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QUESTION: In patients with hypertension who are at high risk for cardiovascular (CV) events, is long acting nifedipine, a calcium channel blocker, as effective as co-amilozide (hydrochlorothiazide and amiloride) for preventing CV and cerebrovascular mortality and morbidity?
Randomised (allocation concealed*), blinded (patients, physicians, and outcome assessors),* placebo controlled trial with ≥3 years follow up (Intervention as a Goal in Hypertension Treatment [INSIGHT] trial).
703 centres in 8 countries in western Europe and Israel.
7343 patients with hypertension were enrolled, 6575 were randomised, and 6321 (mean age 65 y, 54% women) were studied after exclusion of 9 centres because of protocol violations. Patients were required to have ≥1 additional CV risk factor (hypercholesterolaemia, smoking, family history of early myocardial infarction [MI], left ventricular hypertrophy or strain, coronary artery disease, or peripheral vascular disease). Follow up was 94%.
3157 patients were analysed in the long acting nifedipine group (30 mg/d), and 3164 were in the co-amilozide group (hydrochlorothiazide, 25 mg/d, and amiloride, 2.5 mg/d). If hypertension persisted, the regimen was intensified in steps that included doubling the dose of the study drug; adding atenolol, 25 mg/day, or enalapril, 5 mg/day; doubling the dose of the second drug; and adding another antihypertensive drug other than a calcium channel blocker or diuretic.
Main outcome measures
A composite end point of CV or cerebrovascular death and non-fatal MI, stroke, and heart failure. Secondary outcomes were all cause mortality, vascular death, and non-fatal vascular events.
Blood pressure (BP) decreased in both groups to approximately 138/82 mm Hg. Non-fatal heart failure was more common in the nifedipine group than in the co-amilozide group (0.8% v 0.3%, p=0.028) as were fatal MI (0.5% v 0.2%, p=0.017) and all adverse events (49% v 42%, p<0.001). Withdrawals because of adverse effects were higher in the nifedipine group than in the co-amilozide group (23% v 16%, p<0.001). The groups did not differ for the primary outcomes, including the composite end point (6.3% in the nifedipine group v 5.8% in the co-amilozide group, p=0.35), all cause (p=0.95) or cause specific mortality (p≥0.14), non-fatal MI (p=0.52), sudden death (p=0.43), stroke (p≥0.52), fatal heart failure (p=0.63), or non-fatal CV events (p≥0.1).
Nifedipine and co-amilozide were equally effective for preventing cardiovascular and cerebrovascular mortality and morbidity in high risk patients with hypertension. Fewer patients, however, tolerated nifedipine.
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.