Response to Letter by Barrios and Escobar
We thank Drs Barrios and Escobar1 for their interest in our work and suggestion that information from randomized clinical trials may not always be reliable for clinical practice due to selection bias, stricter follow-up, a more favorable clinical profile and motivation.
We agree that there may be potential for selection bias when using controlled clinical trial data instead of data from observational cohorts, but this relates to sample size, number of sites, their location and the study’s specific protocol selection criteria (design characteristics of the trial). However, from over 800 sites in 14 countries, the INternational VErapamil SR-trandolapril STudy (INVEST) enrolled over 22 000 patients with hypertension and coronary artery disease and applied very few exclusions (eg, acute events, early post revascularizations and contraindications to study medications) that may have the potential to bias baseline demographics.2,3 Clearly the patients did not have a favorable clinical profile as their mean age was 66 years with a third older than 70. About half had a smoking history, one third a prior MI and 28% diabetes. They were likely more motivated than nonparticipants, but there are many highly motivated patients in clinical practice that are not in trials. So the INVEST population can be considered as all inclusive for stable coronary artery disease patients age 50 and older who are candidates for either β-blocker or heart-rate–slowing calcium antagonist treatment. Thus, we believe that the INVEST results would be useful for this population of patients in the “real world” of clinical practice (using the terms of Barrios and Escobar).
Additionally, Drs Barrios and Escobar mention stricter follow-up in clinical trials and we agree that this clearly could contribute to better treatment results in randomized trials compared with observational data. Indeed, in the INVEST, we found that as the proportion of visits with blood pressure (BP) in control (<140/90) increased the adverse outcome rates (for death, myocardial infarction or stroke) decreased progressively.4 For stroke (fatal and nonfatal), using BP in control for <25% of visits as a reference (hazard ratio [HR]=1.0), when BP was in control for ≥25 to <50% of visits the HR=0.89 (95% CI 0.67 to 1.19), for ≥50 to <75% the HR=0.70 (0.53 to 0.93) and for ≥75% the HR=0.50 (0.37 to 0.67), all P<0.001 for trend. This held true for both the diabetes and nondiabetes subpopulations. Linked closely with follow-up in clinical trials is provision of study medication to participants. For the majority of participants in INVEST, we used a mail order pharmacy mechanism to provide the study medications on a regular basis. While the study medications were provided at no cost to the participants, patients were required to request refills of their medications as necessary until their next study visit. The drug delivery mechanism very closely mimics the prevailing and preferred prescription method for most third party payers in the United States, and thus, again, very closely approximates the “real world” with regard to medication distribution.
Finally, our position that data from randomized clinical trials, when appropriately designed, are in agreement with observational data is supported by Drs Barrios and Escobar’s reference 2.5 After careful study, Concato et al5 concluded that results of well designed observational studies, in hypertension and stroke as well as hypertension and coronary artery disease, agree favorably with results from randomized trials. We would urge clinicians to emulate the trials in terms of BP treatment and control. We believe that clinicians would agree that attempting to reach BP control for most office visits seems well worth the effort to reduce stroke risk.
Barrios V, Escobar C. Importance of blood pressure control in hypertensive patients with coronary heart disease in clinical practice to reduce the risk of stroke. Stroke. 2009; 40: e469.
Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW, for the INVEST investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA. 2003; 290: 2805–2816.
Kolloch R, Legler UF, Champion A, Cooper-DeHoff RM, Handberg E, Zhou Q, Pepine CJ. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: Findings from the INternational VErapamil-SR/trandolapril Study (INVEST). Eur Heart J. 2008; 29: 1218–1220.
Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension. 2007; 50: 299–305.