Medication Treatment of Hypertension – Which Drugs are Best?

Drugs used in the treatment of hypertension include thiazide diuretics, beta blockers, angiotensin converting enzyme (ACE) inhibitors, and calcium channel blockers. The newer ACE inhibitors and calcium channel blockers were promoted as being better for the treatment of hypertension than the older thiazide diuretics and beta blockers, however this was mostly marketing hype since the newer drugs were on patent and made more money for the drug companies. However the studies showed that, at least compared to thiazide diuretics, the newer drugs weren’t as good, even they cost much more.

Thiazide diuretic drugs work for hypertension by increasing urine output and decreasing the volume of fluid in your circulation, which they achieve by increasing sodium excretion from the kidney, which drags water along with it. Examples include hydrochlorothiazide (Esidrix, Hydrodiuril, Microzide) and chlorthalidone (Hygroton). Thiazides promote calcium retention and prevent bone loss and fractures. However, they can negatively interact with an extensive list of medications, which are listed in the Physicians Desk Reference.

Their main problem is that they cause is frequent urination, which is inconvenient to say the least. They can also be associated with a loss of potassium Low serum potassium, or hypokalemia, is a potentially fatal condition, that can be associated with symptoms of muscle weakness, confusion, dizziness that can lead to falls, and heart arrhythmias. For people with a healthy diet, this is not a problem. You can also possible to take potassium supplements by mouth every day, to avoid the problem of potassium depletion with diuretics. A sub-category of these drugs, the so-called thiazide-like diuretic indapamide (Lozol) can cause life-threatening drops of sodium in the blood. In 1992 the Australian authorities reported 164 cases of this potentially life threatening condition, which is associated with confusion, lethargy, nausea, vomiting, dizziness, loss of appetite, fatigue, fainting, sleepiness, and possible convulsions. Since it doesn’t work better than hydrochlorothiazide, and is potentially dangerous, it should not be used.

ACE inhibitors are one of the newest types of hypertension drugs. They act on the renin-angiotensin system that regulates blood pressure and kidney function. Normally, the molecule angiotensin I is converted to angiotensin II by the angiotensin-converting enzyme. Angiotensin II is a potent vasoconstrictor that makes your blood vessels close down. By blocking the angiotensin-converting enzyme, you make the blood vessels relax, decreasing blood pressure. Examples of this type of drug include lisinopril (Prinivil), enalapril (Vasotec), ramipril (Altace), benazepril (Lotensin), fosinopril (Monopril), and captopril (Capoten). Side effects of ACE inhibitors include headache, flushing, diarrhea, rash, and more rarely dizziness, heart failure or stroke. One of the most annoying side effects is a dry persistent cough. Angiotensin receptor blockers (ARBs), like valsartan (Diovan), irbesartan (Avapro), olmesartan (Benicar), candesartan (Atacand), and losartan (Cozaar; Hyzaar when combined with hydrochlorothiazide) act on the angiotensin receptor to block its effects, thereby reducing blood pressure. Side effects include dizziness, diarrhea, rash, and more rarely anxiety, muscle pains, upper respiratory track infection, low blood pressure or elevations in potassium.

Calcium channel blockers act on the lining of the blood vessels. When these channels let calcium in, the blood vessels constrict. By blocking the calcium channels, these drugs cause the vessels to relax, as a result blood pressure goes down. Examples of this type of drug include amlodipine (Norvasc), verapamil (Calan), nifedipine (Procardia, Adalat), and diltiazem (Tiazac). Side effects include constipation, dizziness, headache, nausea, and more rarely low blood pressure, heart failure or arrhythmias.

Calcium channel blockers have not been found to prevent heart attacks better than diuretics (ALLHAT 2002; Black et al 2003; Brown et al 2000; Hansson et al 2000). In fact, one study showed that calcium channel blockers (nifedipine) did not prevent heart attacks or chest pain (angina) any better than a placebo, or sugar pill (Poole-Wilson et al 2004). A meta analysis of all studies combined showed that treatment with calcium channel blockers did not improve mortality more than a placebo, although ACE inhibitors did (BPLTTC. 2000). Another meta analysis found that treatment with calcium channel blockers when compared to other medication treatments for high blood pressure was associated with a relative 26% increase in heart attacks, 25% increase in heart failure, and 10% increase in major cardiovascular events (Pahor et al 2000). Furthermore, for women calcium channel blockers increased the risk of heart attack or stroke by 18% (Poole-Wilson et al 2004). Calcium channel blockers have been found to increase the risk of heart failure relative to other antihypertension drugs in several studies,(Black et al 2003; BPLTTC. 2000; Pahor et al 2000; Pepine et al 2003) overall by about 20% (BPLTTC 2003). In spite of this, one of the calcium channel blockers, amlodipine, continues to be a blockbuster drug, with 2 billion dollars a year in sales reported in 2003, a year after the troubling reports of heart failure with calcium channel blockers was published.

In the NIH-sponsored Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). In ALLHAT, the largest study of antihypertensive medications ever performed, different types of antihypertensive treatments were compared in 33,357 patients with high blood pressure and one other risk factor for heart disease were randomly assigned to the “old” drug chlorthalidone (diuretic), or the “new” drugs amlodipine (calcium channel blocker), or lisinopril (ACE inhibitor). Rates of fatal and nonfatal heart attacks were essentially the same between the three treatments (ALLHAT 2002). There was a 38% increase in heart failure with amlodipine compared to chlorthalidone. For lisinopril there were increased rates of total cardiovascular disease outcomes (10%), stroke (15%) and heart failure (19%) compared to chlorthalidone.

Since the time of ALLHAT other studies have not shown that ACE inhibitors and calcium channel blockers work better than diuretics, even though they cost more. And like ALLHAT, some of these studies show cause for concern.

As I mentioned above, many of the studies involved a comparison of “old” and “new” drugs, showing no difference in heart attacks and strokes for the two types of drugs. For the old drugs the studies often lumped together atenolol and a diuretic. However as I will explain later in more detail atenolol is probably not a very good drug, so these studies may have hid the fact that diuretics are better! In any case they show that there is no reason to spend more money on the new drugs. Follow along now while I spell out some of those studies.

For instance, in the NORdic DILtiazem (NORDIL) study, (Hansson et al 2000) which compared diltiazem (calcium channel blocker) to diuretics and/or beta blockers in 10,881 patients from Norway and Sweden, there were no differences in rates of fatal or non-fatal heart. Other studies which showed essentially identical rates of heart attack or stroke included The Controlled ONset Verapamil INvestigation of Cardiovascular End points (CONVINCE) Trial, a study of 16,602 patients who received verapamil (calcium channel blocker), or atenolol (beta blocker)/hydrochlorothiazide (diuretic) (Black et al 2003). The INternational VErapamil trandolapril STudy (INVEST), which compared the calcium channel blocker verapamil to the beta blocker atenolol in 22,576 patients (Pepine et al 2003). The Swedish Trial in Old Patients with Hypertension 2 (STOP-2) (Hansson et al 1999a) study, which randomised 6614 patients age 70-84 to either “new” drugs like calcium channel blockers or ACE inhibitors, or “old” drugs diuretics and beta blockers, and the CAptopril Prevention Project (CAPPP) as study of captopril (ACE inhibitor) versus diuretics and/or beta blocker in 10,985 patients (Hansson et al 1999b).

Not only was it difficult to show that the new drugs were better than the old (the marketing goal that drove the design of the studies), it wasn’t easy to show that taking the drugs was better than doing nothing. For instance, in the ACTION Study (A Coronary disease Trial Investigating Outcome with Nifedipine), 7665 patients with stable angina received the calcium channel blocker nifedipine or placebo in a randomized trial (Poole-Wilson et al 2004). There was no difference in a combined measure of fatal and non-fatal heart attack or stroke, revascularization, or heart failure. Death from heart disease was equal in the groups, and there was a 16% increase in non-cardiac deaths with nifedipine that was not statistically significant. Women on nifedipine had an 18% increase in this measure of cardiac events, although the difference was not statistically significant. In the Heart Outcomes Prevention Evaluation (HOPE) Study, 9297 patients at high risk for heart disease were randomized to the ACE inhibitor ramipril or placebo in addition to their usual treatment (HOPE 2000). A fatal or non-fatal heart attack or stroke was seen in 14.0% of the ramipril patients compared to 17.8% on placebo, a difference that was statistically significant. In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial, a study of 8290 patients with heart disease, the addition of the ACE inhibitor Trandolapril had no effect on reducing heart attacks and coronary revascularization procedures compared to a placebo (PEACE 2004). These results led to an editorial called “ACE inhibitors in Patients with Stable Heart Disease-may they rest in Peace?”

The Valsartan Antihypertensive Long term Use Evaluation (VALUE) study compared the ARB valsartan to the calcium channel blocker amlodipine in 15,245 patients over age 50 with high blood pressure and a high risk of heart disease (Julius et al 2004). The study found no difference between the two drugs in fatal and non-fatal heart attacks and other cardiac events. More non-fatal heart attacks were seen with valsartan, but there was also less development of diabetes. This study led to an editorial called “Is there Value in Value?”

When new drugs were compared to diuretics alone, their performance was worse. For instance, the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) compared the calcium channel blocker isradipine to the diuretic chlorthalidone in 883 patients with high blood pressure. Twenty five patients on isradipine had a major cardiovascular event (heart attack, stroke, heart failure, death or angina) compared to 14 on diuretic, a difference which was statistically significant (Borhani et al 1996). In the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study (Brown et al 2000) 6321 patients aged 55-80 with hypertension and one risk factor for heart disease were randomly assigned to nifedipine or co-amilozide (hydrochlorothiazide+amiloride, both diuretics). In the nifedipine group, 200 had cardiovascular death, heart attack, heart failure or stroke (combined) versus 182 in the diuretic group, which was not statistically significant. The nifedipine group did have significantly more fatal heart attacks (16 versus 5) and non-fatal heart failure (24 versus 11).

Dr. Bruce Psaty and colleagues from the University of Washington in Seattle looked at all of the data from trials that had been published up to 2003. Overall they found that diuretics were superior to all other treatments (Psaty et al 2003). Compared to placebo diuretics reduced the risk of heart disease by 21%, heart failure by 49%, stroke by 29% and total mortality by 10% (all significant). Diuretics compared to calcium channel blockers had 6% fewer cardiovascular disease events and 26% less heart failure; compared to ACE inhibitors there was 12% less heart failure, 6% less cardiovascular disease events and 14% less stroke. Diuretics compared to beta blockers had 11% less cardiovascular disease events. All treatments were similar in their ability to lower blood pressure. The authors concluded that diuretics (but not beta blockers, as was the recommendation at the time) should be the first line of treatment for high blood pressure.

Most of the studies of antihypertensive medications have been done in men. In the only study focused on women, 30,219 women with hypertension without heart disease were assessed for the relationship between anti-hypertensive therapy and outcome. Use of calcium channel blockers compared to diuretic was associated with a 55% increased risk of cardiovascular death, diuretic plus calcium channel blocker was associated with an 85% increased risk of cardiovascular death compared to diuretic plus beta-blocker. The risk increased to 2.16 when women with diabetes were excluded (Bhatt et al 2006; Wassertheil-Smoller et al 2004).

The alpha-blockers block the alpha noradrenergic receptor in the heart and blood vessels, and include doxazosin (Cardura), prazosin (Minipress) and terazosin (Hytrin). A related drug called Labetalol (Normodyne) blocks both alpha and beta-receptors. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Study showed that the alpha blocker Cardura doubled the risk of heart failure and increased the risk of stroke and all cardiovascular disease when compared to diuretic. This led to the study being stopped early; the authors of ALLHAT concluded that alpha-blockers should not be used in the treatment of hypertension (Davis 2000). Based on this I believe that there is no role for alpha-blockers in the treatment of patients with hypertension.

What is the bottom line for the treatment of hypertension? First things first. Cut sodium from your diet. That means making your own dinner whenever possible, since processed, canned and frozen foods are full of sodium, as food meals. Exercise by moderate walking for 30 minutes three times a week. Try stress reduction or meditation. Stop smoking. Do not drink alcohol in excessive amounts.

If these changes fail to lower your blood pressure, you may need medication. Work with your doctor to find out what works best for you. You may need to be started on the standard and least expensive treatment, diuretics. They work better than the newer drugs, based on the research I outlined earlier, and they have fewer side effects overall than the newer medications. This is especially true if you are African-American. You should definitely not take an ACE inhibitor or calcium channel blocker if you are not taking a diuretic.

Alpha-blockers should not be taken under any circumstances. These drugs seem to cause more heart problems than conventional diuretic treatments. Potassium sparing diuretics are dangerous and should be avoided.

If your blood pressure is not controlled with a diuretic, you may need to add another medication. This means going to a beta blocker, ACE inhibitor or calcium channel blocker. I do not recommend atenolol; you can use another beta blocker like metoprolol. Women should not take a calcium channel blocker. ACE inhibitors or ARB drugs can help whites with left ventricular (heart pump) failure.

ALLHAT (2002): Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Journal of the American Medical Association 288:2981-2997.

Bhatt D, Fox KAa, Hacke W, et al (2006): Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. New England Journal of Medicine 354:1706-1717.
Black HR, Elliott WJ, Grandits G, et al (2003): Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial. Journal of the American Medical Association 289:2073-2082.

Borhani N, Mercuir M, Borhani PA, et al (1996): Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS): A randomized controlled trial. Journal of the American Medical Association 276:785-791.

BPLTTC (2003): Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 362:1527-1535.

BPLTTC. (2000): Blood Pressure Lowering Treatment Trialists Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 355:1955-1964.

Brown MJ, Palmer CR, Castaigne A, et al (2000): Morbidity and mortality in patients randomised to double-blind treatment with long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 356:366-372.

Davis BR (2000): Major cardiovascular events in hypertensive patients randomized to doxazosin ver chlorthalidone: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Journal of the American Medical Association 283:1967-1975.

Hansson L, Hedner T, Lund-Johansen P, et al (2000): Randomised trial of effects of calcium antagonists compared with diuretics and beta blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 356:359-365.

Hansson L, Lindholm LH, Ekborn T, et al (1999a): Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 354:1751-1756.

Hansson L, Lindholm LH, Niskanen L, et al (1999b): Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captropril Prevention Project (CAPPP) randomised trial. Lancet 353:611-616.
HOPE (2000): Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. New England Journal of Medicine 342:145-153.

Julius S, Kjeldsen SE, Weber B, et al (2004): Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 363:2022-2031.

Pahor M, Psaty BM, Alderman MH, et al (2000): Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet 356:1949-1954.

PEACE (2004): The PEACE Trial Investigators. Angiotensin-Converting Enzyme inhibition in stable coronary artery disease. New England Journal of Medicine 351:2058-2068.
Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al (2003): A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. Journal of the American Medical Association 21:2805-2816.

Poole-Wilson PA, Lubsen J, Kirwan B-A, et al (2004): Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION): randomised controlled trial. Lancet 364:849-857.

Psaty BM, Lumley T, Furberg CD, et al (2003): Health outcomes associated with various antihypertensive therapies used as first-line agents: A network meta-analysis. Journal of the American Medical Association 289:2534-2544.

Wassertheil-Smoller S, Psaty B, Greenland P, et al (2004): Association between cardiovascular outcomes and antihypertension drug treatment in older women. Journal of the American Medical Association 292:2849-2859.