Elsevier

American Heart Journal

Volume 164, Issue 3, September 2012, Pages 303-312
American Heart Journal

Curriculum in Cardiology
Implications of geographical variation on clinical outcomes of cardiovascular trials

https://doi.org/10.1016/j.ahj.2012.06.006Get rights and content

Cardiovascular clinical trials are increasingly conducted globally as a means to reduce costs, expedite timelines, provide broad applicability, and satisfy regulatory authorities. Potential problems with trial globalization include regional differences in patient characteristics, medical practice patterns, and health policies which may influence outcomes and limit generalizability. Moreover, concerns have been raised about ethical misconduct and unsatisfactory quality oversight in regions with less trial experience and infrastructure. This article reviews geographical differences in cardiovascular trials in heart failure, acute coronary syndromes, hypertension and atrial fibrillation. It also explores potential explanations for these differences and methods to standardize the presentation of trial results. This review is based on discussions between basic scientists and clinical trialists at the 8th Global Cardio Vascular Clinical Trialists Forum 2011 in Paris, France, from December 2 to 3.

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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