Hypertension treatment still an empirical dilemma
Step-down strategies help control costs
What's becoming clear from recently published research is that some older drug regimens that may be successfully controlling high blood pressure in many patients may not have any lessening effect on the heart attacks and strokes the condition can lead to. Consequently, clinicians are tailoring specific therapies to individual patients, while decreasing interaction risks and total costs by pursuing "step-down" strategies.
"[Patient tailoring] is becoming increasingly important," says Thomas Rihn, PharmD, senior director of clinical operations at Stadtlanders Pharmacy Services and associate professor of clinical pharmacy at Duquesne University, both in Pittsburgh. "With over 90% of patients having primary hypertension with no known cause, we cannot necessarily target pharmacologic therapies to a specific type of hypertension because we don't know the mechanism. So we are still empiric in how we approach treatment."
Nonetheless, Rihn is encouraged by the research. "I think it speaks to the normal course of research in general," he notes. "For the most part, these drugs have been around for quite some time, but as the research evolves we are gaining more knowledge." But Rihn does say that despite some recent discoveries in the genetic research, real breakthroughs in hypertension studies are not at hand. "My own impression is that we're not really close to finding that actual cause."
For clinical pharmacists like Barry Browne, PharmD, coordinator of drug information services at Scott & White Hospital in Temple, TX, matching patient intolerance to available hypertensives is a sound first step in finding a regimen that will work. Scott & White staff are developing an updated algorithm on hypertension treatment.
"We know that in some patients, calcium channel blockers can lead to peripheral edema, that beta blockers are not good for asthma patients, and that diuretics can lead to electrolyte imbalances in others. The trick is finding the right drug for the right person," he says.
Says Rihn, "There are current guidelines that continue to indicate certain beta blockers and diuretics as first-line drugs, but in practice what happens are the concurrent patient conditions, and you have practitioners weighing in and going in different directions."
This lack of a standard treatment regimen for all HT patients has kept pharmaceutical manufacturers pumping out new hypertensives at a steady rate. It was probably inevitable that one would prove troublesome, and the calcium channel blocker mibefradil (Posicor) has done so. Four days after it was taken off the market June 8, based on increasingly dangerous interactions with just over two dozen other drugs, manufacturer Roche Laboratories issued a supplemental warning against immediate drug switching.
That June 12 alert came after four known patients went into shock within 12 hours of starting new drug regimens. Three of the four survived after emergency treatment, while one patient died.
Roche is advising a seven-day "washing out" period before a patient is switched to most other calcium channel or beta blockers on the market. The company advises a two-week wait before specific switches to the dihydropyridine calcium channel blocker felodipine or the beta blocker timolol. The company is advising that no delay is needed for switches to angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists and diuretics. The four cases of shock all involve patients taking 50 to 100 mg of mibe fradil, who were all changed to other calcium channel blockers, namely nifedipine, felodipine and nisoldipine.
The recall and new warnings are rooted in the same problem. "The drug affected a subset of calcium channels and is metabolized in the liver, as are loads of other drugs," says Browne. "When Posicor began inhibiting the breakdown of other drugs, including some affecting serum concentrations, the toxicity effects began to increase." Another factor calling for a safe waiting period is the drug's relatively long half-life of 17 to 25 hours.
Posicor was narrowly approved by the Food and Drug Administration (by a 5-3 vote) in June 1997. The approval included strong label warnings against mixing the drug with terfenadine, astemizole, and cisapride. By August 1997, the Institute for Safe Medication Practices in Warminster, PA, issued a warning about interactions between mibefradil and 16 other drugs. By December, the FDA issued a warning against mixing the drug with the statin class of cholesterol-lowering drugs, just as Roche was increasing its warnings to include interactions with digoxin, diltiazem, and verapamil. Within the next six months, the FDA had compiled 400 cases of health problems associated with mibefradil, along with a growing list of 26 drugs that posed interaction problems centering around hypotension and irregular heartbeat.
Roche estimates that 200,000 U.S. patients were taking Posicor at the time of the recall. Pharmacists say if there's any lesson to be learned from its quick demise, it's that the overall science of hypertension treatment and the tailoring of patient regimens needs to advance, not the sheer availability of new drugs in existing classes.
JNC-VI is guideline of choice
Both Rihn and Browne advocate adherence to the new JNC-VI guidelines, which continue to recommend the safer and cheaper diuretics and beta blockers as front-line treatment in patients without complications. Updated for the first time since 1993 by the National Heart, Lung & Blood Institute and the National Institutes of Health, the guidelines also address the newer areas of step-down therapy and expanded treatment regimens tailored to each patient.
"JNC-VI added the category of compelling indications with different subsets of patients with special clinical conditions that drugs like the ACE inhibitors or calcium channel blockers could be better for," says Rihn. Overall, the guidelines offer 29 possible drug combinations based on a patient's condition, blood pressure levels, and risk factors.
JNC-VI also expanded basic treatment recommendations into three categories of blood pressure levels and three risk factor profiles that can be cross-matched toward appropriate therapy. The guidelines also note that various patient conditions, like end-stage renal failure, can be linked to hypertension, leading the authors to stress continual reassessment of diagnosis and treatment options.
Specifically, the guidelines recommend dietary potassium be increased in hypertensive patients, diabetics with proteinuria be given ACE inhibitors, and patients with heart failure be treated with ACE inhibitors and diuretics.
Beta blockers are recommended for post-MI patients; ACE inhibitors for patients with systolic and left ventricular dysfunction. Alpha blockers are recommended for elderly male patients with benign prostatic hypertrophy, and a cardioselective beta blocker is recommended for surgery patients carrying cardiovascular risk factors.
The complete JNC-VI guidelines can be obtained by contacting the National Heart, Lung & Blood Institute at (301) 496-4236.
For more information, contact: Roche Laboratories, 340 Kingsland St., Nutley, NJ 07110. Telephone: (800) 526-6367. The Institute for Safe Medication Practices, 300 West Street Road, Warminster, PA 18974. Telephone: (215) 956-9181. Thomas Rihn, PharmD, Senior Director, Clinical Operations, Stadtlanders Pharmacy Services, Pittsburgh. Telephone: (412) 825-8592. Barry Browne, PharmD, Coordinator, Drug Information Services, Scott & White Hospital, 2401 S. 31st St., Temple, TX 76508.
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