be reassessed through large-sized controlled trials and population-based studies. In addition, the previously ignored complications associated with laparoscopic methods should be studied in detail. Since the cases of obesity have been ever increasing and bariatric surgery is also gaining in popularity, it is important that the safest procedure should be identified. The main objective of this review was to compare the benefits and risks associated with open versus laparoscopic mode of bariatric surgery with a greater focus on the laparoscopic method. Although there are few reviews that have compared the two methods, none have focused on the complications of the two approaches. All these aspects have been dealt in detail here.     

Bridging case-control studies and randomized trials

Randomized trials and observational studies, such as case-control studies, are often seen as opposing approaches. However, in many instances results obtained by different designs may complement each other. For instance, case-control studies on aetiology of disease may help to give the direction of future trials. In this commentary, the author discusses the purpose of randomization and observation, and under which conditions one design may be preferred to another. Randomization is useful to combat 'confounding by indication', and is therefore the design of choice for most therapeutic trials. When this confounding is not an issue, as in studies of genetic risk factors or side-effects, then case-control studies are preferred.     

Accelerated clinical discovery using self-reported patient data collected online and a patient-matching algorithm

Patients with serious diseases may experiment with drugs that have not received regulatory approval. Online patient communities structured around quantitative outcome data have the potential to provide an observational environment to monitor such drug usage and its consequences. Here we describe an analysis of data reported on the website PatientsLikeMe by patients with amyotrophic lateral sclerosis (ALS) who experimented with lithium carbonate treatment. To reduce potential bias owing to lack of randomization, we developed an algorithm to match 149 treated patients to multiple controls (447 total) based on the progression of their disease course. At 12 months after treatment, we found no effect of lithium on disease progression. Although observational studies using unblinded data are not a substitute for double-blind randomized control trials, this study reached the same conclusion as subsequent randomized trials, suggesting that data reported by patients over the internet may be useful for accelerating clinical discovery and evaluating the effectiveness of drugs already in use.     

NSAID use selectively increases the risk of non-fatal myocardial infarction: a systematic review of randomised trials and observational studies

Background

Recent clinical trials and observational studies have reported increased coronary events associated with non steroidal anti-inflammatory drugs (NSAIDs). There appeared to be a disproportionate increase in non-fatal versus fatal events, however, numbers of fatal events in individual studies were too small, and event rates too low, to be meaningful.

Objectives

We undertook a pooled analysis to investigate the effect of NSAIDs on myocardial infarction (MI) risk with the specific aim to differentiate non-fatal from fatal events.

Methods

We searched Pubmed (January, 1990 to March, 2010) for observational studies and randomised controlled trials that assessed the effect of NSAIDs (traditional or selective COX-2 inhibitors [coxibs]) on MI incidence separately for fatal and non-fatal events. Summary estimates of relative risk (RR) for non-fatal and fatal MIs were calculated with a random effects model.

Results

NSAID therapy carried a RR of 1.30 (95% CI, 1.20–1.41) for non-fatal MI with no effect on fatal MI (RR 1.02, 95% CI, 0.89–1.17) in six observational studies. Overall, the risk increase for non-fatal MI was 25% higher (95% CI, 11%–42%) than for fatal MI. The two studies that included only individuals with prior cardiovascular disease presented risk estimates for non-fatal MI on average 58% greater (95% CI, 26%–98%) than those for fatal MI. In nine randomised controlled trials, all investigating coxibs, the pooled RR estimate for non-fatal MI was 1.61 (95% CI, 1.04–2.50) and 0.86 (95% CI 0.51–1.47) for fatal MIs.

Conclusions

NSAID use increases the risk of non-fatal MI with no substantial effect on fatal events. Such differential effects, with potentially distinct underlying pathology may provide insights into NSAID-induced coronary pathology. We studied the association between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of myocardial infarction (MI), separating non-fatal from fatal events, summarizing the evidence from both observational studies and randomised controlled trials. An increased risk of non-fatal MI was clearly found in both types of studies while use of NSAID did not confer an increased risk of fatal MI. Our findings provide support for the concept that thrombi generated under NSAID treatment could be different from spontaneous thrombi.     

Osteoporosis: combination therapy for better or worse

Osteoporosis is a condition that is associated with an increased susceptibility for fractures. In the past few years, several drugs have become available that can reduce the incidence of fractures in patients with osteoporosis. Since these drugs work through different cellular mechanisms, combining agents of different classes may have an additive or multiplicative effect on fracture risk reduction. Combination treatments that have been evaluated in clinical trials include bisphosphonates with estrogen, raloxifene or PTH/ bisphosphonates and PTH/ estrogen. In general, these trials have shown increases in bone mineral density over that observed with each agent alone. However, whether anti-fracture efficacy is improved, or worsened remains to be established. This article reviews the combination treatments that have been evaluated in clinical trials, with a discussion of the potential benefits and risks that those treatments entail. Integrating safety and cost issues will eventually determine whether those combinations will become the standard of care.