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QUESTION: In middle aged patients with hypertension, is diltiazem, a non-dihydropyridine calcium antagonist, as effective as diuretics, β blockers, or both at preventing cardiovascular (CV) events?
Design
Randomised (allocation concealed*), blinded (outcome assessors),* controlled trial with mean follow up of 4.5 years (Nordic Diltiazem [NORDIL] study).
Setting
1032 primary healthcare centres in Norway and Sweden.
Patients
10 881 patients (mean age 60 y, 51% women) who had hypertension (diastolic blood pressure [BP] ≥100 mm Hg on 2 occasions) and were aged 50 to 69 years (extended to 74 y during the study). Follow up was >99%.
Intervention
Patients were allocated to diltiazem (n=5410) or to diuretics or β blockers, or both (n=5471). If hypertension persisted, the regimen was intensified. Diltiazem was started at 180 to 360 mg/day, with stepped addition of an angiotensin converting enzyme (ACE) inhibitor, a diuretic or α blocker, and any other antihypertensive drug. In the other group, a thiazide diuretic or β blocker was started with stepped addition of the other drug, an ACE inhibitor or α blocker, and any other antihypertensive drug except a calcium antagonist.
Main outcome measures
BP and combined fatal and non-fatal stroke, fatal and non-fatal myocardial infarction (MI), and other CV death.
Main results
Mean BP decreased in both groups, to 155/89 in the diltiazem group and to 152/89 mm Hg in the diuretics and β blocker group. For patients who remained in the study for ≥24 months, decreases in systolic but not diastolic BP were smaller in the diltiazem group than in the diuretics and β blocker group (20/19 v 23/19 mm Hg, p<0.001). The groups did not differ for the combined primary end point (16.6 v 16.2 events/1000 patient years, p=0.97), all MI (7.4 v 6.3, p=0.17), CV death (5.2 v 4.5, p=0.41), all cause mortality (9.2 v 9.0, p=0.99), all cardiac events (20.2 v 19.2, p=0.57), diabetes mellitus (9.4 v 10.8, p=0.14), and congestive heart failure (2.5 v 2.1, p=0.42). Patients in the diltiazem group had fewer strokes than patients in the diuretics and β blocker group (6.4 v 7.9 events/1000 patient-years, p=0.04). The rate of adverse effects was similar among the groups.
Conclusion
Diltiazem was as effective as diuretics, β blockers, or both for preventing the combined end point of stroke, myocardial infarction, and other cardiovascular death.
Commentary
INSIGHT and NORDIL add to the acronymic litany of recent trials addressing pharmacotherapy of hypertension—this litany consists of multiple trials with multiple comparisons spawned by multiple drugs from multiple classes with multiple actions. With the addition of the INSIGHT trial and NORDIL study, we have 10 completed long term trials that compare calcium antagonists with other antihypertensive drugs.
Such trials that evaluate morbidity and mortality effects of calcium antagonists have variable findings that are difficult to interpret:
None was large enough to reliably detect moderate differences (10% to 15%) in such clinically important outcomes as MI1
BP control with monotherapy was not achieved in as many as one third to one half of trial participants, depending on baseline and target BP concentrations
Comparisons among agents were usually complicated by the addition of second and third drugs
In large trials, such as INSIGHT and the Swedish Trial in Old Patients (STOP-2),2 a third or more of the participants were withdrawn from their initially assigned regimens because of adverse effects, difficulty with adherence to long term treatment, or both
Occasional findings within trials, such as more fatal MI and non-fatal heart failure with calcium antagonists in the INSIGHT trial and fewer strokes with calcium antagonists in the NORDIL study, may result from chance because several comparisons were usually done
Intermediate and long acting non-dihydropyridine and dihydropyridine calcium antagonists were being evaluated. Clinicians are rightfully wary of generalising beneficial and harmful class effects across these agents
Calcium antagonists are being compared with different agents within different classes. Clinicians realise that simple conclusions about calcium antagonists compared with “all other” agents are unlikely
Some trials, such as NORDIL, do not achieve equivalence in BP lowering among calcium antagonists and other agents.
Given these complexities, we clinicians can embrace the following “truths.” We have no strong, consistent evidence that intermediate or long acting calcium antagonists are superior or inferior to other antihypertensive agents in reducing CV disease and mortality. We have suggestive worrisome evidence that some intermediate and long acting calcium antagonists may increase such cardiac harms as MI and heart failure more than do diuretics (INSIGHT trial) or ACE inhibitors.2–5 We know that adverse effects of antihypertensive treatments vary. For example, peripheral edema is reported by as many as 25% of people taking calcium antagonists (INSIGHT trial),2 and cough is reported by as many as 30% of those taking ACE inhibitors.2 We know calcium antagonists are often more expensive than other anti-hypertensive agents. While we await results of additional large, long term trials, many evidence-based clinicians will continue to choose agents other than calcium antagonists as firstline treatment for patients with hypertension.
Footnotes
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Source of funding: Pharmacia.
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For correspondence: Professor L Hansson, Department of Public Health and Social Sciences, University of Uppsala, PO Box 609, S-751 25 Uppsala, Sweden. Fax +46 18 611 79 73.