Evidence of potential bias in a comparison of β blockers and calcium channel blockers in patients with chronic obstructive pulmonary disease and acute coronary syndrome: results of a multinational study

Abstract

ObjectivesA number of observational studies have reported that, in patients with chronic obstructive pulmonary disease (COPD), β blockers (BBs) decrease risk of mortality and COPD exacerbations. To address important methodological concerns of these studies, we compared the effectiveness and safety of cardioselective BBs versus non-dihydropyridine calcium channel blockers (non-DHP CCBs) in patients with COPD and acute coronary syndromes (ACS) using a propensity score (PS)-matched, active comparator, new user design. We also assessed for potential unmeasured confounding by examining a short-term COPD hospitalisation outcome.Setting and participantsWe identified 22 985 patients with COPD and ACS starting cardioselective BBs or non-DHP CCBs across 5 claims databases from the USA, Italy and Taiwan.Primary and secondary outcome measuresStratified Cox regression models were used to estimate HRs for mortality, cardiovascular (CV) hospitalisations and COPD hospitalisations in each database after variable-ratio PS matching. Results were combined with random-effects meta-analyses.ResultsCardioselective BBs were not associated with reduced risk of mortality (HR, 0.90; 95% CI 0.78 to 1.02) or CV hospitalisations (HR, 1.06; 95% CI 0.91 to 1.23), although statistical heterogeneity was observed across databases. In contrast, a consistent, inverse association for COPD hospitalisations was identified across databases (HR, 0.54; 95% CI 0.47 to 0.61), which persisted even within the first 30 days of follow-up (HR, 0.55; 95% CI 0.37 to 0.82). Results were similar across a variety of sensitivity analyses, including PS trimming, high dimensional-PS matching and restricting to high-risk patients.ConclusionsThis multinational study found a large inverse association between cardioselective BBs and short-term COPD hospitalisations. The persistence of this bias despite state-of-the-art pharmacoepidemiologic methods calls into question the ability of claims data to address confounding in studies of BBs in patients with COPD.

Bias in pharmacoepidemiologic studies using secondary health care databases: a scoping review

“…frailty). If confounding cannot be completely controlled for, the residual confounding effect of some factors remains in the final effect that is observed[1–3, 6, 14, 15, 18, 58, 62, 80–83, 86, 89, 91–93, 96, 101, 103, 108, 110, 113, 116, 119, 125, 127, 130, 132, 134, 136, 139]28.2 Healthy user/adherer effectAccess to health care resources is associated with a higher level of education and health-seeking behavior. Furthermore, patients who comply with the treatment during prolonged periods of time tend to be healthier[2, 18, 91, 96, 125, 127]5.1Selection biasThe study sample population is not representative of the target population to which the results will be extrapolated[2, 16, 18, 22, 40, 41, 54, 57, 58, 63, 81, 83, 84, 87, 88, 90, 91, 93–95, 99, 101–103, 105, 107–109, 111–113, 115–119, 121, 122, 124, 125, 135–137, 140–151]47.0 Protopathic biasThe treatment is associated with subclinical disease stages (an early manifestation of the still undiagnosed condition under study gives rise to prescription o...…”

“…flawed measurement, non-compliance with treatment, inappropriate use of time windows)[2, 3, 16, 40, 41, 54, 55, 58, 87, 91, 93, 94, 96, 101, 110, 119, 121, 130, 138, 140, 146, 147, 152, 154, 156, 158, 159, 164]23.9 Misclassification of outcomeError in the diagnosis (e.g. clinical ambiguity, non-uniform coding)[2, 3, 6, 7, 16, 40, 41, 54, 58, 87, 91, 93, 94, 96, 101, 110, 112, 114, 121, 125, 135–137, 141, 143, 149, 153, 155, 157, 160–163]28.2Time-related biasFollow-up time and exposure status are inadequately taken into account in the study-design or analysis stages[2, 7, 40, 41, 57, 68–75, 77, 83, 86, 87, 90, 99, 101, 105–107, 111, 114, 118, 128, 129, 133, 142, 165–170…”

β-blockers after acute myocardial infarction in patients with chronic obstructive pulmonary disease: A nationwide population-based observational study

“…Dong et al [26] pooled data from several claims databases and demonstrated a protective effect of cardioselective β-blockers over NDCCBs in preventing COPD hospitalizations within as early as 30 days. However, the authors attributed this effect to a potential bias, arguing that the cardioselective β-blockers could not have possibly exerted its protective effects within only 30 days.…”

Therapeutic effects of nebulized verapamil on chronic obstructive pulmonary disease: A randomized and double‐blind clinical trial

“…Moreover, controversy continues on the benefits of employing non‐selective vasodilators in COPD regarding the increased ventilation/perfusion (V/Q) mismatch, short effectiveness and their cardiac side effects . In fact research in this field is very dynamic and various CCBs with different dosage are under consideration . In the case of using verapamil as a bronchodilator, COPD patients could benefit from the therapeutic effects of CCBs such as bronchodilation and pulmonary hypertension reduction.…”

“…15 In fact research in this field is very dynamic and various CCBs with different dosage are under consideration. 16 In the case of using verapamil as a bronchodilator, COPD patients could benefit from the therapeutic effects of CCBs such as bronchodilation and pulmonary hypertension reduction. This study investigates the therapeutic effects of Nebulized Verapamil on Chronic Obstructive Pulmonary Disease.…”