Curriculum in CardiologyImplications of geographical variation on clinical outcomes of cardiovascular trials
Section snippets
Heart failure trials
The first study demonstrating the survival benefit of angiotensin-converting enzyme inhibitors in HF was conducted in Scandinavia4 with confirmation in North American studies.5, 6 Conversely, variation in the benefits of β-blockers based on world region remains an area of controversy.7, 8 An improved understanding of the etiologies and implications of regional differences in HF is necessary to inform clinical trial design and improve patient outcomes.
ST-elevation MI experience: from GUSTO to HERO
One of the first studies to investigate the impact of regional differences on outcomes in ACS was an analysis of the GUSTO trial.16 Patients from the United States (n = 23,105; 56%) had more comorbidities and prior revascularization, but shorter length of stay (LOS) compared with 14 other countries. Non-US patients were older and tended to have more anterior MIs with treatment later after the onset of symptoms. Overall, the greater use of invasive procedures and CV medications in the United
Atrial fibrillation trials
Three recent trials of novel anticoagulants in AF patients have presented subgroup data related to region of enrollment, but to date, no further analyses of the variation in baseline clinical characteristics and outcomes by region have been published.
The RELY trial investigated dabigtran versus warfarin in 18,113 patients with AF enrolled in 44 countries.32 The regions included in the trial were North America (36%), Western Europe (22%), Central Europe (16%), East Asia (9%), South America (6%),
Hypertension trials
An analysis of one large HTN trial reported regional differences. The CONVINCE trial investigated initial therapy with verapamil versus atenolol or diuretic.40 The study was stopped early (n = 16,602 from 15 countries) by the sponsor for “commercial reasons” as the study fell short of demonstrating equivalence between verapamil and atenolol or hydrochlorothiazide as previously reviewed.41 Regional differences were exhibited in the baseline patient characteristics, blood pressure levels, and
The FDA perspective
In general, the FDA accepts foreign data so long as there is reason to believe it applies to the US setting. In practice, the FDA have rarely insisted on some minimum US enrollment. Experience to date has not caused the FDA to be more insistent on US representation in CV trials. For instance, the FDA recommended against the approval of the intravenous medication tedisamil for AF not only because phase 3 data were exclusively from studies in Eastern Europe, but also due to concerns about the
Summary of potential explanations for regional variation in outcome
Table I summarizes explanations for geographical variations in outcome. Geographic variation in the baseline characteristics of patients contributes to a significant proportion of the regional differences in outcome. Geography reflects race, ethnicity, social circumstances, lifestyle, and cultural attitudes.47 Race is related to genetics, yet medication responses also occur independent of race.7 Geographic region is associated with varying disease etiology and severity, comorbidity profiles,
Potential methods for standardization
Table II summarizes potential methods for improved standardization of global trials to reflect the importance of geographical variations in outcome. Future trials should attempt to enroll large sample sizes from global populations and prespecify analysis based on region.48 Several contemporary CV trials have attempted to enroll > 10% from each trial region,33, 34 but further investigation is needed to determine the appropriate target enrollment percentages for specific trials. Such decisions
Limitations
The aforementioned examples of regional differences in clinical trials should be taken as exploratory. The potential for spurious statistically significant differences on post-hoc subgroup analyses should be highlighted. The potential pitfalls of subgroup analyses have been previously reviewed.2 One memorable example of statistical chance in subgroup analyses comes from the ISIS-2 trial.56 The authors presented a cautionary note when they showed that patients born under the Gemini or Libra
Conclusions
Cardiovascular clinical trials are increasingly conducted globally. We have outlined the recognized geographical differences in cardiovascular trials. Potential explanations for these differences include patient level characteristics, medical system differences, and treatment variation including hospital LOS. Methods to standardize the presentation of trial results while recognizing the importance of regional differences include enrolling adequate regional sample sizes, pre-specifying regional
Outside funding
No extramural funding was used to support this work.
Authorship
The authors are solely responsible for the drafting and editing of the paper and its final contents.
Disclosures
FZ has received honoraria from and served on advisory boards for Pfizer. BP is a consultant to Pfizer, Merck, Novartis, Takeda, Astra Zeneca, Bayer, Lilly, BMS, Cytopherx, Amorcyte, Relypsa, BG-Medicine, Aurasense, GE-Health Care; stocks options in Relypsa, BG-Medicine, and Aurasense; grants from Novartis, Forrest Laboratories, and Medtronic. The other authors report no relevant conflicts of interest related to this work.
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Global geographical variation in patient characteristics in percutaneous coronary intervention clinical trials: A systematic review and meta-analysis
2018, American Heart JournalCitation Excerpt :Based on these findings, the generalizability and applicability of various PCI trials may be associated with significant challenges because these clinical trials may not be directly comparable. Although the worldwide difference in prevalence of cardiovascular risk factors (notably HTN, HL, DM, and smoking) has been well described in the cardiology literature,23 little has been published on the variations of these risk factors between continents within CAD patients enrolled in PCI trials. Our findings have potential implications on the recruitment strategy and data analysis of future PCI trials.
Hector O. Ventura MD, served as guest editor for this article.