Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Long-acting nifedipine was as effective as hydrochlorothiazide plus amiloride for reducing mortality and morbidity in hypertension

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ACP J Club. 2001 Jan-Feb;134:6. doi:10.7326/ACPJC-2001-134-1-006

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Source Citation

Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000 Jul 29;356:366-72. [PubMed ID: 10972368]


Abstract

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?

Design

Randomized (allocation concealed*), blinded (patients, physicians, and outcome assessors),* placebo-controlled trial with ≥ 3-year follow-up (Intervention as a Goal in Hypertension Treatment [INSIGHT] trial).

Setting

703 centers in 8 countries in western Europe and Israel.

Patients

7343 patients with hypertension were enrolled, 6575 were randomized, and 6321 (mean age 65 y, 54% women) were studied after exclusion of 9 centers because of protocol violations. Patients were required to have ≥ 1 additional CV risk factor (hypercholesterolemia, smoking, family history of early myocardial infarction [MI], left ventricular hypertrophy or strain, coronary artery disease, or peripheral vascular disease). Follow-up was 94%.

Intervention

3157 patients were analyzed 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/d, or enalapril, 5 mg/d; 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 nonfatal MI, stroke, and heart failure. Secondary outcomes were all-cause mortality, vascular death, and nonfatal vascular events.

Main results

Blood pressure (BP) decreased in both groups to approximately 138/82 mm Hg. Nonfatal heart failure was more common in the nifedipine group than in the coamilozide group (0.8% vs 0.3%, P = 0.028) as were fatal MI (0.5% vs 0.2%, P = 0.017) and all adverse events (49% vs 42%, P < 0.001). Withdrawals because of adverse effects were higher in the nifedipine group than in the co-amilozide group (23% vs 16%, P < 0.001). The groups did not differ for the primary outcomes, including the composite end point (6.3% in the nifedipine group vs 5.8% in the co-amilozide group, P = 0.35), all-cause (P = 0.95) or cause-specific mortality (P≥ 0.14), nonfatal MI (P = 0.52), sudden death (P = 0.43), stroke (P≥ 0.52), fatal heart failure (P = 0.63), or nonfatal CV events (P≥ 0.1).

Conclusions

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.

*See Glossary.

Source of funding: Bayer AG.

For correspondence: Professor M.J. Brown, Clinical Pharmacology Unit, Level 6, ACCI, Box 110, Addenbrooke's Hospital, Cambridge CB2 2QQ, England, UK. FAX 44-1223-762576.


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 were large enough to reliably detect moderate differences (10% to 15%) in such clinically important outcomes as MI (1).

• 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 levels.

• 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 therapy, or both.

• Occasional findings within trials, such as more fatal MI and nonfatal 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 nondihydropyridine and dihydropyridine calcium antagonists were being evaluated. Clinicians are rightfully wary of generalizing beneficial and harmful class effects across these agents.

• Calcium antagonists are being compared with different agents within different classes. Clinicians realize 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 therapies vary. For example, peripheral edema is reported by as many as 25% of persons 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 antihypertensive 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 first-line therapy for patients with hypertension.

Cynthia D. Mulrow, MD, MSc
Audie L. Murphy Memorial Veterans Administration Hospital
San Antonio, Texas, USA


References

1. MacMahon S, Neal B. Differences between blood-pressure-lowering drugs. Lancet. 2000;356:352-3.

2. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity in the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;354:1751-6.

3. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:597-603.

4. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998; 338:645-52.

5. Casiglia E, Spolaore P, Mazza A, et al. Effect of two different therapeutic approaches on total and cardiovascular mortality in a Cardiovascular Study in the Elderly (CASTEL). Jpn Heart J. 1994;35:589-600.