Underestimating an Opponent Often Leads to Defeat

The Chinese are not just stealing our intellectual property. They are building a scientific establishment equal to our own and I am going to show you a concrete example of that. In my last post, I wrote about the critical role our university systems, science education, immigration of scientific talent, massive funding for scientific research, and our federal science agencies played in making America great in the aftermath of WWII. That was the model the greatest generation used to make American the leader of the free world and the most powerful economic engine in history. Now all that has changed. In our country, scientific research funding has been slashed, our universities are under attack, and the best minds are looking elsewhere. While we are attacking our universities and slashing research funding the Chinese are gaining ground.

The New England Journal of Medicine is the most prestigious medical journal in the world. Any medical researcher would be thrilled to have their work published in the New England Journal. Just over a month ago, Chinese investigators had this piece published in the journal—Intensive Blood-Pressure Control in Patients with Type 2 Diabetes. This is a very important topic with a history.

In my last post, I wrote about the failure of the intensive sugar lowering arm of the ACCORD trial and how our team had 180 patients in the trial. The results of that trial were also published in the New England Journal. The ACCORD trial also had an arm that tested the benefit of more aggressively lowering blood pressure to a top number of 120 vs 140. That trial also failed to show benefit. High blood pressure is the most common additional condition in patients who have type 2 diabetes. It increases the risk of cardiovascular disease in patients with diabetes and is the easiest risk factor to treat in these patients. Because of the ACCORD trial failure, until this Chinese study the blood pressure targets in people who have diabetes have been unclear.

In the ACCORD BP hypertension trial, participants were randomly assigned to intensive therapy that targeted systolic blood pressures of less than 120 mm Hg or standard therapy that targeted systolic blood pressures of less than 140 mm Hg. The results of this study were also published in the New England Journal. This trial was a test of aggressive lowering the blood pressure risk factor, rather than how you lowered it. At the last visit, 61% of intensively treated patients were on a beta blocker like metoprolol and only 42% were on a calcium channel blocker like amlodipine. 23% were on an alpha blocker like terazosin, and 7% were on reserpine. No one received spironolactone or eplerenone. Amlodipine as a single agent was not supplied. Metoprolol, terazosin, reserpine, and hydralazine were all provided study drugs. It was another test of the old idea. It is all about getting the risk factor down. It is not how you get it down. They did not provide the drugs that most effectively protect cells and organs.

These patients all had type 2 diabetes. Only 63% of the intensively treated patients were on metformin which improves cardiovascular outcomes. Almost as many, 62% were on insulin which has never been shown to decrease cardiovascular outcomes and may actually worsen them. Another 39% were on a sulfonylurea which increases insulin levels. Only 57% of intensively treated patients were on a statin. The patients were not on best practice care. The ACCORD BP trial did not show any benefit for aggressive blood pressure management.

The Chinese did exactly what the ACCORD investigators did except they used a hypertension management protolol. They used a few best practice medications rather than any medicine approved to lower blood pressure. They had the same targets— a top number of 140 for the intensive management group and a top number of 120 for the usual care group, but in the intensively managed group they started with two or three drugs in modest doses depending on the level of blood pressure elevation. They used a diuretic like hydrochlorothiazide, and ACE inhibitor like lisinopril or an ARB like losartan and a calcium channel blocker like amlodipine. Beta blockers could be used in patients with a compelling reason to take them like angina or chest pain. They used medications that more effectively protect cells and organs.

There was a big difference in the Chinese treatment compared to the ACCORD treatment. In the intensive group, the Chinese patients were primarily on ACE inhibitors like lisinopril, ARBs like losartan, CCBs like amlodipine, and diuretics like hydrochlorothiazide with much lower reliance on other drug classes. Only 30% of intensively treated patients were on a beta blocker in China compared with 61% in this country. 2.3% were on an alpha blocker compared with 23%. There was much lower use of other drug classes. The number of patients on statins was comparable as were the numbers on metformin. The numbers on insulin and especially sulfonylureas were far less.

The results of the ACCORD blood pressure study and the Chinese blood pressure study were dramatically different.

Here are the results for the ACCORD trial.

“In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events.”

Here are the results of the Chinese trial on the same type of patient population with the same objective. During a median follow-up of 4.2 years, primary-outcome events (major cardiovascular events) occurred in 393 patients in the intensive-treatment group and 492 patients in the standard-treatment group.” That was a highly significant 21% reduction in major cardiovascular events.

Both studies taught us something. The American ACCORD study taught us that lowering the blood pressure “risk factor” by using any medication approved for that purpose fails to show benefit.

The Chinese study proved that it is not just lowering the “risk factor” that matters, it is how you lower it. The Chinese did the same thing that most American clinicians agree on today. They used a protocol including ACE inhibitors like lisinopril, ARBs like losartan, diuretics like hydrochrorothiazide and calcium channel blockers like amlodipine. Lisinopril is the third most commonly prescribed drug in the US. Amlodipine is fifth, losartan is eighth, and hydrochlorothiazide is twelfth. Most people agree on that in this country and the Chinese got that right, but neither group got the fourth drug in the protocol correct and with that addition their results would have been even better.

If these four classes of drugs don’t control the blood pressure— if three drugs that include a diuretic don’t control the blood pressure— the patient by definition has resistant hypertension. They best drug to address resistant hypertension as the fourth drug is eplerone or spironolactone. Adding that would have made the outcomes even better.

Now we know. Now we have the facts and the evidence. More aggressive control of the blood pressure to a target of 120 for top number or the systolic blood pressure using a protocol including those specific drugs does make a different in outcomes and you should insist on that for the patients that you are responsible for.

There is one other factor. While some drugs that lower the blood pressure don’t seem to improve outcomes, there is good evidence that others cause harm. Since we have other alternatives, that makes a difference. We should not use beta blockers for blood pressure control unless there is another indication for their use. “We systematically analyzed all available outcome studies and found no evidence that beta-blocker based therapy, despite lowering blood pressure, reduced the risk of heart attacks or strokes. Despite the inefficacy of beta-blockers, the incidence of adverse effects is substantial. In the MRC study, for every heart attack or stroke prevented, three patients withdrew from atenolol because of impotence, and another seven withdrew because of fatigue. Thus the risk/benefit ratio of beta-blockers is characterized by lack of efficacy and multiple adverse effects.” Older beta blockers cause weight gain and adverse metabolic effects. They are not best practice drugs for high blood pressure.

The point of all of this is simple. The three landmark trials in hypertension and the two landmark trials in hypertension with type 2 diabetes were all published in the New England Journal of Medicine. The latest of those trials was conducted entirely in mainland China. The Chinese are not merely stealing our intellectual property, they are aggressively developing scientific capabilities of their own and they are answering important questions. They are catching us and building their science and university system while our government is attacking ours. We claim the Chinese are getting ahead by stealing our intellectual property and some American leaders are dismissing them as peasants. Underestimating the Chinese may cause our defeat. They have come a long way. I have written extensively about the shortcomings of American medical science translation. I know we need change. The answer is not to cut funding and take a punitive approach. The answer is to provide adequate funding and make our universities and research better.